Porphyrin-hydroporphyrin compounds, compositions containing same, and methods of use thereof

Abstract

Described herein is a compound comprising a first porphyrin and a first hydroporphyrin, wherein the first porphyrin is attached to the first hydroporphyrin.The compound can be a light-emitting compound (e.g., a fluorescent compound).Also provided are particles and compositions comprising the compounds described herein.Further provided are the particles and methods of making and using them.

Description

[Technical field]

[0001] Statement of U.S. Government Support This invention was made with government support under Grant No. AI112302 awarded by the National Institutes of Health. The United States Government has certain rights in this invention.

[0002] The present invention relates to compounds, such as porphyrin-hydroporphyrin compounds, and compositions comprising same. The present invention also relates to the compounds for use in biomedical applications and methods of using the compounds in biomedical applications. [Background technology]

[0003] Molecules (chromophores) that absorb or emit ultraviolet, visible or near-infrared (NIR) light are used in a variety of biomedical and related applications, such as flow cytometry, molecular optical imaging, and photodynamic therapy. As applications continue to expand and become more sophisticated, there is a greater demand for specific photophysical properties. Relevant photophysical properties include the absorption wavelength, the emission (fluorescence or phosphorescence) wavelength, the separation between the absorption and fluorescence wavelengths, the fluorescence lifetime, the fluorescence quantum yield, the triplet lifetime, and the triplet yield. Another relevant electronic property is the redox property of the molecule, which controls charge transfer reactions that are undesirable for typical applications. For most chromophores, it is often very difficult to obtain a suitable large separation between the longest wavelength absorption feature and the shortest wavelength fluorescence feature (the so-called "Stokes shift"). However, for many biomedical applications, independent control of two or more of these photophysical properties is desirable, and in some cases essential, to meet the fundamental or technical requirements of the application. Summary of the Invention [Problem to be solved by the invention]

[0004] For example, in biomedical diagnostics, there is a need for fluorescent reagents that can be excited at a common wavelength and detect fluorescence emission at multiple different wavelengths. Generally, this is known as a "multiplex" assay and is represented by flow cytometry. Hydroporphyrins, such as chlorins and bacteriochlorins, may exhibit different narrow emission profiles. However, a 405 nm laser is often used in flow cytometry, and hydroporphyrins may not have optimal 405 nm fluorescence excitation, resulting in weak absorption and low brightness, limiting their usefulness, especially for multiplex assays.

[0005] Tunability and independent control of key photophysical properties of molecules for biomedical and other applications can be facilitated by the use of compounds of the invention, e.g., dyads that include two different chromophores (e.g., a donor and an acceptor) that are linked, optionally via a linking group. Compounds of the invention can allow relatively rapid and efficient energy transfer from one chromophore (e.g., a donor chromophore) to another chromophore (e.g., an acceptor chromophore). The donor chromophore may be selected for its absorption attributes and the acceptor chromophore may be selected for its emission attributes. By allowing efficient energy transfer from the donor chromophore to the acceptor chromophore, the absorption and emission characteristics of the chromophores of compounds of the invention can provide the ability to design and / or tune compounds to have desired spectral characteristics.

[0006] The above fluorescent compound is provided according to an embodiment of the present invention, the compound comprising a first porphyrin and a first hydroporphyrin, wherein the first porphyrin is attached to the first hydroporphyrin. In some embodiments, the compound of the present invention is a luminescent compound (e.g., a fluorescent compound) comprising a first porphyrin and a first hydroporphyrin, wherein the first porphyrin is attached to the first hydroporphyrin. In some embodiments, the luminescent compound is a fluorescent compound. In some embodiments, the first porphyrin is attached to the first hydroporphyrin via a linking group. In some embodiments, the first hydroporphyrin is a chlorin. In some embodiments, the first hydroporphyrin is a bacteriochlorin, and in some embodiments, it can be an isobacteriochlorin or an azabacteriochlorin. It is noted that an aspect of the present invention described with respect to one embodiment can be incorporated within a different embodiment, even if not specifically described therewith. That is, all embodiments and / or features of any embodiment may be combined in any manner and / or combination thereof. The applicant reserves the right to modify the originally filed claims and / or to file new claims accordingly, including the right to amend the originally claimed claims to rely on and / or incorporate features of other claims or claims not originally so claimed. These and other objects and / or aspects of the present invention are described in detail in the specification set forth below. Further features, advantages and details of the present invention will be apparent to those skilled in the art from a reading of the figures and the detailed description of the preferred embodiments which follow, however, such description is merely illustrative of the present invention. [Brief description of the drawings]

[0007] [Figure 1] FIG. 1 is a schematic diagram of an exemplary compound of the invention comprising a donor and an acceptor joined by a linker, according to some embodiments. [Diagram 2] FIG. 2 depicts exemplary intermediates that may be used in forming compounds of the invention, according to some embodiments. [Diagram 3] FIG. 3 depicts exemplary intermediates that may be used in forming compounds of the invention, according to some embodiments. [Figure 4] FIG. 4 depicts exemplary intermediates that may be used in forming compounds of the invention, according to some embodiments. [Diagram 5] FIG. 5 shows the fluorescence spectra of exemplary compounds of the invention. [Figure 6] FIG. 6 shows the fluorescence spectra of exemplary compounds of the invention. [Figure 7] FIG. 7 shows the fluorescence spectra of exemplary compounds of the invention. [Figure 8] FIG. 8 shows the fluorescence spectra of exemplary compounds of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present invention will now be described in more detail hereinafter. This invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

[0009] The terms used in the description of the present invention are for the purpose of describing particular embodiments only and are not intended to be limiting of the present invention. As used in the detailed description of the present invention and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms unless the context clearly indicates otherwise.

[0010] Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. It will be further understood that words, such as those defined in commonly used dictionaries, should be interpreted to have a meaning consistent with the meaning in the context of this application and related art, and should not be interpreted in an idealized or overly formal sense unless expressly defined as such in the present specification. The terms used in the detailed description of the present invention herein are intended only to describe specific embodiments, and are not intended to limit the present invention. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of a conflict in terms, the present specification will control.

[0011] Also, as used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted as alternatives ("or").

[0012] Unless the context dictates otherwise, it is expressly intended that the various features of the invention described herein can be used in any combination. Moreover, the invention also contemplates that in some embodiments of the invention, any feature or combination of features described herein can be excluded or omitted. By way of example, if the specification states that a complex comprises component A, component B, and component C, it is expressly intended that any of A, B, or C, or combinations thereof, can be omitted and removed.

[0013] As used herein, the transitional phrase "consisting essentially of" (and grammatical variations thereof) should be interpreted to include the materials or steps recited and "materials or steps that do not materially affect one or more of the basic and novel characteristics" of the claimed invention. In Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976) (emphasis in original); see also MPEP Section 2111.03. Thus, as used herein, the word "consisting essentially of" should not be construed as equivalent to "comprising."

[0014] It will be understood that although the terms "first" and "second" etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are used only to distinguish one element from another. Thus, a "first" element could be termed a "second" element without departing from the teachings of the present embodiments.

[0015] As used herein, the term "about" when referring to a measurable value, such as an amount or concentration, is meant to include not only the stated value, but also ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% variation of the stated value. For example, "about X", where X is a measurable value, is meant to include X and ±10%, ±5%, ±1%, ±0.5%, or ±0.1% variation of X. Ranges of measurable values ​​provided herein may include any other ranges and / or individual values ​​within the range.

[0016] As used herein, "Halo" refers to any suitable halogen atom, including -F, -Cl, -Br, and -I.

[0017] As used herein, "mercapto" refers to a --SH group.

[0018] As used herein, "azide" refers to the group --N3.

[0019] As used herein, "cyano" refers to the group --CN.

[0020] As used herein, "hydroxyl" refers to an --OH group.

[0021] As used herein, "nitro" refers to the group --NO.sub.2.

[0022] As used herein alone or as part of another group, "alkyl" refers to a straight or branched chain hydrocarbon group containing 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. As used herein, "lower alkyl" is a subset of alkyl and, in some embodiments, refers to a straight or branched chain hydrocarbon group containing 1 to 4 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like. The terms "alkyl" or "lower alkyl", unless otherwise specified, are intended to include both substituted and unsubstituted alkyl or lower alkyl, and these groups include any of the following radicals: halogen atoms, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy (thereby producing polyalkoxy, e.g., polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O) m , haloalkyl-S(O) m , alkenyl-S(O) m , alkynyl-S(O) m , cycloalkyl-S(O) m, cycloalkylalkyl-S(O) m , aryl-S(O) m , arylalkyl-S(O) m , heterocyclo-S(O) m , heterocycloalkyl-S(O) m , amino, carboxy, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro, or cyano, where m=0, 1, 2, or 3.

[0023] As used herein alone or as part of another group, "alkenyl" refers to a straight or branched chain hydrocarbon containing 1 to 10 carbon atoms (or 1 to 4 carbon atoms in lower alkenyl) which may contain 1 to 4 double bonds in the normal chain. Representative examples of alkenyl include, but are not limited to, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2,4-heptadiene, and the like. The term "alkenyl" or "lower alkenyl" is intended to include both substituted and unsubstituted alkenyl or lower alkenyl, unless otherwise specified, and these groups may be substituted with groups described in connection with alkyl and lower alkyl above.

[0024] As used herein alone or as part of another group, "alkynyl" refers to a straight or branched chain hydrocarbon containing 1 to 10 carbon atoms (or 1 to 4 carbon atoms in lower alkynyl) with one triple bond in the normal chain. Representative examples of alkynyl include, but are not limited to, 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, and the like. The term "alkynyl" or "lower alkynyl" is intended to include both substituted and unsubstituted alkynyl or lower alkynyl, unless otherwise specified, and these groups may be substituted with the same groups described in connection with alkyl and lower alkyl above.

[0025] As used herein alone or as part of another group, "alkoxy" refers to an alkyl or lower alkyl group, as defined herein, appended to the parent molecular moiety through an oxy group, i.e., -O-, (thus including substituted versions, e.g., polyalkoxy). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0026] As used herein alone or as part of another group, "acyl" refers to a -C(O)R radical, where R is any suitable substituent, such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl, or other suitable substituents described herein.

[0027] As used herein alone or as part of another group, "haloalkyl" refers to at least one halogen atom, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.

[0028] "Alkylthio" as used herein alone or as part of another group refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.

[0029] As used herein alone or as part of another group, "aryl" refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings. Representative examples of aryl include, but are not limited to, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like. The term "aryl", unless otherwise specified, is intended to include both substituted and unsubstituted aryl, and these groups may be substituted with the same groups described in connection with alkyl and lower alkyl above.

[0030] "Arylalkyl" as used herein alone or as part of another group refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.

[0031] As used herein, "amino" refers to the -NH2 radical.

[0032] As used herein alone or as part of another group, "alkylamino" refers to the moiety -NHR radical, where R is an alkyl group.

[0033] As used herein alone or as part of another group, "arylalkylamino" refers to the moiety -NHR radical, where R is an arylalkyl group.

[0034] As used herein alone or as part of another group, "disubstituted amino" refers to -NR a R b means radical, where R a and R b is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, and heterocycloalkyl.

[0035] As used herein alone or as part of another group, "acylamino" refers to -NR a R b means radical, where R a and R b is independently selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, and heterocycloalkyl.

[0036] As used herein alone or as part of another group, "acyloxy" refers to the moiety -OR radical, where R is an acyl group, as defined herein.

[0037] As used herein alone or as part of another group, an "ester" refers to a -C(O)OR radical, where R is any suitable substituent, for example, alkyl, cycloalkyl, alkenyl, alkynyl, or aryl.

[0038] As used herein, "formyl" refers to the group --C(O)H.

[0039] As used herein, "carboxylic acid" refers to the group --C(O)OH.

[0040] As used herein, "sulfoxyl" refers to a compound of formula -S(O)R, where R is any suitable substituent, for example, alkyl, cycloalkyl, alkenyl, alkynyl, or aryl.

[0041] As used herein, "sulfonyl" refers to a compound of the formula -S(O)(O)R, where R is any suitable substituent, for example, alkyl, cycloalkyl, alkenyl, alkynyl, or aryl.

[0042] As used herein, "sulfonate" refers to a compound of formula -S(O)(O)OR, where R is any suitable substituent, such as alkyl, cycloalkyl, alkenyl, alkynyl, or aryl.

[0043] As used herein, "sulfonic acid" refers to a compound of the formula -S(O)(O)OH.

[0044] As used herein alone or as part of another group, "amide" refers to -C(O)NR a R b refers to the radical, where R a and R b is any suitable substituent, for example, alkyl, cycloalkyl, alkenyl, alkynyl, or aryl.

[0045] As used herein alone or as part of another group, "sulfonamide" refers to -S(O)NR a R b refers to the radical, where R a and R b is any suitable substituent, for example, H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroalkyl, or heteroaryl.

[0046] As used herein alone or as part of another group, “urea” refers to —N(R c )C(O)NR a R b refers to the radical, where R a , R b and R c is any suitable substituent, for example, H, alkyl, cycloalkyl, alkenyl, alkynyl, or aryl.

[0047] As used herein alone or as part of another group, “alkoxyacylamino” refers to —N(R a )C(O)OR b refers to the radical, where R a and R b is any suitable substituent, for example, H, alkyl, cycloalkyl, alkenyl, alkynyl, or aryl.

[0048] As used herein alone or as part of another group, "aminoacyloxy" refers to -OC(O)NR a R b refers to the radical, where R a and R b is any suitable substituent, for example, H, alkyl, cycloalkyl, alkenyl, alkynyl, or aryl.

[0049] As used herein alone or as part of another group, "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon group containing 3, 4, or 5 to 6, 7, or 8 carbon atoms, which may be substituted in the heterocyclic groups discussed below. Representative examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. These rings may be optionally substituted with additional substituents, such as halogen atoms or lower alkyl, as described herein. The term "cycloalkyl" is generic and is intended to include the heterocyclic groups discussed below, unless otherwise specified.

[0050] As used herein alone or as part of another group, a "heterocyclic group" or "heterocyclo" refers to an aliphatic (e.g., fully or partially saturated heterocyclo) or aromatic (e.g., heteroaryl) monocyclic or bicyclic system. Monocyclic systems are exemplified by any 5- or 6-membered ring that contains 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur atoms. The 5-membered ring has 0-2 double bonds, and the 6-membered ring has 0-3 double bonds. Representative examples of monocyclic systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic systems are exemplified by any of the above monocyclic systems fused to an aryl group, as defined herein, a cycloalkyl group, as defined herein, or another monocyclic system, as defined herein.Representative examples of bicyclic systems include, but are not limited to, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxin, 1,3-benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, purine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like. These rings, including their quaternized derivatives, may be optionally substituted with groups selected from the following: halogen atoms, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O). m , haloalkyl-S(O) m , alkenyl-S(O) m , alkynyl-S(O) m , cycloalkyl-S(O) m , cycloalkylalkyl-S(O) m , aryl-S(O) m , arylalkyl-S(O) m , heterocyclo-S(O) m , heterocycloalkyl-S(O) m, amino, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro, or cyano, where m=0, 1, 2, or 3. In some embodiments, the heterocyclo group includes pyridyl and / or imidazolyl groups, which terms include their quaternized derivatives, including but not limited to quaternized pyridyl and quaternized imidazolyl groups. Examples of pyridyl and / or imidazolyl groups include, but are not limited to, the following: [ka] wherein R and R' are each a suitable substituent as described above in connection with "alkyl", in particular alkyl (e.g., methyl, ethyl or propyl), arylalkyl (e.g., benzyl), optionally substituted with hydroxy (-OH), phosphonic acid (-PO3H2), or sulfonic acid (-SO3H), and wherein X - is the counter ion.

[0051] "Spiroalkyl" as used herein alone or as part of another group refers to a saturated or unsaturated straight or branched chain hydrocarbon containing 3 to 8 carbon atoms. Representative examples include, but are not limited to, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CHCHCH2-, -CH2CH2CH2CH2CH2-, and the like. The term "spiroalkyl", unless otherwise specified, is intended to encompass both substituted and unsubstituted "spiroalkyl", and these groups may be optionally substituted with groups selected from the following: halogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O) m , haloalkyl-S(O) m , alkenyl-S(O) m , alkynyl-S(O) m , cycloalkyl-S(O) m , cycloalkylalkyl-S(O) m , aryl-S(O) m , arylalkyl-S(O) m , heterocyclo-S(O) m , heterocycloalkyl-S(O) m , amino, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro, or cyano, where m=0, 1, or 2.

[0052] As used herein, "targeting groups", such as antibodies, proteins, peptides, and nucleic acids, may be attached by a linking group.

[0053] As used herein, "treatment" refers to any manner in which one or more symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein, for example, for use in treating a disease or disorder mediated by or involving hyperproliferative tissue or neovascularization. As used herein, improvement of symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any relief that may result from or be associated with administration of the composition, whether permanent or temporary, persistent or transient.

[0054] As used herein, a "prodrug" is a compound that, upon administration in vivo, is metabolized or otherwise converted by one or more steps or processes into the biologically, pharma- ceutical, or therapeutically active form of the compound.

[0055] As used herein, "antibody" generally refers to an immunoglobulin or fragment thereof that specifically binds to an antigen to form an immune complex. The antibody may be any class of whole immunoglobulin, such as IgG, IgM, IgA, IgD, IgE, chimeric or hybrid antibodies with dual or multiple antigen or epitope specificity. The antibody may be a polyclonal antibody, and in some embodiments, an affinity purified antibody from a human or suitable animal, such as a primate, goat, rabbit, mouse, etc. Monoclonal antibodies are also suitable for use in the present invention and may be used due to their high specificity. The monoclonal antibodies are readily prepared by procedures that are now considered conventional, such as immunization of a mammal with an immunogenic antigen preparation, fusion of immune lymphocytes or spleen cells with an immortal myeloma cell line, and isolation of specific hybridoma clones. Less conventional methods of preparing monoclonal antibodies, such as interspecies fusions and genetic engineering of hypervariable regions, are also not excluded. Because it is the antigen specificity of the antibody that primarily determines its usefulness, new techniques for the production of monoclonal antibodies can also be used, such as human monoclonal antibodies, interspecies monoclonal antibodies, chimeric (e.g., human / mouse) monoclonal antibodies, and genetically engineered antibodies.

[0056] As used herein, "infectious agent" refers to an invading microorganism or parasite. As used herein, "microorganism" refers to microorganisms such as viruses, bacteria, rickettsia, mycoplasma, protozoa, fungi, and the like, and "parasite" refers to infectious, generally minute or very small, multicellular invertebrates, such as malarial parasites and spirochetes, or their egg or larval forms, that are susceptible to antibody-induced clearance or lytic or phagocytic destruction.

[0057] As used herein, "tumor" refers to a neoplasm and includes both benign and malignant tumors. The term specifically includes malignant tumors, which may be either solid tumors (e.g., breast, liver, or prostate cancer) or non-solid tumors (e.g., leukemia). Tumors are also further divided into subtypes, such as adenocarcinomas (e.g., adenocarcinomas of the breast, prostate, or lung).

[0058] As used herein, "target" refers to an object that is intended to be detected, diagnosed, damaged or destroyed by the methods provided herein, and includes target cells, target tissues, and target compositions. As used herein, "target tissues" and "target cells" are tissues that are intended to be damaged or destroyed by the treatment methods. Photosensitizing compounds bind to or collect in these target tissues or cells. These tissues or cells are then damaged or destroyed when sufficient radiation is administered. Target cells are cells in target tissues, and target tissues include, but are not limited to, vascular endothelial tissues, abnormal blood vessel walls of tumors, solid tumors, including but not limited to, head and neck tumors, eye tumors, gastrointestinal tumors, liver tumors, breast tumors, prostate tumors, lung tumors, non-solid tumors and malignant cells of hematopoietic and lymphatic tissues, neovascular tissues, other lesions in the vasculature, bone marrow, and tissues or cells associated with autoimmune diseases. Target cells also include cells that undergo substantially more rapid division compared to non-target cells.

[0059] As used herein, a "non-target tissue" is any tissue of a subject that is not intended to be damaged or destroyed by a treatment method. These non-target tissues include, but are not limited to, healthy blood cells and other normal tissues that are not identified as targets.

[0060] As used herein, a "target composition" is a composition intended to be damaged or destroyed by the treatment method and may include one or more pathogens, including but not limited to bacteria, viruses, fungi, protozoa, and toxins, as well as cells and tissues infected or infiltrated therewith. The term "target composition" also includes, but is not limited to, infectious organic particles, such as prions, toxins, peptides, polymers, and other compounds that can be selectively and specifically identified as organic targets intended to be damaged or destroyed by the treatment method.

[0061] As used herein, "hyperproliferative tissue" means tissue that proliferates uncontrollably and includes neoplastic tissue, tumors, and uncontrolled vascular proliferation, such as that seen in age-related macular degeneration and that often occurs after glaucoma surgery.

[0062] As used herein, "hyperproliferative disorder" refers to a condition disorder that shares as an underlying pathology excessive cell proliferation caused by uncontrolled or abnormal cell proliferation, and includes uncontrolled angiogenesis. Examples of such hyperproliferative disorders include, but are not limited to, cancer or carcinoma, acute and membranoproliferative glomerulonephritis, myeloma, psoriasis, atherosclerosis, psoriatic arthritis, rheumatoid arthritis, diabetic retinopathy, macular degeneration, corneal neovascularization, choroidal hemangioma, recurrent pterygium, and scarring from excimer laser surgery and glaucoma filter surgery.

[0063] As used herein, a "therapeutically effective amount" is an amount sufficient to prevent the progression of a disease or to cause regression of a disease, or an amount capable of relieving symptoms caused by a disease.

[0064] As used herein, "illuminating" and "illumination" include exposing a subject to light of any wavelength. In some embodiments, the illumination wavelength is selected to match one or more wavelengths that excite a photosensitive compound. In some embodiments, the illumination wavelength matches the excitation wavelength of the photosensitive compound and has low absorption by non-target tissues of the subject, including blood proteins.

[0065] Irradiation is further defined herein by its coherence (laser) or non-coherence (non-laser), as well as intensity, duration and timing of administration with the photosensitizing compound. The intensity or fluence rate must be sufficient for the light to reach the target tissue. The duration or total fluence must be sufficient to photoactivate enough of the photosensitizing compound to affect the target tissue. The timing of administration of the photosensitizing compound is important because 1) it takes some time for the administered photosensitizing compound to reach the target tissue; and 2) the blood levels of many photosensitizing compounds decrease with time. The radiant energy is provided by an energy source, such as a laser or cold cathode light source, that is external to the subject, or that is implanted within the subject, or that is introduced into the subject, for example by a catheter or fiber optics, or by ingesting a light source in the form of a capsule or tablet (e.g., as disclosed in U.S. Pat. No. 6,273,904 (2001)).

[0066] Although some embodiments of the present invention are directed to the use of light energy to administer photodynamic therapy (PDT) to destroy tumors, other forms of energy are also within the scope of the present invention, as will be appreciated by those skilled in the art. Such forms of energy include, but are not limited to, heat, sonic, ultrasound, chemical, light, microwave, ionizing (e.g., x-rays and gamma rays), mechanical, and electrical. For example, sonodynamically induced or activated agents include gallium-porphyrin complexes (see Yumita et al., Cancer Letters 112:79-86 (1997)); other porphyrin complexes, such as protoporphyrin and hematoporphyrin (see Umemura et al., Ultrasonics Sonochemistry 3:S187-S191 (1996)); and other anticancer drugs used in the presence of ultrasound therapy, such as daunorubicin and adriamycin (see Yumita et al., Japan J. Hyperthermic Oncology 3(2):175-182 (1987)).

[0067] As used herein, a "coupling agent" refers to an agent capable of coupling a photosensitizer to a targeting agent.

[0068] A "targeting group" refers to a compound that resides and / or associates with and / or binds to a particular tissue, receptor, infectious agent or other area of ​​the subject's body to be treated, such as a target tissue or target composition as described above. Examples of targeting groups or agents include, but are not limited to, antibodies, ligands (e.g., drugs), one member of a ligand-receptor binding pair, nucleic acids, proteins and peptides, and liposomal suspensions, such as those described above, including tissue-targeted liposomes.

[0069] As used herein, "specific binding pair" and "ligand-receptor binding pair" refer to two different molecules where one molecule has an area on its surface or within a cavity that specifically attracts or binds to a particular spatial or polar organization of the other molecule, and both molecules have an affinity for one another. The members of a specific binding pair are referred to as a ligand and receptor (antiligand). The terms "ligand" and "receptor" are intended to encompass the entire ligand or receptor, or a sufficient portion thereof for binding to occur between the ligand and receptor. Examples of ligand-receptor binding pairs include, but are not limited to, hormones and hormone receptors, such as epidermal growth factor and epidermal growth factor receptor, tumor necrosis factor alpha and tumor necrosis factor receptor, and interferon and interferon receptor; avidin and biotin or anticotin; antibody-antigen pairs; enzymes and substrates; drugs and drug receptors; cell surface antigens and lectins; two complementary nucleic acid strands; a nucleic acid strand and a complementary oligonucleotide; interleukins and interleukin receptors; and stimulatory factors and their receptors, such as granulocyte-macrophage colony stimulating factor (GMCSF) and GMCSF receptor; and macrophage colony stimulating factor (MCSF) and MCSF receptor.

[0070] As used herein, "biological material" refers to both tissue (eg, biopsy tissue) and cells, as well as biological fluids, such as blood, urine, plasma, cerebrospinal fluid, mucus, sputum, and the like.

[0071] Subjects treated by the methods of the present invention for diagnostic and / or therapeutic purposes include both human subjects and, for veterinary purposes, animal subjects (particularly mammalian subjects, e.g., dogs, cats, horses, monkeys, chimpanzees, etc.).

[0072] A compound comprising at least one porphyrin linked to at least one hydroporphyrin is provided according to an embodiment of the present invention. In some embodiments, the compound of the present invention is a light-emitting compound. As used herein, "light-emitting compound" refers to a compound capable of emitting light, where the compound comprises at least one porphyrin linked to at least one hydroporphyrin. For example, the light-emitting compound can emit light, but the nature of the original state (e.g., singlet, triplet, and / or another state) for the light-emitting compound is not specified. Exemplary light-emitting compounds include, but are not limited to, phosphorescent and / or fluorescent compounds, which produce phosphorescence and / or fluorescence, respectively. In some embodiments, the light-emitting compound can emit fluorescence (e.g., is a fluorescent compound). In some embodiments, the compound of the present invention comprises a first porphyrin and a first hydroporphyrin, where the first porphyrin is attached to the first hydroporphyrin. In some embodiments, the first porphyrin is attached to the first hydroporphyrin via a linking group. In some embodiments, the first porphyrin is attached to the first hydroporphyrin via a direct bond. In some embodiments, two or more porphyrins are linked (either directly or through a linking group) to a hydroporphyrin (e.g., the first hydroporphyrin). The compounds of the present invention include at least one porphyrin that is a donor and at least one hydroporphyrin that is an acceptor. It has been unexpectedly discovered that the compounds of the present invention can provide donor-acceptor (e.g., porphyrin-hydroporphyrin) energy transfer, and in some embodiments, can provide a higher fluorescence quantum yield and / or a simpler (e.g., less complex) spectrum than would be expected for the fluorescence quantum yield and / or spectrum based on the spectral properties of the porphyrin alone. Typically, porphyrins are not expected to be suitable donors because they can have low fluorescence quantum yields and complex emission spectra (e.g., two or more emission peaks).

[0073] In some embodiments of the invention, the compounds of the invention include a porphyrin having a structure of one of Formula Ia or Formula Ib: [ka] or [ka] Where: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently a group selected from the group consisting of a hydrogen atom, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkylalkyl, a cycloalkylalkenyl, a cycloalkylalkynyl, a heterocyclo, a heterocycloalkyl, a heterocycloalkenyl, a heterocycloalkynyl, an aryl, an aryloxy, an arylalkyl, an arylalkenyl, an arylalkynyl, a heteroaryl, a heteroarylalkyl, a heteroarylalkenyl, a heteroarylalkynyl, an alkoxy, a halogen atom, a mercapto, an azido, a cyano, a formyl, a carboxylic acid, a hydroxyl, a nitro, an acyl, an alkylthio, an amino, an alkylamino, an arylalkylamino, a disubstituted amino, an acylamino, an acyloxy, an ester, an amide, a sulfoxyl, a sulfonyl, a sulfonate, a sulfonic acid, a sulfonamide, a urea, an alkoxyl acylamino, an aminoacyloxy, a hydrophilic group, a linking group, a bioconjugable group, a surface attachment group, and a targeting group; or R 1 and R 2 taken together represent a substituted or unsubstituted fused aromatic or heteroaromatic ring system; or R 3 and R 5taken together represent a substituted or unsubstituted fused aromatic or heteroaromatic ring system; or R 4 and R 5 taken together represent a substituted or unsubstituted fused aromatic or heteroaromatic ring system; or R 4 and R 7 taken together represent a substituted or unsubstituted fused aromatic or heteroaromatic ring system; or R 7 and R 8 taken together represent a substituted or unsubstituted fused aromatic or heteroaromatic ring system; or R 9 and R 10 taken together represent a substituted or unsubstituted fused aromatic or heteroaromatic ring system; or R 10 and R 11 taken together represent a substituted or unsubstituted fused aromatic or heteroaromatic ring system; and M 1 is a metal atom, if present (e.g., a zinc atom, a magnesium atom, a gold atom, an aluminum atom, a silicon atom, a palladium atom, an indium atom, a tin atom, a copper atom, or a platinum atom); and Here, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12At least one of is a point of attachment to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin. The fused aromatic or heteroaromatic ring system of the compound of formula Ia or formula Ib may be substituted with one or more substituents, including but not limited to, a substituent selected from the group consisting of halogen atoms, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy (thereby producing a polyalkoxy, e.g., polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O) m , haloalkyl-S(O) m , alkenyl-S(O) m , alkynyl-S(O) m , cycloalkyl-S(O) m , cycloalkylalkyl-S(O) m , aryl-S(O) m , arylalkyl-S(O) m , heterocyclo-S(O) m , heterocycloalkyl-S(O) m , amino, carboxy, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro, and cyano, where m=0, 1, 2, or 3. In some embodiments, the fused aromatic or heteroaromatic ring system of the compound of Formula Ia or Formula Ib may be substituted with an ester or amine.

[0074] In some embodiments, R of formula Ia or formula Ib1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 In some embodiments, one of R of Formula Ia or Formula Ib is linked to the hydroporphyrin via a direct bond. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 In some embodiments, the first porphyrin having the structure of Formula Ia or Formula Ib is linked to a linking group that is linked to the hydroporphyrin. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 In some embodiments, the first porphyrin having the structure of Formula Ia or Formula Ib is linked to the second porphyrin via a direct bond to the second porphyrin, which may optionally have the same structure or a different structure as the first porphyrin. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12and the linking group is attached to a second porphyrin, which may optionally have the same structure or a different structure as the first porphyrin. 3 , R 6 , R 9 and R 12 is independently attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin. 6 is attached to the hydroporphyrin or porphyrin through a linking group or through a direct bond to the hydroporphyrin or porphyrin.

[0075] In some embodiments, the compounds of the present invention include a porphyrin having the structure of formula Ia. The porphyrin of formula Ia lacks a metal ion in the center of the porphyrin (e.g., lacks a metal ion in the cavity / core of the porphyrin) and is therefore in free base form. The porphyrin of formula Ia may also be referred to herein as a free base porphyrin. In some embodiments, the compounds of the present invention include a porphyrin having the structure of formula Ib, and M 1 is a metal, which may optionally be a zinc atom, a magnesium atom, a gold atom, an aluminum atom, a silicon atom, a palladium atom, an indium atom, a tin atom, a copper atom, or a platinum atom. In some embodiments, the compounds of the invention comprise a porphyrin having the structure of Formula Ib, and M 1 is zinc. In some embodiments, the compounds of the present invention include a porphyrin having the structure of formula Ib, and M 1 is magnesium.

[0076] In some embodiments of the present invention, R of formula Ia or formula Ib 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently selected from the group consisting of a hydrogen atom, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkylalkyl, a cycloalkylalkenyl, a cycloalkylalkynyl, a heterocyclo, a heterocycloalkyl, a heterocycloalkenyl, a heterocycloalkynyl, an aryl, an aryloxy, an arylalkyl, an arylalkenyl, an arylalkynyl, a heteroaryl, a heteroarylalkyl, a heteroarylalkenyl, a heteroarylalkynyl, an alkoxy, a halogen atom, a mercapto, an azido, a cyano, a formyl, a carboxylic acid, a hydroxyl, a nitro, an acyl, an alkylthio, an amino, an alkylamino, an arylalkylamino, a disubstituted amino, an acylamino, an acyloxy, an ester, an amide, a sulfoxyl, a sulfonyl, a sulfonate, a sulfonic acid, a sulfonamide, a urea, an alkoxylacylamino, an aminoacyloxy, a hydrophilic group, a linking group, a bioconjugable group, a surface attachment group, and a targeting group; and M 1 is a metal atom, if present (e.g., a zinc atom, a magnesium atom, a gold atom, an aluminum atom, a silicon atom, a palladium atom, an indium atom, a tin atom, a copper atom, or a platinum atom), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin.

[0077] In certain embodiments of the present invention, R of formula Ia or formula Ib 1 , R 2 , R 3 , R4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently selected from the group consisting of hydrogen, halogen, carboxy, cyano, carboxylic acid, alkyl, alkenyl, alkynyl, acyl, acyloxy, sulfonyl, sulfoxyl, amino, amido, nitro, hydroxy, mercapto, alkoxy, ester, phenyl, substituted phenyl, surface attachment groups, linking groups, bioconjugable groups, targeting groups, hydrophilic groups, and combinations thereof; and 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin, and optionally, 3 , R 6 , R 9 , and R 12 is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin. 3 , R 6 , R 9 , and R 12 at least one of R is a halogen atom, carboxy, cyano, carboxylic acid, alkyl, alkenyl, alkynyl, acyl, acyloxy, sulfonyl, sulfoxyl, amino, amido, nitro, hydroxy, mercapto, alkoxy, ester, phenyl, substituted phenyl, a surface attachment group, a linking group, a bioconjugable group, a targeting group, or a hydrophilic group; and R3 , R 6 , R 9 , and R 12 is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin.

[0078] In some embodiments of the present invention, R of formula Ia or formula Ib 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently selected from the group consisting of a hydrogen atom, an alkyl ester (e.g., methyl ester, ethyl ester), an alkyl benzoate (e.g., 4-methyl benzoate, 4-ethyl benzoate), a phenyl (e.g., substituted or unsubstituted phenyl), a carboxy(alkyl or ester)alkylphenyl (e.g., 3-(4-carboxybutyl)phenyl), a trimethylphenyl (e.g., mesityl), and combinations thereof, and optionally, wherein R 3 , R 6 , R 9 , and R 12 is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin. 3 , R 6 , R 9 , and R 12 at least one of R is an alkyl ester (e.g., methyl ester, ethyl ester), an alkyl benzoate (e.g., 4-methyl benzoate, 4-ethyl benzoate), a phenyl (e.g., substituted or unsubstituted phenyl), a carboxy(alkyl or ester)alkylphenyl (e.g., 3-(4-carboxybutyl)phenyl), or a trimethylphenyl (e.g., mesityl), and R3 , R 6 , R 9 , and R 12 is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin.

[0079] In some embodiments, the compounds of the present invention include a porphyrin having a structure of Formula Ia or Formula Ib, and the porphyrin is excited at 405 nm. In some embodiments, the compounds of the present invention include a porphyrin having a structure of Formula Ia or Formula Ib, and the porphyrin is excited at 488 nm. In some embodiments, the compounds of the present invention include a porphyrin having a structure of Formula Ia or Formula Ib, and the porphyrin is excited at 407 nm.

[0080] In some embodiments of the invention, the compound of formula Ia or formula Ib contains up to two aryl or heteroaryl substituents. In some embodiments, the porphyrin of formula Ia or formula Ib has one or two aryl substituents. In some embodiments, the porphyrin of formula Ia or formula Ib has one or two heteroaryl substituents. In some embodiments, the compound of formula Ia or formula Ib contains more than one aryl or heteroaryl substituent. For example, an exemplary porphyrin (e.g., a porphyrin that can be excited at about 488 nm) can have the structure of formula Ib" below. [ka] Here, M 1 is a metal atom (e.g., a zinc atom, a magnesium atom, a gold atom, an aluminum atom, a silicon atom, a palladium atom, an indium atom, a tin atom, a copper atom, or a platinum atom), and R 1b , R 2b , R 3b , R 4b , R 5b , R 6b , R 7b , R 8b , R 9b , R 10b, R 11b , and R 12b are each independently a hydrogen atom, a substituent (e.g., alkyl, ester, or amine), or a direct bond to the hydroporphyrin or porphyrin. In some embodiments, R 1b , R 2b , R 4b , R 5b , R 7b , R 8b , R 10b , and R 11b are each independently a hydrogen atom, an ester, or an amine, and R 3b , R 6b , R 9b , and R 12b are each independently a hydrogen atom or a direct bond to a hydroporphyrin or porphyrin, where R 3b , R 6b , R 9b , and R 12b is a direct bond to the hydroporphyrin or porphyrin. In some embodiments, the porphyrin of formula Ib″ is excited at about 488 nm.

[0081] In some embodiments, the porphyrin (eg, a porphyrin that can be excited at about 445 nm) can have the structure of Formula Ia''' below: [ka] where R of formula Ia′′′ 1c , R 2c , R 3c , R 4c , R 5c , R 6c , R 7c , R 8c , R 9c , R 10c , R 11c , and R 12c are each independently a hydrogen atom, a substituent (e.g., alkyl, ester, or amine), or a direct bond to the hydroporphyrin or porphyrin. 1c, R 2c , R 3c , R 4c , R 5c , R 7c , R 8c , R 10c , and R 11c One or more of are each independently a hydrogen atom or an ester. In some embodiments, R 1c , R 2c , R 3c , R 4c , R 5c , R 7c , R 8c , R 10c , and R 11c In some embodiments, one or more of R of formula Ia''' is an ester, optionally an alkyl ester. 1c , R 2c , R 3c , R 4c , R 5c , R 7c , R 8c , R 10c , and R 11c At least one of R in formula Ia''' is -CO2(alkyl), optionally where the alkyl is methyl, ethyl, propyl, or butyl (e.g., n-butyl, sec-butyl, isobutyl, or tert-butyl). 1c , R 2c , R 3c , R 4c , R 5c , R 7c , R 8c , R 10c , and R 11c is independently -CO2CH3 or -CO2(CH2)3CH3. In some embodiments, R 3c , R 6c , R 9c , and R 12cis attached to the hydroporphyrin via a linking group (e.g., a linking group comprising a phenyl) or via a direct bond to the hydroporphyrin. In some embodiments, the porphyrin of Formula Ia"' is excited at about 445 nm. In some embodiments, the porphyrin of Formula Ib"' is excited at about 447 nm.

[0082] In some embodiments, the compounds of the invention include a hydroporphyrin, and the hydroporphyrin is a chlorin. In some embodiments, the compounds of the invention include a hydroporphyrin, and the hydroporphyrin is a bacteriochlorin. In some embodiments, the bacteriochlorin is an isobacteriochlorin or an azabacteriochlorin.

[0083] In some embodiments of the invention, the compound of the invention comprises a hydroporphyrin comprising one of the structures of Formula IIa-IId below: [ka] [ka] [ka] or [ka] Where: R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34are each independently selected from the group consisting of a hydrogen atom, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkylalkyl, a cycloalkylalkenyl, a cycloalkylalkynyl, a heterocyclo, a heterocycloalkyl, a heterocycloalkenyl, a heterocycloalkynyl, an aryl, an aryloxy, an arylalkyl, an arylalkenyl, an arylalkynyl, a heteroaryl, a heteroarylalkyl, a heteroarylalkenyl, a heteroarylalkynyl, an alkoxy, a halogen atom, a mercapto, an azido, a cyano, a formyl, a carboxylic acid, a hydroxyl, a nitro, an acyl, an alkylthio, an amino, an alkylamino, an arylalkylamino, a disubstituted amino, an acylamino, an acyloxy, an ester, an amide, a sulfoxyl, a sulfonyl, a sulfonate, a sulfonic acid, a sulfonamide, a urea, an alkoxyl acylamino, an aminoacyloxy, a hydrophilic group, a linking group, a bioconjugable group, a surface attachment group, and a targeting group; or R 20 and R 21 taken together are =O or spiroalkyl; or R 22 and R 23 taken together are =O or spiroalkyl; or R 28 and R 33 taken together are =O or spiroalkyl; or R 29 and R 33 taken together are =O or spiroalkyl; or R 24 and R 25 taken together represent a substituted or unsubstituted fused aromatic or heteroaromatic ring system; or R 25 and R 26 taken together represent a substituted or unsubstituted fused aromatic or heteroaromatic ring system; or R 26 and R 27 taken together represent a substituted or unsubstituted fused aromatic or heteroaromatic ring system; or R30 and R 31 taken together represent a substituted or unsubstituted fused aromatic or heteroaromatic ring system; or R 31 and R 32 taken together represent a substituted or unsubstituted fused aromatic or heteroaromatic ring system; or R 32 and R 33 taken together represent a substituted or unsubstituted fused aromatic or heteroaromatic ring system; and M 2 is, when present, a metal atom (e.g., a zinc atom, a magnesium atom, a gold atom, an aluminum atom, a silicon atom, a palladium atom, an indium atom, a tin atom, a copper atom, or a platinum atom); and Here, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34At least one of is a point of attachment to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin. The fused aromatic or heteroaromatic ring systems of the compounds of Formula IIa-IId may be substituted with one or more substituents, including but not limited to, a halogen atom, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy (thereby producing a polyalkoxy, e.g., polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocycloalkyloxy, mercapto, alkyl-S(O) m , haloalkyl-S(O) m , alkenyl-S(O) m , alkynyl-S(O) m , cycloalkyl-S(O) m , cycloalkylalkyl-S(O) m , aryl-S(O) m , arylalkyl-S(O) m , heterocyclo-S(O) m , heterocycloalkyl-S(O) m , amino, carboxy, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro, and cyano, where m=0, 1, 2, or 3.

[0084] In some embodiments, R of Formula IIa to Formula IId 20 , R 21 , R 22 , R 23 , R24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 In some embodiments, one of R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 In some embodiments, the first hydroporphyrin having a structure of Formula IIa-IId is linked to a linking group that is linked to the porphyrin. 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 In some embodiments, the first hydroporphyrin having the structure of Formula IIa-IId is linked to the second hydroporphyrin via a direct bond to the second hydroporphyrin, which may optionally have the same structure or a different structure as the first hydroporphyrin. 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26, R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 to a linking group at one of the linking groups, and the linking group is attached to a second hydroporphyrin, which may optionally have the same structure or a different structure as the first hydroporphyrin.

[0085] In some embodiments, R of Formula IIa to IId 24 , R 25 , R 26 , R 27 , R 30 , R 31 , R 32 , and R 33 At least one of R is independently attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin. 24 , R 25 , R 26 , R 27 , R 30 , R 31 , R 32 , and R 33 In some embodiments, R of Formula IIa-IId is independently linked to the hydroporphyrin or porphyrin through a linking group or through a direct bond to the hydroporphyrin or porphyrin. 24 , R 27 , R 30 , and R 33 In some embodiments, one of R of Formula IIa-IId is attached to the hydroporphyrin or porphyrin through a linking group or through a direct bond to the hydroporphyrin or porphyrin. 25 and R 26In some embodiments, one of R of Formula IIa-IId is attached to the hydroporphyrin or porphyrin through a linking group or through a direct bond to the hydroporphyrin or porphyrin. 31 and R 32 In some embodiments, one of R of Formula IIa-IId is attached to the hydroporphyrin or porphyrin through a linking group or through a direct bond to the hydroporphyrin or porphyrin. 30 is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin, optionally wherein the compound has the structure of Formula IIa or Formula IIb. In some embodiments, R 33 is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin, optionally wherein the compound has the structure of Formula IIc or Formula IId. In some embodiments, R 32 is attached to the hydroporphyrin or porphyrin through a linking group or through a direct bond to the hydroporphyrin or porphyrin. 26 is attached to the hydroporphyrin or porphyrin through a linking group or through a direct bond to the hydroporphyrin or porphyrin. 25 and R 31 is each independently attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin. 26 and R 32 is each independently attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin.

[0086] In some embodiments, the compounds of the present invention have the formula IIa-IId R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , or R 34 R of formula Ia or formula Ib 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 In some embodiments, the compounds of the present invention include a hydroporphyrin having a structure of Formula IIa-IId linked to a porphyrin having a structure of Formula Ia or Formula Ib via a direct bond to R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , or R 34 and the linking group is R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8, R 9 , R 10 , R 11 , or R 12 In some embodiments, the compounds of the present invention are linked to R 24 , R 25 , R 26 , R 27 , R 30 , R 33 , R 31 , or R 32 and the linking group is R 3 , R 6 , R 9 , or R 12 is bound to

[0087] In some embodiments, the compounds of the present invention include a hydroporphyrin having the structure of Formula IIa. In some embodiments, the compounds of the present invention include a hydroporphyrin having the structure of Formula IIb, and M 1 is a metal, which may optionally be a zinc atom, a magnesium atom, a gold atom, an aluminum atom, a silicon atom, a palladium atom, an indium atom, a tin atom, a copper atom, or a platinum atom. In some embodiments, the compounds of the invention include a hydroporphyrin having a structure of Formula IIc. In some embodiments, the compounds of the invention include a hydroporphyrin having a structure of Formula IId, and M 1 is a metal, which may optionally be a zinc atom, a magnesium atom, a gold atom, an aluminum atom, a silicon atom, a palladium atom, an indium atom, a tin atom, a copper atom, or a platinum atom. In some embodiments, the compounds of the invention include a hydroporphyrin having a structure of Formula IIb or Formula IId, and M is zinc. In some embodiments, the compounds of the invention include a hydroporphyrin having a structure of Formula IIb or Formula IId, and M 1is magnesium. The hydroporphyrin of formula IIa and the hydroporphyrin of formula IIc each lack a metal ion in the center of the hydroporphyrin (e.g., lack a metal ion in the cavity / core of the hydroporphyrin) and therefore each is in free base form. The hydroporphyrins of formula IIa and / or formula IIc may also be referred to herein as free base hydroporphyrins.

[0088] In some embodiments of the present invention, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 are each independently selected from the group consisting of a hydrogen atom, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkylalkyl, a cycloalkylalkenyl, a cycloalkylalkynyl, a heterocyclo, a heterocycloalkyl, a heterocycloalkenyl, a heterocycloalkynyl, an aryl, an aryloxy, an arylalkyl, an arylalkenyl, an arylalkynyl, a heteroaryl, a heteroarylalkyl, a heteroarylalkenyl, a heteroarylalkynyl, an alkoxy, a halogen atom, a mercapto, an azido, a cyano, a formyl, a carboxylic acid, a hydroxyl, a nitro, an acyl, an alkylthio, an amino, an alkylamino, an arylalkylamino, a disubstituted amino, an acylamino, an acyloxy, an ester, an amide, a sulfoxyl, a sulfonyl, a sulfonate, a sulfonic acid, a sulfonamide, a urea, an alkoxyl acylamino, an aminoacyloxy, a hydrophilic group, a linking group, a bioconjugable group, a surface attachment group, and a targeting group; 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin.

[0089] In some embodiments of the present invention, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 are each independently selected from the group consisting of a hydrogen atom, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkylalkyl, a cycloalkylalkenyl, a cycloalkylalkynyl, a heterocyclo, a heterocycloalkyl, a heterocycloalkenyl, a heterocycloalkynyl, an aryl, an aryloxy, an arylalkyl, an arylalkenyl, an arylalkynyl, a heteroaryl, a heteroarylalkyl, a heteroarylalkenyl, a heteroarylalkynyl, an alkoxy, a halogen atom, a mercapto, an azido, a cyano, a formyl, a carboxylic acid, a hydroxyl, a nitro, an acyl, an alkylthio, an amino, an alkylamino, an arylalkylamino, a disubstituted amino, an acylamino, an acyloxy, an ester, an amide, a sulfoxyl, a sulfonyl, a sulfonate, a sulfonic acid, a sulfonamide, a urea, an alkoxyl acylamino, an aminoacyloxy, a hydrophilic group, a linking group, a bioconjugable group, a surface attachment group, and a targeting group; 20 , R 21 , R 22 , R 23, R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin.

[0090] In some embodiments of the present invention, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 are each independently selected from the group consisting of hydrogen, halogen, carboxy, cyano, carboxylic acid, alkyl, alkenyl, alkynyl, acyl, acyloxy, sulfonyl, sulfoxyl, amino, amido, nitro, hydroxy, mercapto, alkoxy, ester, phenyl, substituted phenyl, surface attachment groups, linking groups, bioconjugable groups, targeting groups, hydrophilic groups, and combinations thereof; and 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34At least one of R is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin. 24 , R 25 , R 26 , R 27 , R 30 , and R 33 at least one of R is a halogen atom, carboxy, cyano, carboxylic acid, alkyl, alkenyl, alkynyl, acyl, acyloxy, sulfonyl, sulfoxyl, amino, amido, nitro, hydroxy, mercapto, alkoxy, ester, phenyl, substituted phenyl, a surface attachment group, a linking group, a targeting group, or a hydrophilic group; and 24 , R 25 , R 26 , R 27 , R 30 , R 33 , R 31 , and R 32 is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin.

[0091] In some embodiments of the present invention, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34are each independently selected from the group consisting of a hydrogen atom, phenyl, halophenyl, alkoxy (e.g., methoxy, ethoxy), alkyl ester (e.g., methyl ester, ethyl ester), alkyl benzoate (e.g., 4-methyl benzoate, 4-ethyl benzoate), carboxy(alkyl or ester)alkylphenyl (e.g., 3-(4-carboxybutyl)phenyl), trimethylphenyl (e.g., mesityl), alkyl carboxylic acid, alkyl alkyl ester, (alkyl ester)phenylethynyl, linking group, bioconjugable group, surface attachment group, targeting group, or combinations thereof; and 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 At least one of R is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin. 24 , R 25 , R 26 , R 27 , R 30 , and R 33 at least one of R is a phenyl, halophenyl, alkoxy (e.g., methoxy, ethoxy), alkyl ester (e.g., methyl ester, ethyl ester), alkyl benzoate (e.g., 4-methyl benzoate, 4-ethyl benzoate), carboxy(alkyl or ester)alkylphenyl (e.g., 3-(4-carboxybutyl)phenyl), trimethylphenyl (e.g., mesityl), alkyl carboxylic acid, alkyl alkyl ester, (alkyl ester)phenylethynyl, linking group, bioconjugable group, surface attachment group, or targeting group; and 24 , R 25 , R 26 , R27 , R 30 , R 33 , R 31 , and R 32 is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin.

[0092] In some embodiments, R of Formula IIa to Formula IId 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 At least one of the above has a structure of Formula A or Formula B below: [ka] [ka]

[0093] In some embodiments, in the compound of Formula IIa-IId, R 24 , R 25 , R 26 , R 27 , R 30 , and R 33 at least one of has a structure of formula A or a structure of formula B, and R 24 , R 27 , R 30 , R 33 , R 31 , and R 32 is attached to the hydroporphyrin or porphyrin via a linking group or via a direct bond to the hydroporphyrin or porphyrin.

[0094] In some embodiments, the compounds of the invention include a porphyrin attached to a hydroporphyrin at the meso position of the porphyrin and at the beta position of the hydroporphyrin, either via a direct bond or via a linking group. Thus, in certain embodiments, the compounds of the invention may include a hydroporphyrin attached to a porphyrin having the structure of Formula Ia or Formula Ib, where the hydroporphyrin (optionally at the beta position of the hydroporphyrin) has the R 3 , R 6 , R 9 , or R 12 In some embodiments, the compounds of the present invention include a porphyrin that is attached to a hydroporphyrin at the meso position of the porphyrin and at the meso position of the hydroporphyrin through a direct bond or through a linking group. In some embodiments, the compounds of the present invention include a porphyrin that is attached to a hydroporphyrin at the beta position of the porphyrin and at the meso position of the hydroporphyrin through a direct bond or a linking group. In some embodiments of the present invention, the compounds of the present invention include a hydroporphyrin that is attached to a porphyrin at the beta position of the hydroporphyrin and at the beta position of the porphyrin through a direct bond or a linking group.

[0095] In some embodiments of the invention, the compounds of the invention include a first hydroporphyrin having a structure of Formula IIa or IIb, and R 32 is a direct bond to the first porphyrin (e.g., having the structure of Formula Ia or Formula Ib) or is a bond to a linking group that is attached to the first porphyrin; and R 30 is a bioconjugable group, such as a carboxylic acid or ester thereof, an amine, an isothiocyanate, an isocyanate, a maleimide, and an iodoacetamide. In some embodiments, R of Formula IIa or Formula IIb 30 has a structure of Formula A or Formula B.

[0096] In some embodiments of the invention, the compounds of the invention include a first hydroporphyrin having a structure of Formula IIc or Formula IId, and R 32 is a direct bond to the first porphyrin (e.g., having the structure of Formula Ia or Formula Ib) or is a bond to a linking group that is attached to the first porphyrin; and R 30 is a bioconjugable group, such as a carboxylic acid or ester thereof, an amine, an isothiocyanate, an isocyanate, a maleimide, and an iodoacetamide. In some embodiments, R of Formula IIc or Formula IId is 30 has a structure of Formula A or Formula B.

[0097] In some embodiments of the invention, the compounds of the invention include a first hydroporphyrin having a structure of Formula IIa or IIb, and R 20 , R 21 , R 22 , and R 23 Each independently is a hydrogen atom or alkyl (e.g., methyl). In some embodiments, R 20 , R 21 , R 22 , and R 23 In some embodiments, the compounds of the present invention include a first hydroporphyrin having a structure of Formula IIc or Formula IId, and one, two, three, or all of R 20 , R 21 , R 22 , R 23 , R 28 , R 29 , R 33 , and R 34 Each independently is a hydrogen atom or alkyl (e.g., methyl). In some embodiments, R 20 , R 21 , R 22 , R 23 , R 28 , R 29 , R 33 , and R 34one, two, three, four, five, six, seven, or all of are alkyl (e.g., methyl). In some embodiments, the compounds of the invention include a first hydroporphyrin having a geminal dialkyl group in each reduced pyrroline ring (e.g., a hydroporphyrin having a structure of one of Formulas IIa-IId), optionally where the hydroporphyrin includes a geminal dimethyl group.

[0098] In some embodiments, the compounds of the invention include one or more porphyrins (e.g., 1, 2, 3, 4, or more porphyrins). In some embodiments, the compounds of the invention include a first porphyrin, a second porphyrin, and a first hydroporphyrin, optionally, where the first hydroporphyrin is a chlorin or a bacteriochlorin. In some embodiments, the first hydroporphyrin is between the first porphyrin and the second porphyrin. In some embodiments, the second porphyrin is between the first porphyrin and the first hydroporphyrin. In certain embodiments of the invention, the first porphyrin and / or the second porphyrin have a structure of Formula Ia, and / or the first hydroporphyrin has a structure of Formula IIa or Formula IIc. In some embodiments of the invention, the first porphyrin and / or the second porphyrin have a structure of Formula Ia, and / or the first hydroporphyrin has a structure of Formula IIb or Formula IId, optionally, where M 1 and / or M 2 is zinc or magnesium. In certain embodiments of the invention, the first porphyrin and / or the second porphyrin have the structure of formula Ib and / or the first hydroporphyrin has the structure of formula IIb or IId, optionally wherein M 1 and / or M 2 is zinc or magnesium. In some embodiments of the invention, the first porphyrin and / or the second porphyrin have a structure of Formula Ib and / or the first hydroporphyrin has a structure of Formula IIa or Formula IIc.

[0099] In some embodiments, the compounds of the present invention may include large clusters or arrays of porphyrins (e.g., having the structure of Formula Ia or Formula Ib) linked to at least one hydroporphyrin (e.g., having the structure of one of Formulas IIa-IId). For example, in some embodiments, linear arrays of porphyrins (e.g., two, three, four, five, or more) are provided, with hydroporphyrins optionally linked at the meso position of the porphyrin ring as acceptors, and optionally linked at the beta position of the hydroporphyrin ring. In some embodiments, the hydroporphyrins are at the ends (e.g., terminus) of the compounds. As another example, the compound may comprise a dendritic cluster of porphyrins (e.g., 4, 5, 6, 7, 8, or more), which may be optionally linked at the meso positions of the porphyrin ring, and may be optionally attached to the hydroporphyrin at the center of the compound, and may be optionally linked at the beta positions of the hydroporphyrin ring, so that the energy of the porphyrin leaks to the acceptor hydroporphyrin. In some embodiments, the compounds of the present invention comprise a star-shaped structure having multiple porphyrins (e.g., 3, 4, 5, or more), which may be optionally linked at the meso positions of the porphyrin ring, and may be optionally attached to the hydroporphyrin at the beta positions of the hydroporphyrin ring, so that the energy of the porphyrin leaks to the acceptor hydroporphyrin.

[0100] In some embodiments, when two or more porphyrins are attached to a hydroporphyrin, the hydroporphyrin is attached to each of the porphyrins at a beta position on the hydroporphyrin ring via a direct bond or a linking group, In some embodiments, each of the two or more porphyrins is attached to the hydroporphyrin at a meso position on the porphyrin ring via a direct bond or a linking group.

[0101] As used herein, the terms "linking group," "linker," and "attachment moiety" are used interchangeably herein and refer to a functional group that provides a reactive site for conjugation and / or a functional group that is used to attach (for example) two compounds (e.g., used to attach and / or facilitate the attachment of a porphyrin and a hydroporphyrin). In some embodiments, a linking group attaches a porphyrin to a hydroporphyrin, a porphyrin to another porphyrin, or a hydroporphyrin to another hydroporphyrin (porphyrins and hydroporphyrins may collectively be referred to herein as heterocyclic macrocycles). As noted above, in some embodiments, there are no linking groups between multiple heterocyclic macrocycles in the compounds of the invention. However, in some embodiments, the compounds of the present invention include a linking group between at least two of the macrocycles (e.g., between a first porphyrin and a first hydroporphyrin), and the linking group attaches the two macrocycles. In some embodiments, the linking group includes at least one substituent (e.g., ethynyl) that can change the emission wavelength of the compound compared to the emission wavelength of the compound without the substituent. In some embodiments, the linking group includes at least one site (e.g., a functional group or a substituent) for a bioconjugation reaction.

[0102] In some embodiments of the invention, the linking group between the two heterocyclic macrocycles (e.g., the first porphyrin and the first hydroporphyrin) is an alkyl group (e.g., a C1-C20 alkyl group), an alkenyl group (e.g., a C2-C20 alkenyl group), an alkynyl group (e.g., a C2-C20 alkynyl group), a cycloalkyl group (e.g., a C3-C20 cycloalkyl group), an aryl group, an alkenylaryl group, an alkynylaryl group, an alkynylalkynyl group, a heterocyclo group, a heteroaryl group, an amino group, an amido group, and / or a peptidyl group, each of which may be substituted or unsubstituted. In some embodiments, the linking group is a nucleic acid (e.g., RNA and / or DNA, e.g., single stranded DNA (ssDNA)), polymer, biomolecule (e.g., peptide, etc.), alkyl (e.g., C1-C20 alkyl), alkenyl (e.g., C2-C20 alkenyl), alkynyl (e.g., C2-C20 alkynyl), cycloalkyl (e.g., C3-C20 cycloalkyl), aryl, alkenylaryl, alkynylaryl, alkynylalkynyl, heterocyclo, heteroaryl, amino, amido, and any combination thereof. In some embodiments, the linker comprises a nucleic acid, optionally DNA. In some embodiments, the linker is an ethyne, ethane, p-phenylene, 4,4'-biphenyl, 4,4"-terphenyl, 1,4-diphenylethyne, phenylethyne, thienyl, or peptidyl group, which may be optionally substituted or unsubstituted. In some embodiments, the linker is phenylethyne, which may be optionally substituted or unsubstituted. In some embodiments, the linking group is an aromatic or aliphatic group (which may be substituted or unsubstituted and may optionally contain heteroatoms, e.g., N, O, or S), such as, but not limited to, aryl, alkyl, heteroaryl, heteroalkyl (e.g., oligoethylene glycol), peptide, and / or polysaccharide linkers.

[0103] Energy transfer from the donor to the acceptor in the compounds of the invention may occur through a bond (i.e., through bond energy transfer (TBET)) or through space. The linking group between the two heterocyclic macrocycles in the compounds of the invention may affect the type of energy transfer. In some embodiments, energy transfer from the donor (e.g., a porphyrin) to the acceptor (e.g., a hydroporphyrin) in the compounds of the invention occurs via Forster resonance energy transfer (FRET). In some embodiments, energy transfer in the compounds of the invention occurs via FRET, and the compounds include a linking group that includes at least one, and in some embodiments at least two, rotatable bonds. In some embodiments, energy transfer from the donor (e.g., a porphyrin) to the acceptor (e.g., a hydroporphyrin) in the compounds of the invention occurs via Dexter energy transfer. When Dexter energy transfer occurs in a compound of the invention, a linker present in the compound may provide conjugation and / or electron delocalization.

[0104] Non-limiting examples of linking groups include: [ka] [ka] [ka] [ka] [ka] [ka] Where: [ka] is a point of attachment to another compound (e.g., a porphyrin or hydroporphyrin). In some embodiments, the left attachment point in one or more of the exemplary linkers above is attached to a porphyrin, and the right attachment point in one or more of the exemplary linkers above is attached to a hydroporphyrin.

[0105] In some embodiments, a linking group attaches at least a portion of a compound of the invention to another compound or entity. A "linking group" may link two or more heterocyclic macrocycles in a compound of the invention, and in some embodiments, a linking group may alternatively or additionally be used to connect a compound of the invention to a different compound or entity. For example, a compound of the invention may include a linking group that provides a reactive site for conjugation, such that the compound can be bound and / or conjugated to other compounds or groups, such as proteins, peptides, targeting agents (e.g., antibodies), polymers, particles (e.g., nanoparticles, organic beads, polymeric or inorganic beads, other solid support surfaces, etc.). In some embodiments, these other compounds or groups can be attached to the linking group of a compound of the invention, optionally via a linking group, such as the linking groups described above, including aryl, alkyl, heteroaryl, heteroalkyl (e.g., oligoethylene glycol), peptide, polysaccharide functional groups, etc. The linking group may simply be a reactive attachment group (e.g., -R', where R' is a reactive group, e.g., bromo), or may include a combination of reactive groups and intervening groups (e.g., -R"R', where R' is a reactive group and R' is an intervening group, e.g., a hydrophilic group). In some embodiments, the compounds of the invention may include a first linking group that attaches at least one heterocyclic macrocycle of the compound and to a protein, peptide, targeting agent (e.g., an antibody), polymer, or particle (e.g., a nanoparticle, organic bead, polymeric bead, or inorganic bead, other solid support surface, etc.), and the compound may optionally include a second linking group that attaches two heterocyclic macrocycles.

[0106] For bioconjugation purposes, the selection of one or more water-solubilizing groups and conjugation groups can be made to achieve orthogonal coupling. For example, if a carboxylic acid is used for water solubility, an aldehyde can be used for bioconjugation (via reductive amination with an amino-substituted biomolecule). If a carboxylic acid is used for bioconjugation (via carbodiimide activation and coupling with an amino-substituted biomolecule), a complementary group can be used for water solubility (e.g., sulfonic acid, guanidinium, pyridinium). Bioconjugable groups include, but are not limited to, carboxylic acids or their esters, amines (including amine derivatives), such as isocyanates, isothiocyanates, iodoacetamides, azides, diazonium salts, and the like, or acids or acid derivatives, such as N-hydroxysuccinimide esters (more commonly, active esters derived from carboxylic acids; e.g., p-nitrophenyl esters), acid hydrazides, and the like, and other linking groups, such as aldehydes, sulfonyl chlorides, sulfonyl hydrazides, epoxides, hydroxyl groups, thiol groups, maleimides, aziridines, acryloyls, halo groups, biotin, 2-iminobiotin, etc. Such linking groups are known and are described in U.S. Pat. Nos. 6,728,129; 6,657,884; 6,212,093; and 6,208,553.

[0107] Other functional groups that may be attached to the compounds of the invention (e.g., compounds comprising a porphyrin of Formula Ia or Formula Ib attached to a hydroporphyrin of Formula IIa-IId) and / or that may adjust or tune the solubility properties of the compounds include, but are not limited to, hydrophobic groups, hydrophilic groups, polar groups, and / or amphiphilic groups. Polar groups include carboxylic acid, sulfonic acid, guanidinium, carbohydrate, hydroxy, amino acid, pyridinium, imidazolium, and the like. Such groups may be attached to substituents that are linear or branched alkyl (e.g., swallowtail), aryl, heteroaryl, heteroalkyl (e.g., oligoethylene glycol), peptides, polysaccharides, and the like. Suitable hydrophilic groups may include polyol or polyalkylene oxide groups, such as those described above, including linear and / or branched polyols, with specific examples including, but not limited to, poly(propylene glycol), polyethylene-polypropylene glycol, and / or poly(ethylene glycol). In some embodiments, the hydrophilic group may have a number average molecular weight of 20,000 to 40,000 or 60,000. Suitable hydrophilic groups and methods of their coupling are known and described, for example, in U.S. Pat. Nos. 4,179,337; 5,681,811; 6,524,570; 6,656,906; 6,716,811; and 6,720,306. For example, a compound can be pegylated with a single 40,000 molecular weight polyethylene glycol moiety attached to the compound of the invention. Suitable hydrophilic groups also include linear or branched alkyl groups substituted with ionic or polar groups, examples of which include, but are not limited to, swallow tail groups, such as those described in U.S. Pat. No. 8,530,459 by Borbas and Lindsey.In some embodiments, hydrophilic groups may be attached at one or more sites of the porphyrins or hydroporphyrins of the invention, e.g., covalently attached thereto, in accordance with known techniques (e.g., to the N-terminus of the peptide), to facilitate their delivery or to improve their stability.

[0108] Targeting groups include biomolecules, such as antibodies, proteins, peptides, and nucleic acids, each of which may be attached by a linking group. Particles, such as nanoparticles, glass beads, may be attached by a linking group. When such additional compounds are attached to the compounds of the present invention, they may be directly bonded to the compounds or may be attached by an intermediate group, such as a linker or hydrophilic group.

[0109] In some embodiments of the present invention, the compound of the present invention further comprises an auxochrome, optionally wherein the auxochrome is attached to an atom of a porphyrin (e.g., the first porphyrin) and / or an atom of a hydroporphyrin (e.g., the first hydroporphyrin) present in the compound. Any of the substituents described with reference to Formulae Ia-Ib and IIa-IId can be an auxochrome, but in some embodiments of the present invention, the auxochrome is an acyl group, an acyloxy group, an ester group (e.g., an alkyloxycarbonyl group or an aryloxycarbonyl group), a carboxylic acid group, a cyano group, a sulfonyl group, a sulfoxyl group, an alkene group, an alkyne group, an arene group, an amino group, a nitro group, a hydroxyl group, a mercapto group, and / or an alkoxy group, which may be optionally substituted or unsubstituted. In some embodiments, the auxochrome can be on any meso or beta site around the heterocyclic macrocycle. In some embodiments, the auxochrome can be present on the 2-, 3-, 12-, and / or 13-positions of the hydroporphyrin.

[0110] In some embodiments, the compounds of the invention may have the general structure shown in FIG. 1, where the donor is at least one porphyrin (e.g., having formula Ia or Ib), the acceptor is a hydroporphyrin (e.g., having formula IIa-IId), and the tether is a linking group that provides space (distance) between the hydroporphyrin and the bioconjugable group.

[0111] The surface attachment group may be a reactive group directly attached to the porphyrin or hydroporphyrin or may be attached to the porphyrin or hydroporphyrin by an intervening linker. The surface attachment group may be in protected or unprotected form. Linking groups linked to the surface attachment group may include, for example, aryl, alkyl, alkenyl, alkynyl, heteroaryl, heteroalkyl, oligoethylene glycol (e.g., PEG), peptide, polysaccharide, and the like. Examples of surface attachment groups (reactive sites or groups in unprotected form) include, but are not limited to, alkenes, alkynes, alcohols, thiols, selenyl, phosphono, telluryl, cyano, amino, formyl, halogen atoms, boryl, and carboxylic acid surface attachment groups, such as, but not limited to, the following compounds: 4-Carboxyphenyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 2-(4-carboxyphenyl)ethynyl, 4-(2-(4-carboxyphenyl)ethynyl)phenyl, 4-carboxymethylphenyl, 4-(3-carboxypropyl)phenyl, 4-(2-(4-carboxymethylphenyl)ethynyl)phenyl;4-hydroxyphenyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-(4-hydroxyphenyl)ethynyl, 4-(2-(4-hydroxyphenyl)ethynyl)phenyl, 4-hydroxymethylphenyl, 4-(2-hydroxyethyl)phenyl, 4-(3-hydroxypropyl)phenyl, 4-(2-(4-hydroxymethylphenyl)ethynyl)phenyl;4-mercaptophenyl, mercaptomethyl, 2-mercaptoethyl, 3-mercaptopropyl, 2-(4-mercaptophenyl)ethynyl, 4-(2-(4-mercaptophenyl)ethynyl, 4-(2-(4-mercaptomethylphenyl)ethynyl)phenyl; 4-mercaptomethylphenyl, 4-(2-mercaptoethyl)phenyl, 4-(3-mercaptopropyl)phenyl, 4-(2-(4-mercaptomethylphenyl)ethynyl)phenyl; 4-selenylphenyl, selenylmethyl, 2-selenylethyl, 3-selenylpropyl, 2-(4-selenylphenyl)ethynyl, 4-selenylmethylphenyl, 4-(2-selenylethyl)phenyl, 4-(3-selenylpropyl)phenyl; 4-selenylmethylphenyl, 4-(2-(4-selenylphenyl)ethynyl)phenyl;4-tellurylphenyl, tellurylmethyl, 2-tellurylethyl, 3-tellurylpropyl, 2-(4-tellurylphenyl)ethynyl, 4-(2-(4-tellurylphenyl)ethynyl)phenyl, 4-tellurylmethylphenyl, 4-(2-tellurylethyl)phenyl, 4-(3-tellurylpropyl)phenyl, 4-(2-(4-tellurylmethylphenyl)ethynyl)phenyl; 4-(dihydroxyphosphoryl)phenyl,(dihydroxyphosphoryl)methyl,2-(dihydroxyphosphoryl)ethyl,3-(dihydroxyphosphoryl)propyl,2-[4-(dihydroxyphosphoryl)phenyl]ethynyl,4-[2-[4-(dihydroxyphosphoryl)phenyl]ethynyl]phenyl,4-[(dihydroxyphosphoryl)methyl]phenyl,4-[2-(dihydroxyphosphoryl)ethyl]phenyl,4-[2-[4-(dihydroxyphosphoryl)methylphenyl]ethynyl]phenyl;4-(hydroxy(mercapto)phosphoryl)phenyl,( hydroxy(mercapto)phosphoryl)methyl, 2-(hydroxy(mercapto)phosphoryl)ethyl, 3-(hydroxy(mercapto)phosphoryl)propyl, 2-[4-(hydroxy(mercapto)phosphoryl)phenyl]ethynyl, 4-[2-[4-(hydroxy(mercapto)phosphoryl)phenyl]ethynyl]phenyl, 4-[(hydroxy(mercapto)phosphoryl)methyl]phenyl, 4-[2-(hydroxy(mercapto)phosphoryl)ethyl]phenyl, 4-[2-[4-(hydroxy(mercapto)phosphoryl)methylphenyl]ethynyl]phenyl; 4-cyanophenyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 2-(4-cyanophenyl)ethynyl, 4-[2-(4-cyanophenyl)ethynyl]phenyl, 4-(cyanomethyl)phenyl, 4-(2-cyanoethyl)phenyl, 4-[2-[4-(cyanomethyl)phenyl]ethynyl]phenyl; 4-cyanobiphenyl;4-aminophenyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 2-(4-aminophenyl)ethynyl, 4-[2-(4-aminophenyl)ethynyl]phenyl, 4-aminobiphenyl; 4-formylphenyl, 4-bromophenyl, 4-iodophenyl, 4-vinylphenyl, 4-ethynylphenyl, 4-allylphenyl, 4-[2-(trimethylsilyl)ethynyl]phenyl, 4-[2-(triisopropylsilyl)ethynyl]phenyl, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl; Formyl, bromo, iodo, bromomethyl, chloromethyl, ethynyl, vinyl, allyl; 4-(ethynyl)biphen-4-yl, 4-[2-(triisopropylsilyl)ethynyl]biphen-4-yl, 3,5-diethynylphenyl; 4-(Bromomethyl)phenyl, and 2-bromoethyl.

[0112] In addition to the monodentate linker-surface attachment groups described above, polydentate linkers may be used [Nikitin, K. Chem. Commun. 2003, 282-283; Hu, J.; Mattern, DLJ Org. Chem. 2000, 65, 2277-2281; Yao, Y.; Tour, JM J Org. Chem. 1999, 64, 1968-1971; Fox, MA et al. Langmuir, 1998, 14, 816-820; Galoppini, E.; Guo, WJ Am. Chem. Soc. 2001, 123, 4342-4343; Deng, X. et al. J. Org. Chem. 2002, 67, 5279-5283; Hector Jr., LGet al. Surface Science, 2001, 494, 1-20; Whitesell, JK; Chang, HK Science, 1993, 261, 73-76; Galoppini, E. et al. J. Am. Chem. Soc. 2002, 67, 7801-7811; Siiman, O. et al. Bioconjugate Chem. 2000, 11, 549-556]. Tripodal linkers bearing thiol, carboxylic acid, alcohol, or phosphonic acid units are particularly attractive for firmly anchoring molecular devices on flat surfaces. Specific examples of such linkers are built around triphenylmethane or tetraphenylmethane units and include: 1,1,1-tris[4-(S-acetylthiomethyl)phenyl]methyl, 4-{1,1,1-tris[4-(S-acetylthiomethyl)phenyl]methyl}phenyl, 1,1,1-tris[4-(dihydroxyphosphoryl)phenyl]methyl, 4-{1,1,1-tris[4-(dihydroxyphosphoryl)phenyl]methyl}phenyl, 1,1,1-tris[4-dihydroxyphosphorylmethyl)phenyl]methyl, and 4-{1,1,1-tris[4-(dihydroxyphosphorylmethyl)phenyl]methyl}phenyl; All are described in U.S. Patent Application Serial No. 10 / 867,512, filed June 14, 2004, by BalakuMar, MuthukuMaran and Lindsey. See also U.S. Patent Application Publication No. 20050096465, published May 5, 2005, by Lindsey, Loewe, MuthukuMaran, and Ambroise, particularly paragraph 51 thereof. Additional examples of multidentate linkers include, but are not limited to, the following: Alkene surface attachment groups (2, 3, or 4 carbon atoms), e.g., 3-vinylpenta-1,4-dien-3-yl, 4-(3-vinylpenta-1,4-dien-3-yl)phenyl, 4-(3-vinylpenta-1,4-dien-3-yl)biphen-4'-yl, 4-arylhepta-1,6-dien-4-yl, 4-(4-allylhepta-1,6-dien-4-yl)phenyl, 4-(4-arylhepta-1,6-dien-4-yl)biphen-4'-yl, 5-(1-buten-4-yl)nona-1,8-dien-5-yl, 4-[5-(1-buten-4-yl)nona-1,8-dien-5-yl]phenyl, 4-[5-(1-buten-4-yl)nona-1,8-dien-5-yl]biphen-4'-yl, etc.; Alkyne surface attachment groups (2, 3, or 4 carbon atoms), e.g. 3-ethynylpenta-1,4-diyn-3-yl, 4-(3-ethynylpenta-1,4-diyn-3-yl)phenyl, 4-(3-ethynylpenta-1,4-diyn-3-yl)biphen-4'-yl, 4-propargylhepta-1,6-diyn-4-yl, 4-(4-propargylhepta-1,6-diyn-4-yl)phenyl, 4-(4-propargylhepta-1,6-diyn-4-yl)biphen-4-yl, 5-(1-butyn-4-yl)nona-1,8-diyn-5-yl, 4-[5-(1-butyn-4-yl)nona-1,8-diyn-5-yl]phenyl, 4-[5-(1-butyn-4-yl)nona-1,8-diyn-5-yl]biphen-4-yl; Alcohol surface attachment groups (1, 2, or 3 carbon atoms), e.g. 2-(hydroxymethyl)-1,3-dihydroxyprop-2-yl, 4-[2-(hydroxymethyl)-1,3-dihydroxyprop-2-yl]phenyl, 4-[2-(hydroxymethyl)-1,3-dihydroxyprop-2-yl]biphen-4-yl, 3-(2-hydroxyethyl)-1,5-dihydroxypent-3-yl, 4-[3-(2-hydroxyethyl)-1,5-dihydroxypent-3-yl]phenyl, 4-[3-(2-hydroxyethyl)-1,5-dihydroxypent-3-yl]biphen-4-yl, 4-(3-hydroxypropyl)-1,7-dihydroxyhept-4-yl, 4-[4-(3-hydroxypropyl)-1,7-dihydroxyhept-4-yl]phenyl, 4-[4-(3-hydroxypropyl)-1,7-dihydroxyhept-4-yl]biphen-4-yl, etc.; Thiol surface attachment groups (1, 2, or 3 carbon atoms), e.g., 2-(mercaptomethyl)-1,3-dimercaptoprop-2-yl, 4-[2-(mercaptomethyl)-1,3-dimercaptoprop-2-yl]phenyl, 4-[2-(mercaptomethyl)-1,3-dimercaptoprop-2-yl]biphen-4-yl, 3-(2-mercaptoethyl)-1,5-dimercaptopent-3-yl, 4-[3-(2-mercaptoethyl)-1,5-dimercaptopent-3-yl]phenyl, 4-[3-(2-mercaptoethyl)-1,5-dimercaptopent-3-yl]biphen-4-yl, 4-(3-mercaptopropyl)-1,7-dimercaptohept-4-yl, 4-[4-(3-mercaptopropyl)-1,7-dimercaptohept-4-yl]phenyl, 4-[4-(3-mercaptopropyl)-1,7-dimercaptohept-4-yl]biphen-4-yl, etc.; Selenyl surface attachment groups (1, 2, or 3 carbon atoms), e.g., 2-(selenylmethyl)-1,3-diselenylprop-2-yl, 4-[2-(selenylmethyl)-1,3-diselenylprop-2-yl]phenyl, 4-[2-(mercaptomethyl)-1,3-dimercaptoprop-2-yl]biphen-4-yl, 3-(2-selenylethyl)-1,5-diselenylpent-3-yl, 4-[3-(2-selenylethyl)-1,5-diselenylpent-3-yl]phenyl, 4-[3-(2-selenylethyl)-1,5-diselenylpent-3-yl]biphen-4-yl, 4-(3-selenylpropyl)-1,7-diselenylhept-4-yl, 4-[4-(3-selenylpropyl)-1,7-diselenylhept-4-yl]phenyl, 4-[4-(3-selenylpropyl)-1,7-diselenylhept-4-yl]biphen-4-yl, etc.; Phosphono surface attachment groups (1, 2, or 3 carbon atoms), such as 2-(phosphonomethyl)-1,3-diphosphonoprop-2-yl, 4-[2-(phosphonomethyl)-1,3-diphosphonoprop-2-yl]phenyl, 4-[2-(phosphonomethyl)-1,3-diphosphonoprop-2-yl]biphen-4-yl, 3-(2-phosphonoethyl)-1,5-diphosphonopent-3-yl, 4-[3-(2-phosphonoethyl)-1,5-diphosphonopent-3-yl]phenyl, 4-[3-(2-phosphonoethyl)-1,5-diphosphonopent-3-yl]biphen-4-yl, 4-(3-phosphonopropyl)-1,7-diphosphonohept-4-yl, 4-[4-(3-phosphonopropyl)-1,7-diphosphonohept-4-yl]phenyl, 4-[4-(3-phosphonopropyl)-1,7-diphosphonohept-4-yl]biphen-4-yl, and the like; Carboxylic acid surface attachment groups (1, 2, or 3 carbon atoms), such as 2-(carboxymethyl)-1,3-dicarboxyprop-2-yl, 4-[2-(carboxymethyl)-1,3-dicarboxyprop-2-yl]phenyl, 4-[2-(carboxymethyl)-1,3-dicarboxyprop-2-yl]biphen-4-yl, 3-(2-carboxyethyl)-1,5-dicarboxypent-3-yl, 4-[3-(2-carboxyethyl)-1,5-dicarboxypent-3-yl]phenyl, 4-[3-(2-carboxyethyl)-1,5-dicarboxypent-3-yl]biphen-4-yl, 4-(3-carboxypropyl)-1,7-dicarboxyhept-4-yl, 4-[4-(3-carboxypropyl)-1,7-dicarboxyhept-4-yl]phenyl, 4-[4-(3-carboxypropyl)-1,7-dicarboxyhept-4-yl]biphen-4-yl and the like.

[0113] It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be in either the (R) or (S) configuration, or a combination thereof. Thus, the compounds provided herein may be enantiomerically pure or may be a mixture of stereoisomers or diastereomers. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Thus, one skilled in the art will recognize that administration of a compound in the (R) form of a compound that undergoes epimerization in vivo is equivalent to administration of the compound in the (S) form.

[0114] In some embodiments of the present invention, the compound of the present invention further comprises at least one additional chromophore, optionally, wherein the at least one additional chromophore is perylene, a carotenoid, dipyrrinatoboron difluoride, or a bis(dipyrrinato)metal complex.

[0115] Also provided in accordance with embodiments of the present invention are particles comprising the compounds of the present invention. In some embodiments, the particles are microparticles or nanoparticles. A plurality of such particles are also provided herein.

[0116] In some embodiments, the particles comprise a shell and a core. In some embodiments, the compounds of the present invention are present in the core. In some embodiments, the compounds of the present invention are encapsulated in a polymer, and the polymer forms the shell, and optionally, the polymer comprises one or more hydrophobic units and one or more hydrophilic units, and optionally comprises a bioconjugated group. In some embodiments, the particles maintain the compounds of the present invention in a non-aggregated state. In some embodiments, foldamers or single chain nanoparticles (SCNPs) can be used to encapsulate or contain the compounds of the present invention. The compounds of the present invention can be used as dyes and / or as acceptor dyes and donor emitters in the polymers and / or particles described in U.S. Patent Publication No. 2020 / 0385583, International Application No. PCT / US19 / 054008, and International Application No. PCT / US20 / 61285, which are incorporated herein by reference in their entirety. In some embodiments, the polymers and / or particles of the present invention have a structure as described in U.S. Application Publication No. 2020 / 0385583, International Application No. PCT / US19 / 054008, and International Application No. PCT / US20 / 61285, which are incorporated by reference in their entireties.

[0117] In certain embodiments of the invention, the particles of the invention comprise a compound of the invention attached to a polymer such that the resulting compound has the structure of Formula IIIa or Formula IIIb: ABC(IIIa), also h CAB(IIIb) where A is a compound of the invention; B is a polymer; and C is an optional bioconjugated group. In some embodiments, C is not present in the particle (i.e., the particle lacks a bioconjugated group), and thus the particle has the structure AB, where A is a compound of the invention and B is a polymer. In some embodiments, C is present in the particle. In some embodiments, polymer B has a molecular weight in the range of about 1,000 Da to about 175,000 Da, including a molecular weight of about 1,000, about 5,000, about 10,000, about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, about 100,000, about 110,000, about 120,000, about 130,000, about 140,000, about 150,000, about 160,000, about 170,000, about 175,000 Da, and any range defined therebetween.

[0118] In some embodiments of the present invention, the compound of the present invention is attached to the surface of a particle (e.g., nanoparticle).In some embodiments, the particle comprises polystyrene and / or silica.In some embodiments, the compound of the present invention is attached to a particle and / or bead as described in U.S. Patent Application Publication No. 2019 / 0264102, the entirety of which is incorporated herein by reference.

[0119] In some embodiments of the present invention, the particles of the present invention are soluble in water or aqueous solution.In certain embodiments, the particles of the present invention have a solubility in water at room temperature of about 1 mg / mL, about 10, about 50, or about 100 mg / mL or more (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg / L, or any range defined therebetween).

[0120] The methods of the invention may provide for the synthesis of compounds of the invention. In some embodiments, at least one porphyrin of formula Ia-Ib and at least one hydroporphyrin of formula IIa-IId may be reacted to attach at least two compounds, thereby forming a compound of the invention. In some embodiments, intermediates used in forming compounds of the invention may have structures as shown in FIG. 2, which shows exemplary porphyrins, optionally including one or more substituents (e.g., auxochromes, linking groups, bioconjugable groups, etc.). In some embodiments, intermediates used in forming compounds of the invention may have structures as shown in FIG. 3 and FIG. 4, which show exemplary chlorins and bacteriochlorins, respectively, optionally including one or more substituents (e.g., auxochromes, linking groups, bioconjugable groups, etc.).

[0121] General methods of porphyrin and hydroporphyrin synthesis, including the incorporation of functional groups on the ring, are known in the art. Examples include, but are not limited to, the compounds and methods described in U.S. Pat. Nos. 8,097,609, 10,919,904, and 10,836,774, and International Publication Nos. WO2020 / 236828 and WO2020 / 236818, which are incorporated herein by reference in their entirety. A porphyrin having a first substituent or group thereon may be reacted with a hydroporphyrin having a second substituent or group thereon that is reactive with the first substituent or group of the porphyrin. In some embodiments, the first substituent or group, the second substituent or group, or their reaction product, once reacted, forms a direct bond or linking group between the porphyrin and the hydroporphyrin. Any of the linking groups described herein may be formed in this manner. Linking groups, attachment groups, bioconjugable groups, and targeting groups can be added prior to attaching any two of the heterocyclic macrocycles, during attachment of the heterocyclic macrocycles, and / or after attachment of such heterocyclic macrocycles.

[0122] The methods and intermediates described herein may be useful for the synthesis of the compounds described herein. Such compounds may be useful per se or in further modified form (e.g., as salts, metallated compounds, conjugates, and / or prodrugs) for diagnostic and / or therapeutic purposes, as well as other compounds described for photodynamic therapy as described in U.S. Patent Application Publication No. 2004 / 0044197 to Pandey et al. and described in more detail below. In some embodiments, the compounds of the present invention may be used in applications where wavelength tuning and / or bioconjugation is utilized and / or desired. The methods and / or compounds of the invention may provide for one or more (e.g., 1, 2, 3, 4, 5, or more) different substituents to be attached to one or more (e.g., 1, 2, 3, 4, 5, or more) positions on the compounds of the invention (e.g., on the AD moiety but not on the BC moiety, or vice versa), which may be advantageous in applications including, but not limited to, wavelength tuning and / or bioconjugation reactions.

[0123] The compounds of the present invention may have desirable photophysical properties. In some embodiments of the present invention, for compounds of the present invention that include a porphyrin (e.g., a first porphyrin) and a hydroporphyrin (e.g., a first hydroporphyrin), the lowest energy singlet excited state of the porphyrin is greater than the lowest energy singlet excited state of the hydroporphyrin. This promotes singlet energy transfer from the porphyrin to the hydroporphyrin. In some embodiments, the energy transfer pathway is effective enough to dominate the intrinsic excited state de-excitation pathway of the porphyrin, including fluorescence emission. Instead, fluorescence is generated from the acceptor hydroporphyrin after receiving energy transfer from the porphyrin. Thus, in some embodiments, the fluorescent properties of the compound may be substantially unaffected by the porphyrin.

[0124] In some embodiments, the compound of the present invention is excited by wavelengths in the violet region of visible light spectrum.In some embodiments, the compound of the present invention is excited by wavelengths in the range of about 350nm or more, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200 or about 1300nm or less, for example, about 350nm or more, about 360nm, about 370nm, about 380nm, about 390nm, about 400nm, about 410nm, about 420nm, about 430nm, about 440nm, about 450nm, about 460nm, about 470nm, about 480nm, about 490nm, about 500nm, about 600nm, about 700nm, about 800nm, about 900nm, about 1000nm, about 1100nm, about 1200nm or less, including the above wavelengths and any ranges defined therebetween. The compounds of the present invention may be excited with a laser (e.g., a laser emitting a wavelength in the range of about 350 nm or more, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, or about 1300 nm or less). In some embodiments, the compounds of the present invention are excited with a wavelength in the range of about 350 nm to about 500 nm. In some embodiments, the compounds of the present invention are excited with a wavelength in the range of about 375 nm to about 440 nm. In some embodiments, the compounds of the present invention are excited with a wavelength of about 405 nm. In some embodiments, the compounds of the present invention are excited with a wavelength of about 445 nm. In some embodiments, the compounds of the present invention are excited with a violet laser, optionally with a wavelength of about 407 nm. In some embodiments, the compounds of the present invention are excited with a wavelength for use in flow cytometry and / or are used in flow cytometry. In some embodiments, the compounds of the present invention can be exposed to light having a wavelength in the range of about 675 nm to about 1300 nm and / or used in and / or for photoacoustic imaging.

[0125] In some embodiments, the compounds of the present invention emit light at wavelengths in the red and / or near infrared regions of the visible light spectrum. In some embodiments, the compounds of the present invention emit light (e.g., emission maximum) at wavelengths ranging from about 610 nm to about 2500 nm, and in some cases at wavelengths ranging from about 610 nm or greater to about 625 nm or greater and up to about 810 nm. In some embodiments, the compounds of the present invention emit light at wavelengths in the range of about 610, about 620, about 630, about 640, about 650, about 660, about 670, about 680, about 690, about 700, about 710, about 720, about 730, about 740, about 750, about 760, about 770, about 780, about 790, about 800, about 810, about 850, about 900, about 950, about 1000, about 1250, about 1500, about 1750, about 2000, about 2250, or about 2500 nm, and any range of wavelengths defined therebetween. In some embodiments, the compounds of the present invention emit heat, which can be detected by methods known in the art (e.g., using ultrasound imaging and / or photoacoustic imaging).

[0126] In some embodiments, the compound of the present invention comprises a first porphyrin and a first hydroporphyrin, and the compound has a brightness greater than that of the first porphyrin alone and / or greater than that of the first hydroporphyrin alone, optionally wherein the brightness of the compound is greater than the sum of the brightness of the first porphyrin and the brightness of the first hydroporphyrin.In some embodiments, the compound of the present invention comprises a first porphyrin and a first hydroporphyrin, and the compound has a brightness that is increased compared to that of the first hydroporphyrin alone, optionally wherein the brightness of the compound is increased by about 2-fold, 4-fold, 6-fold, 8-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, or more compared to that of the hydroporphyrin alone.As used herein, the term "brightness" refers to the product (ε×φ) of molar extinction coefficient and fluorescence quantum yield. See, e.g., Lavis DL, Raines RT (2008) "Bright Ideas for Chemical Biology" ACS Chem. Biol. 3:142-155.

[0127] In some embodiments, the compounds of the present invention have a molecular weight of about 10,000 M -1 cm -1 More than about 110,000, about 200,000, about 300,000, about 400,000, or 500,000M -1 cm -1 The following ranges, for example, about 10,000, about 11,000, about 12,000, about 13,000, about 14,000, about 15,000, about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, about 100,000, about 150,000, about 200,000, about 250,000, about 300,000, about 350,000, about 400,000, about 450,000, or about 500,000M -1 cm -1 , and any range defined therebetween. In some embodiments, the compounds of the present invention have a brightness at the absorption maximum of about 8,000 M -1cm -1 ~About 90,000M -1 cm -1 For example, about 8,000, about 9,000, about 10,000, about 15,000, about 20,000, about 25,000, about 30,000, about 35,000, about 40,000, about 45,000, about 50,000, about 55,000, about 60,000, about 65,000, about 70,000, about 75,000, about 80,000, about 85,000, about 88,000, about 90,000, about 100,000, about 150,000, about 200,000, about 250,000, about 300,000, about 350,000, about 400,000, about 450,000, or about 500,000M -1 cm -1 The brightness upon excitation at 405 nm is in the above ranges inclusive, and any range defined therebetween.

[0128] In some embodiments, the compounds of the present invention include a first porphyrin and a first hydroporphyrin, and the compound has an emission wavelength of the first porphyrin that is reduced compared to the emission wavelength of the first porphyrin alone or is absent.

[0129] In some embodiments, a compound of the present invention comprises a first porphyrin and a first hydroporphyrin, and the compound has a fluorescence quantum yield of energy transfer from the first porphyrin to the first hydroporphyrin of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, optionally wherein the emission wavelength of the first hydroporphyrin is different from and / or distinguishable from the emission wavelength of the first porphyrin.

[0130] In some embodiments, the compounds of the present invention have an energy transfer from the first porphyrin to the first hydroporphyrin that is about 100 picoseconds or less.

[0131] In some embodiments, the first porphyrin has an emission peak with a first intensity, and the first hydroporphyrin has an emission peak with a second intensity, and the first intensity is 5% or less than the second intensity.

[0132] Surprisingly, in some embodiments, the compounds of the present invention exhibit a significant reduction in absorbance and / or emission between the absorbance and emission peaks ("middle band"), which may be advantageous for certain applications, such as multiplex applications. In some embodiments, the compounds include a first porphyrin and a first hydroporphyrin, and the compounds have an absorption and emission spectrum that includes an emission peak from the first hydroporphyrin having a second intensity, and there are no additional emission peaks or emission peaks with an intensity greater than the second intensity between the excitation wavelength of the compound and the emission peak.

[0133] In some embodiments, the compounds of the present invention surprisingly exhibit a relatively clear emission band. In some embodiments, the first hydroporphyrin of the compounds has an emission wavelength with a full width half maximum in the range of about 10 to about 50 nm, for example, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, including the above ranges, and any ranges defined therebetween. In some embodiments, the full width at half maximum of the compound is in the range of about 14 to about 31 nm. Full width at half maximum is the distance between the rise of the peak at half its maximum amplitude and the fall of the peak at half its maximum amplitude.

[0134] In some embodiments, the first porphyrin alone has an absorbance maximum of at least about 200,000 M-1 cm -1 (at least about 220,000, at least about 250,000, at least about 300,000, and at least about 350,000 M -1 cm -1 In some embodiments, the first porphyrin alone has a molar extinction coefficient of at least about 200,000 M at 405 nm. -1 cm -1 (at least about 205,000, at least about 220,000, at least about 230,000, and at least about 250,000 M -1 cm -1 (including )

[0135] In some embodiments, the compounds of the present invention have a molar extinction coefficient and / or a fluorescence quantum yield greater than the molar extinction coefficient and / or a fluorescence quantum yield, respectively, of the first hydroporphyrin alone. -1 cm -1 or more, about 450,000, about 750,000, about 1,000,000, or about 1,250,000M -1 cm -1In the following ranges, for example, about 124,000, about 130,000, about 140,000, about 150,000, about 160,000, about 170,000, about 180,000, about 190,000, about 200,000, about 210,000, about 220,000, about 230,000, about 240,000, about 250,000, about 260,000, about 270,000, about 280,000, about 290,000, about 300,000, about 310,000, about 320,000, about 330,000, about 340,000, about 350,000 , about 360,000, about 370,000, about 380,000, about 390,000, about 400,000, about 410,000, about 420,000, about 430,000, about 440,000, about 450,000, about 500,000, about 550,000, about 600,000, about 650,000, about 700,000, about 750,000, about 800,000, about 850,000, about 900,000, about 950,000, about 1,000,000, about 1,100,000, about 1,200,000, or about 1,250,000M -1 cm -1 The compounds of the present invention have a molar extinction coefficient with a maximum absorbance in the ranges above and including, as well as any ranges defined therebetween. The compounds of the present invention can be placed in solution to determine their molar extinction coefficient peaks at the indicated wavelengths; and the compounds may exhibit additional peaks outside this range, or multiple peaks within this range. In some embodiments, the compounds of the present invention have a molar extinction coefficient of 110,000 M at wavelengths of about 350 or 375 nm or more and about 440 or 500 nm or less. -1 cm -1 or more, about 350,000, about 450,000, about 750,000, about 1,000,000, or about 1,250,000M -1 cm -1, for example, about 115,000, about 120,000, about 130,000, about 140,000, about 150,000, about 160,000, about 170,000, about 180,000, about 190,000, about 200,000, about 210,000, about 220,000, about 230,000, about 240,000, about 250,000, about 260,000, about 270,000, about 280,000, about 290,000, about 300,000, about 310,000, about 320,000, about 330,000, about 340,000, about 350, 000, about 360,000, about 370,000, about 380,000, about 390,000, about 400,000, about 410,000, about 420,000, about 430,000, about 440,000, about 450,000, about 500,000, about 550,000, about 600,000, about 650,000, about 700,000, about 750,000, about 800,000, about 850,000, about 900,000, about 950,000, about 1,000,000, about 1,100,000, about 1,200,000, or about 1,250,000M -1 cm -1 In some embodiments, the compounds of the present invention have a molar extinction coefficient of about 110,000 M -1 cm -1 or more, about 350,000, about 380,000, about 450,000, about 750,000, about 1,000,000, or about 1,250,000M -1 cm -1For example, about 115,000, about 120,000, about 130,000, about 140,000, about 150,000, about 160,000, about 170,000, about 180,000, about 190,000, about 200,000, about 210,000, about 220,000, about 230,000, about 240,000, about 250,000, about 260,000, about 270,000, about 280,000, about 290,000, about 300,000, about 310,000, about 320,000, about 330,000, about 340,000, about 350, 000, about 360,000, about 370,000, about 380,000, about 390,000, about 400,000, about 410,000, about 420,000, about 430,000, about 440,000, about 450,000, about 500,000, about 550,000, about 600,000, about 650,000, about 700,000, about 750,000, about 800,000, about 850,000, about 900,000, about 950,000, about 1,000,000, about 1,100,000, about 1,200,000, or about 1,250,000M -1 cm -1 , inclusive of the above ranges, as well as any ranges defined therebetween.

[0136] In some embodiments, the compounds of the present invention have a fluorescence quantum yield at 405 nm in the range of 0.04 to 0.35, for example, the above ranges including 0.04, 0.10, 0.15, 0.20, 0.25, 0.30, 0.34, 0.35, and any ranges defined therebetween.

[0137] In some embodiments, the compounds of the present invention have a second lowest (Qx) energy absorption band that is red-shifted (e.g., by at least 20 nm) relative to the excitation wavelength of the first porphyrin. In some embodiments, the compounds of the present invention are red-shifted such that they do not interact or do not substantially interact with the 488 nm laser emission.

[0138] In some embodiments, the compounds of the present invention have a peak emission wavelength and a peak excitation wavelength, and the difference between the peak emission wavelength and the peak excitation wavelength is at least 50 nm, and in some embodiments, at least 80 nm.

[0139] In some embodiments, the compounds of the present invention have an emission wavelength from the first porphyrin that does not overlap with the emission wavelength from the first hydroporphyrin. In some embodiments, the compounds of the present invention have an emission wavelength from the first porphyrin that does not overlap with the peak emission wavelength from the first hydroporphyrin.

[0140] Compositions comprising the compound of the present invention (also referred to herein as "active compound") and / or particles are also provided according to the present invention.In some embodiments, the composition comprises water, and the compound and / or particles are present in water, optionally, wherein the compound and / or particles have a water solubility in the range of about 1 mg / mL or more, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, or about 100 mg / mL or less at room temperature.

[0141] In some embodiments, the composition is devoid of organic solvent.In some embodiments, the composition of the present invention comprises a first compound (e.g., a first light-emitting compound) having a first absorption and emission spectrum comprising a first emission wavelength, and a second compound (e.g., a second light-emitting compound) having a second absorption and emission spectrum comprising a second emission wavelength, where the first emission wavelength and the second emission wavelength are different and / or distinct, and the first compound and the second compound are both compounds of the present invention.In some embodiments, the first compound and the second compound are each excited by the same excitation wavelength.Thus, in such embodiments, a single absorbance wavelength can be used to generate a variety of different emission wavelengths.

[0142] In some embodiments, additional chromophores and / or compounds (e.g., luminescent compounds) may be included in the compositions of the present invention. Examples of such compounds include, but are not limited to, perylene, carotenoids, dipyrrinoatoborondifluoride, or bipyrrinato metal complexes. In some embodiments, such additional chromophores and / or compounds may enhance absorption in selected spectral regions.

[0143] The compounds of the present invention may be provided as pharma- ceutically acceptable salts, including but not limited to amine salts, such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine, and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine, and tris(hydroxymethyl)aminomethane; Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkyl esters of ...

[0144] The active compounds of the present invention include prodrugs of the compounds described herein. As described above, a "prodrug" is a compound that, upon in vivo administration, is metabolized or otherwise converted into the biologically, medicamentously, or therapeutically active form of the compound by one or more steps or processes. To produce the prodrug, the pharmacoactive compound is modified so that the active compound is regenerated by metabolic processes. The prodrug is designed to change the metabolic stability or transport properties of the drug, or to mask side effects or toxicity, improve the taste of the drug, or to change other properties or characteristics of the drug. With knowledge of in vivo pharmacodynamic processes and drug metabolism, one skilled in the art can design a prodrug of a pharmacoactive compound, given the compound (see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).

[0145] In some embodiments, a "neat" composition may be provided that consists of an active compound of the invention or a pharma- ceutically acceptable salt, prodrug, or conjugate thereof (e.g., a conjugate with a targeting agent, such as a protein, peptide, or antibody).

[0146] In some embodiments, the invention may provide a composition that comprises or consists essentially of an active compound of the invention (or a pharma- ceutically acceptable salt, prodrug, or conjugate thereof (e.g., a conjugate with a targeting agent, e.g., a protein, peptide, or antibody) in a solvent. The amount of solvent is not critical and may comprise from about 0.01 or 1 weight percent or more to about 99 or 99.99 weight percent or less of the composition. It will be understood that agitation may be required to bring aggregated particles back into solution before determining molar absorption, although some degree of aggregation may actually be desired for practical use of the composition. Suitable solvents will depend on the particular compound and the intended use of the compound, but include both organic solvents, aqueous solvents, and combinations thereof.

[0147] The composition, either in the "neat" form or mixed with a solvent, may have or show a loss of not more than 10, 15 or 20% by weight of the compound of the invention (due to its decomposition) when stored in a sealed container (e.g., flask, ampoule or vial) in the absence of ambient light at room temperature for at least 3 or 4 months. Decomposition may be determined by spectroscopy, thin layer chromatography, NMR spectroscopy, and / or mass spectrometry, according to known techniques.

[0148] According to some embodiments, pharmaceutical compositions are provided. The pharmaceutical compositions of the present invention may comprise a therapeutically effective amount of one or more compounds of the present invention in a pharma- ceutical acceptable carrier, which may be useful for the prevention, treatment, and / or amelioration of one or more symptoms of diseases or disorders associated with hyperproliferative tissue or neovascularization, or diseases or disorders involving hyperproliferative tissue or neovascularization. Diseases or disorders associated with hyperproliferative tissue or neovascularization include, but are not limited to, cancer, psoriasis, atherosclerosis, heart disease, and age-related macular degeneration. Pharmaceutical carriers suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for a particular mode of administration.

[0149] The pharmaceutical compositions may exhibit absorption and / or storage and / or stability characteristics as described herein.

[0150] In addition, the compounds may be formulated as the sole pharma- ceutical active ingredient in the composition or may be combined with other active ingredients.

[0151] The composition may comprise one or more compounds of the present invention.In some embodiments, the compound may be formulated into suitable pharmaceutical preparations for oral administration, such as solution, suspension, tablet, powder, pill, capsule, powder, sustained release preparation or elixir, or sterile solution or suspension for parenteral administration, as well as transdermal patch preparation and dry powder inhalant.In one embodiment, the above-mentioned compound is formulated into pharmaceutical composition using techniques and procedures well known in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 126).

[0152] In the composition, an effective concentration of one or more compounds or pharma- ceutically acceptable derivatives thereof may be mixed with a suitable pharmaceutical carrier. The compounds may be derivatized as corresponding salts, esters, enol ethers or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates, or prodrugs prior to formulation, as described above. The concentration of the compounds in the composition may be effective for delivery of an amount that, upon administration, treats, prevents, and / or ameliorates one or more symptoms of a disease or disorder associated with or involving hyperproliferative tissue or neovascularization.

[0153] In one embodiment, the composition is formulated for single administration. To formulate the composition, a weight fraction of the compound of the present invention is dissolved, suspended, dispersed, or otherwise mixed in a selected carrier at an effective concentration such that the treated condition is alleviated, prevented, or one or more symptoms are ameliorated.

[0154] The active compound may be included in a pharma- ceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect without undesirable side effects on the subject being treated. Therapeutically effective concentrations can be empirically determined by testing the compound in the in vitro and in vivo systems described herein and in U.S. Patent No. 5,952,366 to Pandey et al. (1999), and then extrapolating therefrom the dosage for humans.

[0155] The concentration of active compound in the pharmaceutical composition may depend on the absorption, inactivation and excretion rates of the active compound, the physicochemical properties of the compound, the administration schedule and / or the dosage, as well as other factors known to those skilled in the art. For example, the amount delivered may be sufficient to ameliorate one or more of the symptoms of a disease or disorder associated with or involving hyperproliferative tissue or neovascularization, as described herein.

[0156] In one embodiment, a therapeutically effective dosage should result in a serum concentration of the active ingredient of about 0.1 ng / ml or more and about 50-100 μg / ml or less. In one embodiment, a therapeutically effective dosage is 0.001, 0.01 or 0.1 or more and 10, 100 or 1000 mg or less of active compound per kg of body weight per day. Pharmaceutical dosage unit forms can be prepared to provide about 0.01 mg, about 0.1 mg or about 1 mg or more, about 500 mg, about 1000 mg or about 2000 mg or less of the active ingredient or combination of essential ingredients per dosage unit form, in one embodiment about 10 mg to about 500 mg.

[0157] The active ingredient may be administered at once or may be divided into several small amounts to be administered at regular intervals. It is understood that the exact dosage and duration of administration is a function of the disease being treated and may be empirically determined using known testing protocols or by extrapolation from in vivo or in vitro test data. It is noted that concentrations and dosages may also vary with the severity of the condition to be alleviated. It is further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0158] In cases where the compound exhibits insufficient solubility, methods for solubilizing the compound can be used. Such methods are known to those skilled in the art and include the use of cosolvents, such as dimethylsulfoxide (DMSO), detergents, such as Tween (Tween 20), and the like. (登録商標) ), or by dissolving in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs, may also be used in formulating effective pharmaceutical compositions.

[0159] Upon mixing or adding one or more compounds, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture will depend on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle, as described above. The effective concentration will be sufficient for ameliorating the symptoms of the disease, disorder, or condition being treated, and may be empirically determined.

[0160] The pharmaceutical compositions may be provided for administration to humans and / or animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, as well as oil-water emulsions containing an appropriate amount of the compound or a pharma- ceutically acceptable derivative thereof. The pharma- ceutically therapeutically active compounds and their derivatives are, in one embodiment, formulated and administered in unit dosage forms or multiple dosage forms. As used herein, unit dosage forms refer to physically discrete units suitable for human and animal subjects, individually packaged as known in the art. Each unit dosage contains a predetermined amount of the therapeutically active compound sufficient to produce a desired therapeutic effect, in association with the necessary pharmaceutical carrier, vehicle, or diluent. Examples of unit dosage forms include ampoules and syringes, individually packaged tablets or capsules. A unit dosage form may be administered in fractions or multiples thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container to be administered in separate unit dosage forms. Examples of multiple dose forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Thus, a multiple dose form is a multiple of unit doses that are not segregated in packaging.

[0161] Pharmaceutically administrable liquid compositions can be prepared, for example, by dissolving, dispersing or otherwise mixing the active compound defined above and any pharmaceutical adjuvants in a carrier, such as water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc., thereby forming a solution or suspension. If desired, the pharmaceutical composition to be administered can also contain small amounts of non-toxic auxiliary substances, such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like, such as acetate salts, sodium citrate salts, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.

[0162] Actual methods for preparing such dosage forms are known, or will be apparent, to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975.

[0163] Dosage forms or compositions may be prepared that contain 0.005%-100% of the active ingredient, with the remainder consisting of non-toxic carriers. Methods for the preparation of these compositions are known to those skilled in the art. Contemplated compositions may contain 0.001%-100% of the active ingredient, in one embodiment 0.1-95%, in another embodiment 75-85%.

[0164] In some embodiments, the compositions of the present invention may be suitable for oral administration. Oral pharmaceutical dosage forms may be either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. They include oral tablet types, compressed, chewable lozenges, and tablets that may be enteric coated, sugar coated or film coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form by combining with other ingredients known to those skilled in the art.

[0165] In some embodiments, the formulation is a solid dosage form, in one embodiment, a capsule or tablet. Tablets, pills, capsules, lozenges, etc. may contain one or more of the following ingredients, or compounds with similar properties: binders; lubricants; diluents; lubricants; disintegrants; colorants; sweeteners; flavorings; wetting agents; emetic coatings; and film coatings. Examples of binders include microcrystalline cellulose, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, molasses, polyvinylpyrrolidine, povidone, crospovidone, sucrose, and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium, and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate. Lubricants include, but are not limited to, colloidal silicon dioxide. Disintegrants include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Coloring agents include, for example, any of the approved water-soluble FD and C dyes, mixtures thereof; and water-insoluble FD and C dyes suspended on alumina hydrate. Sweeteners include sucrose, lactose, mannitol, and artificial sweeteners, such as saccharin, and any number of spray-dried flavors. Flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that produce a pleasant sensation, such as peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene laural ether. Emetic coating agents include fatty acids, oils, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Film coatings include hydroxyethylcellulose, gellan gum, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate.

[0166] The compound or its pharma- ceutically acceptable derivatives can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other such ingredients. When the dosage unit form is a capsule, the capsule can contain liquid carriers, such as fatty oils, in addition to the above types of materials. In addition, dosage unit forms can contain other various materials that modify the physical form of the dosage unit, such as sugar and other enteric coating agents. The compound can be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum, etc. In addition to the active compound, the syrup can contain sucrose as a sweetener, as well as certain preservatives, dyes, colorings, and flavors.

[0167] The active material may also be mixed with other active materials that do not impair the desired activity, or with materials that supplement the desired activity, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound described herein or a pharma- ceutical acceptable derivative thereof. Higher concentrations, up to about 98% by weight, of the active ingredient may also be included.

[0168] In all embodiments, tablets and capsules may be coated as known by those skilled in the art to modify or sustain dissolution of the active ingredient. Thus, for example, tablets and capsules may be coated with conventional enterically digestible coatings, such as phenyl salicylate, waxes and cellulose acetate phthalate.

[0169] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

[0170] Elixirs are clear, sweetened hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of sugars, such as sucrose, which may contain preservatives. Emulsions are two-phase systems, one liquid dispersed in the form of small globules throughout the other liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifiers, and preservatives. For suspensions, pharma- ceutical acceptable suspending agents and preservatives are used. Pharmaceutically acceptable substances used in non-effervescent granules to be reconstituted into liquid oral dosage forms include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable substances used in effervescent granules to be reconstituted into liquid oral dosage forms include organic acids, and a source of carbon dioxide. Coloring and flavoring agents are used in all the above dosage forms. Solvents include glycerin, sorbitol, ethyl alcohol, and syrups. Examples of preservatives include glycerin, methylparaben, propylparaben, benzoic acid, sodium benzoate, and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, xanthan gum, veegum, and acacia. Sweetening agents include sucrose, syrups, glycerin, and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Coloring agents include the approved water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds that produce a pleasant sensation. In the case of solid dosage forms, the solution or suspension, for example in propylene carbonate, vegetable oils or triglycerides, is in one embodiment encapsulated in a gelatin capsule.Such solutions, and their preparation and encapsulation, are disclosed in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharma- ceutically acceptable liquid carrier, for example water, to be easily measured for administration.

[0171] Alternatively, liquid or semisolid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers and encapsulating these solutions or suspensions within hard or soft gelatin capsule shells. Other useful formulations include those described in U.S. Patents RE28,819 and 4,358,603. Briefly, such formulations include, but are not limited to, formulations containing the compounds provided herein, such as, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol), and one or more antioxidants, such as, but not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0172] Other formulations include, but are not limited to, aqueous alcohol solutions containing pharma- ceutically acceptable acetals. The alcohols used in these formulations are pharma- ceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl)acetals of lower aldehydes, such as acetaldehyde diethyl acetal.

[0173] In one embodiment, parenteral administration, characterized by injection, either subcutaneously, intramuscularly or intravenously, is also contemplated herein. Injectables can be prepared in conventional forms, as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or emulsions. The injectables, solutions and emulsions also contain one or more additives. Suitable additives are, for example, water, saline, glucose, glycerol or ethanol. In addition, if desired, the pharmaceutical composition to be administered can contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.

[0174] Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained (see, e.g., U.S. Pat. No. 3,710,795), is also contemplated herein. Briefly, the compounds provided herein are dispersed in a solid internal matrix, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol surrounded by an outer polymeric membrane, and partially hydrolyzed polyvinyl alcohol. Crosslinked polyvinyl acetate, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer (insoluble in body fluids). The compound diffuses through the outer polymeric membrane in a release rate controlling process. The percentage of active compound contained in such parenteral compositions is highly dependent on its specific nature, as well as the activity of the compound and the needs of the subject.

[0175] Parenteral administration of the composition includes intravenous administration, subcutaneous administration, and intramuscular administration. Formulations for parenteral administration include sterile solutions ready for injection, lyophilized powders, sterile dry soluble products ready for use, such as the above-mentioned sterile dry soluble products, including subcutaneous tablets, sterile suspensions ready for injection, sterile dry insoluble products ready for use, and sterile emulsions. The solutions may be aqueous or non-aqueous.

[0176] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing viscosity enhancing and solubilizing agents, such as glucose, polyethylene glycol and polypropylene glycol, and mixtures thereof.

[0177] Pharmaceutically acceptable carriers used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering agents or chelating agents, and other pharma- ceutically acceptable substances.

[0178] Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antibacterial agents, which must be added to parenteral preparations packaged in multi-dose containers at bacteriostatic or bacteriostatic concentrations, include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonicity agents include sodium chloride and dextrose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, xanthan gum, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. The emulsifier is Polysorbate 80 (Tween (登録商標) ) 80). Sequestering or chelating agents of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles, sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjusting agents.

[0179] The concentration of the pharma- ceutical active compound is adjusted so that injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the subject or animal, as is known in the art.

[0180] Unit dose parenteral preparations are packaged in ampoules, vials, or syringes with needles. All preparations for parenteral administration must be sterile, as is known in the art.

[0181] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing the active material, injected as needed to produce the desired pharmacological effect.

[0182] Injectables are designed for local and systemic administration. In one embodiment, a therapeutically effective dose is formulated to contain a concentration of active compound in one or more tissues to be treated of at least about 0.1% w / w, up to about 90% w / w or more, and in some embodiments, greater than 1% w / w.

[0183] The compound may be suspended in micronized or other suitable form, or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle, as described above. The effective concentration is sufficient to ameliorate the symptoms of the condition, and may be empirically determined.

[0184] The lyophilized powders can be reconstituted for administration as solutions, emulsions and other mixtures and may be used to practice the present invention. The lyophilized powders may also be reconstituted and formulated as solids or gels.

[0185] Sterile lyophilized powders are prepared by dissolving a compound provided herein or a pharma- ceutically acceptable derivative thereof in a suitable solvent. The solvent may contain additives that improve the stability or other pharmacological components of the powder or a reconstituted solution prepared from the powder. Additives that may be used include, but are not limited to, dextrose, sorbital, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agents. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate, or other such buffers known to those skilled in the art at about neutral pH in one embodiment. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those skilled in the art provides the desired formulation. In one embodiment, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dose or multiple doses of the compound. The lyophilized powders can be stored under suitable conditions, such as at about 4°C to room temperature.

[0186] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The exact amount will depend on the compound selected. Such amounts can be empirically determined.

[0187] Topical mixtures can be prepared as described for local and systemic administration. The resulting mixture can be a solution, suspension, emulsion, etc., and is formulated as a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, irrigation, spray, suppository, bandage, skin patch, or other formulation suitable for topical administration.

[0188] The compound or its pharma- ceutically acceptable derivatives can be formulated as aerosols for topical application, such as inhalants (see, for example, U.S. Pat. Nos. 4,044,126; 4,414,209; and 4,364,923, which describe aerosols for the delivery of steroids useful for the treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of aerosols or solutions for nebulizers, or as fine powders for insufflation, alone or in combination with inert carriers, such as lactose. In such cases, the particles of the formulation have a diameter of less than 50 microns, in one embodiment, less than 10 microns.

[0189] The compounds may be formulated for local or topical application, for example, to the skin and mucous membranes, for example in the form of gels, creams and lotions, for topical application to the eye, or for intrathoracic or intraspinal application. Topical application is contemplated for transdermal delivery, and also for administration to the eye or mucous membranes, or for inhalation therapy. Nasal solutions of the active compounds alone or in combination with other pharma- ceutically acceptable excipients may be administered. These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% to 10% isotonic solutions, pH about 5 to 7, containing appropriate salts.

[0190] Other routes of administration, such as transdermal patches as described above, including iontophoretic and electrophoretic devices, and rectal administration, are also contemplated herein.

[0191] Transdermal patches, such as those described above, including iontophoretic and electrophoretic devices, are well known to those skilled in the art.For example, such patches are described in U.S. Patent No. 6,267,983; U.S. Patent No. 6,261,595; U.S. Patent No. 6,256,533; U.S. Patent No. 6,167,301; U.S. Patent No. 6,024,975; U.S. Patent No. 6,010715; U.S. Patent No. 5,985,317; U.S. Patent No. 5,983,134; U.S. Patent No. 5,948,433; and U.S. Patent No. 5,860,957.

[0192] For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules, and tablets for systemic administration. As used herein, rectal suppositories refer to solid bodies for insertion into the rectum that melt or soften at body temperature to release one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents for increasing the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), and suitable mixtures of mono-, di-, and triglycerides of fatty acids. Combinations of various bases may be used. Agents for increasing the melting point of the suppository include spermaceti and wax. Rectal suppositories may be prepared by compression or molding. The weight of a rectal suppository is, in one embodiment, about 2 to 3 mg.

[0193] Tablets and capsules for rectal administration are manufactured using the same pharma- ceutically acceptable substance and by the same methods as formulations for oral administration.

[0194] The compounds provided herein or pharma- ceutically acceptable derivatives thereof can also be formulated to target specific tissues, receptors, infectious agents, or other areas of the subject's body to be treated. Many such targeting methods are well known to those skilled in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non-limiting examples of targeting methods, see, for example, U.S. Patent No. 6,316,652; U.S. Patent No. 6,274,552; U.S. Patent No. 6,271,359; U.S. Patent No. 6,253,872; U.S. Patent No. 6,139,865; U.S. Patent No. 6,131,570; U.S. Patent No. 6,120,751; U.S. Patent No. 6,071,495 ...120,751; U.S. Patent No. 6,071,495; U.S. Patent No. 6,120,751; U.S. Patent No. 6,120,751; U.S. Patent No. 6,120,751; U.S. Patent No. 6,120,751; U. Patent No. 6,060,082; U.S. Patent No. 6,048,736; U.S. Patent No. 6,039,975; U.S. Patent No. 6,004,534; U.S. Patent No. 5,985,307; U.S. Patent No. 5,972,366; U.S. Patent No. 5,900,252; U.S. Patent No. 5,840,674; U.S. Patent No. 5,759,542, and U.S. Patent No. 5,709,874.

[0195] In one embodiment, liposome suspensions, such as those described above, including tissue-targeted liposomes (e.g., tumor-targeted liposomes), may also be suitable as pharma- ceutically acceptable carriers. They may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Pat. No. 4,522,811. Briefly, liposomes, such as multilamellar vesicles (MLV's), may be formed by drying egg phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS. In some embodiments of the present invention, the use of the compound, particle, composition and / or kit of the present invention in flow cytometry is provided.Flow cytometry is known and is described, for example, in U.S. Patent No. 5,915,925; U.S. Patent No. 6,248,590; U.S. Patent No. 6,589,792; U.S. Patent No. 6,890,487, U.S. Patent No. 8,980,565 and U.S. Patent No. 9,417,245.In some embodiments, a target (e.g., a compound, a particle, a cell, etc.) is labeled with the compound of the present invention, and the labeled target is subsequently detected, for example, by a flow cytometry method.Labeling can be performed by any suitable technique, for example, by binding the compound of the present invention to another compound, for example, an antibody, by the compound specifically binding to a particle or cell, by the uptake or internalization of the compound into a cell or particle, by non-specific adsorption of the compound to a cell or particle, etc.The compounds described herein may be useful in flow cytometry, and flow cytometry techniques (including fluorescence activated cell sorting or FACS) may be performed according to known techniques or variations thereof that will be apparent to those of skill in the art based on the instant disclosure.

[0196] In some embodiments, the method of the present invention includes one, two, or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) labeled targets. As used herein, a "labeled target" refers to a target (e.g., a compound, a particle, a cell, etc.) that is associated with (e.g., bound to, e.g., covalently or non-covalently bound to) a detectable compound. The detectable compound is excited in an excitation wavelength band and emits in an emission wavelength band. In some embodiments, the labeled target and / or the detectable compound can include a compound of the present invention. In some embodiments, the method of the present invention includes a first labeled target and a second labeled target, the first labeled target includes a compound of the present invention, and the second labeled target is different from the first labeled target. The first labeled target and the second labeled target each comprise a detectable compound that is excited at an excitation wavelength band (optionally excited at the same excitation wavelength or at different excitation wavelengths), where the first labeled target may have an emission wavelength band different from the emission wavelength band of the second labeled target. In some embodiments, the emission wavelength band of the first labeled target and the emission wavelength band of the second labeled target are characterized by peaks that are at least 5 nanometers apart from each other (i.e., the first labeled target has a peak emission wavelength band that is at least 5 nanometers apart from the peak emission wavelength band of the second labeled target). The method may include detecting the first labeled target, detecting the second labeled target, and distinguishing the first labeled target and the second labeled target from one another, optionally where the distinguishing is performed by detecting and / or determining an emission wavelength band associated with the first labeled target and / or detecting and / or determining an emission wavelength band associated with the second labeled target.In some embodiments, the first labeled target comprises a first compound of the invention, and the second labeled target comprises a second compound of the invention, and the first compound and the second compound have different emission wavelength bands (e.g., the peak emission wavelength band of the first compound is different from the peak emission wavelength band of the second compound (e.g., at least 5 nanometers apart). In some embodiments, the first labeled target comprises a first compound of the invention, and the second labeled target comprises a detectable compound that is not a compound of the invention (e.g., is not a dyad of the invention), optionally where the detectable compound of the second labeled target is a chlorin, a bacteriochlorin, an isobacteriochlorin, or a porphyrin.

[0197] The method of using the compound, composition, particle and kit of the present invention is also provided herein.In some embodiments, the method of detecting cells and / or particles using flow cytometry is provided.In some embodiments, the method includes labeling cells and / or particles with the compound, particle, composition and / or kit of the present invention; and detecting the compound by flow cytometry, thereby detecting cells and / or particles.

[0198] In the case of multicolor applications, members of a set of porphyrin pigments can be tailored to absorb / emit at different wavelengths through the use of auxochromes. In particular, by using a set of different hydroporphyrin acceptors with the same porphyrin donor, it may be possible to provide a gradation of emission wavelengths where all members are excited at the same absorption wavelength, but all with a large interval of absorption fluorescence. In a typical multicolor application, a set of antibodies is labeled with a set of fluorochromes (one type of fluorochrome for a given monoclonal antibody). The ability to distinguish multiple colors allows the set of antibodies to be used in parallel on heterogeneous cell pools. The present invention provides spectrally distinct stable fluorochromes. Alternatively, a series of spectrally distinct donor porphyrins can be used in combination with a single type of acceptor. In this case, relying on a single wavelength of detection, but different excitation wavelengths. Regardless of the experimental design, spectral tuning can be achieved through the use of (i) different pigments, (ii) different metals in the porphyrin pigments, (iii) auxochromes.

[0199] Also provided is a method for detecting tissue and / or agents (e.g., cells, infectious agents, etc.) in a subject. In some embodiments, the method includes administering to the subject a compound, particle, composition, or kit of the present invention, optionally wherein the compound associates with tissue and / or agents; and detecting the compound in the subject, thereby detecting the tissue and / or agents. In the case of optical imaging, in some embodiments, two porphyrinic chromophores can be linked with hydroporphyrin to form a dyad with a large shift (e.g., greater than 50 nm) between the absorption maximum and the fluorescence emission maximum. The large spectral interval minimizes artifacts (due to scattering of the excitation light reaching the fluorescence detection system) that impair imaging quality, especially in deep tissue applications. The excitation light removal efficiency can increase as the absorption-fluorescence interval increases. In some embodiments, compounds containing bacteriochlorins as acceptors allow excitation at the relatively sharp (<20 nm) and intense NIR band maxima of the energy absorber / donor subunits and detection at the NIR peak of the emitter / acceptor. In some embodiments, the spectral features of the bacteriochlorins are shifted (e.g., over at least 50 nm) to obtain donors and acceptors that can be useful for optical imaging.

[0200] Also provided are methods of treating cells and / or tissues (e.g., diseased cells and / or tissues) in a subject in need of such treatment. In some embodiments, the methods include administering a compound, particle, composition, or kit of the present invention, optionally wherein the compound associates with the cells and / or tissues, and irradiating the subject or a portion thereof (e.g., where the cells and / or tissues are present) with light of a wavelength and intensity sufficient to treat the cells and / or tissues, optionally wherein the light activates the compound or a portion thereof. In some embodiments, the cells and / or tissues are hyperproliferative tissues (e.g., tumors).

[0201] In some embodiments of the invention, there is provided the use of the compounds, particles, compositions, and / or kits of the invention in imaging (eg, photoacoustic imaging) and / or microscopy.

[0202] Also provided herein is a method for imaging tissues and / or agents (e.g., cells, infectious agents, etc.) in a subject. In some embodiments, the method comprises administering to a subject a compound, particle, composition, and / or kit of the present invention; and detecting the compound in the subject, thereby imaging the tissue and / or the agent. In certain embodiments, detecting the compound in the subject comprises irradiating the subject or a portion thereof (e.g., where the compound is present and / or where it is to be imaged) with light of a wavelength and intensity sufficient to generate ultrasound (e.g., ultrasound pressure waves), optionally wherein the irradiation is performed using a laser and / or by exposing the subject to one or more non-ionizing laser pulses. In some embodiments, detecting the compound in the subject comprises detecting ultrasound, optionally using an ultrasound detector. In some embodiments, the method for imaging the tissue and / or the agent in the subject comprises photoacoustic imaging of the tissue and / or the agent.

[0203] In some embodiments, the compounds of the present invention may be used in photodynamic therapy applications. In this application, the acceptor chromophore may be tailored by the selection of central metal and peripheral substituents to have (1) a high formation yield of the excited triplet state from the excited singlet state, (2) a long triplet excited state lifetime, and (3) a high energy transfer yield from the triplet excited state to oxygen to form reactive oxygen species (ROS), i.e., its lowest singlet delta excited state. In some embodiments, to enhance the first factor, a different metal ion (heavy metal ion, e.g., palladium) may be utilized in the acceptor chromophore to enhance spin-orbit coupling and thus the rate of singlet-triplet intersystem crossing. Thus, fluorescence may be substantially eliminated, which is not necessary in this application. However, it is worth noting that tetrapyrrole chromophores generally exhibit high triplet excited state yields even in the absence of heavy atom effect. Thus, the same acceptor chromophore may be detected at the appropriate location (cancer cell, membrane compartment, etc.) by optical imaging at low light intensity and then utilized for photodynamic therapy at high light intensity. This may improve the ability to assess both the localization and efficacy of photodynamic therapy reagents. These applications will be facilitated by the use of the compounds of the present invention rather than monomeric reagents due to the ability to independently tune the absorption properties (e.g., of the porphyrin) and the reactivity properties of the acceptor (e.g., hydroporphyrin) essential for cell killing.

[0204] In another embodiment, the disclosed compounds can be targeted to a specific target tissue or composition using a ligand specific to the target tissue or composition, such as a ligand or a ligand-receptor pair, such as an antibody or an antigen. Antibodies against tumor antigens and antibodies against pathogens are known. For example, antibodies and antibody fragments that specifically bind to markers produced by or associated with tumors or infectious lesions, including viral, bacterial, fungal and parasitic infections, and to antigens and products associated with such microorganisms are disclosed, inter alia, in U.S. Pat. No. 3,927,193 by Hansen et al., and in U.S. Pat. Nos. 4,331,647; 4,348,376; 4,361,544; 4,468,457; 4,444,744; 4,818,709 and 4,624,846 by Goldenberg. Antigens such as antibodies against gastrointestinal, lung, breast, prostate, ovarian, testicular, brain or lymphoid tumors, sarcoma or melanoma may be used.

[0205] A wide variety of monoclonal antibodies against infectious diseases have been developed and are readily available as summarized in the review by Polin, Eur. J. Clin. Microbiol., 3(5):387-398 (1984). These include monoclonal antibodies (Mabs) against pathogens and their antigens, such as the monoclonal antibodies described below: Anti-bacterial Mabs, such as Streptococcus agalactiae, Legionella pneumophilia, Streptococcus pyogenes, Escherichia coli, Neisseria gonorrhosae, Neisseria meningitidis, Pneumococcus, Hemophilis influenzae B, Treponema pallidum, Lyme disease, spirochetes, Pseudomonas aeruginosa, Mycobacterium leprae, Anti-bacterial Mabs as mentioned above against Bacillus leprae, Brucella abortus, Mycobacterium tuberculosis and Tetanus toxin;Anti-protozoan Mabs, such as Plasmodium falciparum, Plasmodium vivax, Toxoplasma gondii, Trypanosoma rangeli, Trypanosoma cruzi, Trypanosoma rhodesiensei, Trypanosoma brucei, Schistosoma mansoni, Schistosoma japanicum, Mesocestoides corti, Emeria tenella, Onchocerca volvulus, Leishmania The above-mentioned Anti-protozoan Mabs against Trichinella spiralis, Theileria parva, Taenia hydatigena, Taenia ovis and Taenia saginata;Anti-viral MAbs, e.g. those against HIV-1, HIV-2 and HIV-3, Hepatitis A, B, C and D, Rabies virus, Influenza virus, Cytomegalovirus, Herpes simplex I and II, Human serum parvo-like virus, Respiratory syncytial virus, Varicella-Zoster virus, Hepatitis B virus, Measles virus, Adenovirus, Human T-cell leukemia viruses, Epstein-Barr virus, Mumps virus, the above anti-viral MAbs against the following viruses: Sindbis virus, Mouse mammary tumor virus, Feline leukemia virus, Lymphocytic choriomeningitis virus, Wart virus, Blue tongue virus, Sendai virus, Reo virus, Polio virus, Dengue virus, Rubella virus, and Murine leukemia virus;as well as antimycoplasmal MAbs, such as those against Acholeplasma laidlawii, Mycoplasma arthritidis, Mycoplasma hyorhinis, Mycoplasma orale, Mycoplasma arginini and Mycoplasma pneumonia;

[0206] Suitable MAbs have been developed against most of the microorganisms (bacteria, viruses, protozoa, and other parasites) that cause the majority of infectious diseases in humans, many of which have been used previously for in vitro diagnostic purposes. These antibodies, and new MAbs that can be generated by conventional methods, will be suitable for use as targeting agents for the compounds provided herein.

[0207] MAbs against malaria parasites can be directed against sporozoite, merozoite, schizont and gametocyte stages. Monoclonal antibodies have been raised against sporozoites (circumsporozoite antigens) and shown to neutralize sporozoites in vitro and in rodents (N. Yoshida et al., Science 207:71-73 (1980)). Monoclonal antibodies against T. gondii, the protozoan parasite responsible for toxoplasmosis, have been developed (Kasper et al., J. Immunol. 129:1694-1699 (1982)). MAbs have been developed against surface antigens of schistosomula and have been found to be active against schistosomula in vivo or in vitro (Simpson et al., Parasitology 83:163-177 (1981); Smith et al., Parasitology 84:83-91 (1982); Gryzch et al., J. Immunol. 129:2739-2743 (1982); Zodda et al., J. Immunol. 129:2326-2328 (1982); Dissous et al., J. Immunol. 129:2232-2234 (1982)).

[0208] It should be noted that mixtures of antibodies and immunoglobulin classes can be used as well as hybrid antibodies. Multispecific (including bispecific and hybrid) antibodies and antibody fragments can be used in the methods of the present invention for detecting and treating target tissues and can include at least two different substantially monospecific antibodies or antibody fragments, where at least two of the antibodies or antibody fragments specifically bind to at least two different antigens produced in the target lesion or associated with the target lesion, or to at least two different epitopes or marker substance molecules produced in the target tissue or associated with the target tissue. Multispecific antibodies and antibody fragments with dual specificity can be prepared similarly to the anti-tumor marker hybrids disclosed in U.S. Pat. No. 4,361,544. Other techniques for preparing hybrid antibodies are disclosed, for example, in U.S. Pat. Nos. 4,474,544 and 4,479,895, and in Milstein et al., Immunol.Today 5:299 (1984).

[0209] Antibody fragments useful in the present invention include F(ab')2, F(ab)2, Fab', Fab, Fv, etc., including hybrid fragments. In some embodiments, the fragments are Fab', F(ab')2, Fab, and F(ab)2. Any subfragment that retains the hypervariable antigen-binding region of an immunoglobulin and has a size similar to or smaller than a Fab' fragment is also useful. This includes engineered and / or recombinant proteins, whether single-chain or multi-chain, that incorporate an antigen-binding site and otherwise function in vivo as a targeting vehicle in substantially the same manner as a natural immunoglobulin fragment. Such single-chain binding molecules are disclosed in U.S. Pat. No. 4,946,778, which is incorporated herein by reference. Fab' antibody fragments can be conveniently generated by reductive cleavage of F(ab')2 fragments, and Fab' antibody fragments themselves can be generated by pepsin digestion of intact immunoglobulins. Fab antibody fragments can be produced by papain digestion of intact immunoglobulins under reducing conditions, or by careful papain digestion of whole immunoglobulins followed by cleavage of the resulting F(ab)2 fragment.

[0210] A ligand, or one member of a ligand-receptor binding pair, may be conjugated to the compounds provided herein to target the compounds to a particular target tissue or composition. Examples of ligand-receptor binding pairs are described in U.S. Pat. Nos. 4,374,994 and 3,817,837, the teachings of which are incorporated herein by reference.

[0211] Many compounds have been identified that serve as targets for ligand-receptor binding pairs, more specifically antibodies, and techniques for constructing conjugates of such ligands with photosensitizers are well known to those skilled in the art. For example, Rakestraw et al. teach the conjugation of Sn(IV) chloride 6 via covalent linkage to monoclonal antibodies using modified dextran carriers (Rakestraw, SL, Tompkins, RD, and Yarmush, ML, Proc. Nad. Acad. Sci. USA 87:4217-4221 (1990)). The compounds disclosed herein can also be conjugated to ligands, such as antibodies, by using coupling agents. Any bond that can link multiple components so as to be stable under physiological conditions for the time required for administration and treatment is suitable. In some embodiments, the bond can be a covalent bond. The link between the two components may be direct, e.g., the photosensitizer is linked directly to the targeting agent, or it may be indirect, e.g., the photosensitizer is linked to an intermediate which is linked to the targeting agent.

[0212] Coupling agents should function under conditions of temperature, pH, salt, solvent system, and other reactants that substantially maintain the chemical stability of the photosensitizer, backbone (if present), and targeting agent. Coupling agents should stably link multiple component moieties with minimal or no denaturation or inactivation of the photosensitizer or targeting agent. Many coupling agents react with amines and carboxylates to form amides, or alcohols and carboxylates to form esters. Coupling agents are known in the art (see, for example, M. Bodansky, "Principles of Peptide Synthesis", 2nd ed., and T. Greene and P. Wuts, "Protective Groups in Organic Synthesis," 2nd Ed, 1991, John Wiley, NY).

[0213] Conjugates of the compounds provided herein with ligands, such as antibodies, can be prepared by cleaving the ester on the "E" ring and coupling the compound to the antibody through the N-terminus via a peptide bond, or by other methods known in the art, to the targeting moiety. A variety of coupling agents, including, for example, crosslinking agents, can be used for covalent conjugation. Examples of crosslinkers include N,N'-dicyclohexylcarbodiimide (DCC), N-succinimidyl-S-acetylthioacetate (SATA), N-succinimidyl-3-(2-pyridyldi-thio)propionate (SPDP), ortho-phenylene-dimaleimide (o-PDM), and sulfosuccinimidyl 4-(N-maleimido-methyl)-cyclohexane-1-carboxylate (sulfo-SMCC). See, e.g., Karpovsky et al., J. Exp. Med. 160:1686 (1984); and Liu, MA et al., Proc. Natl. Acad. Sci. USA 82:8648 (1985). Other methods include those described by Brennan et al., Science 229:81-83 (1985) and Glennie et al., J. Immunol. 139:2367-2375 (1987). Numerous coupling agents for peptides and proteins, along with buffers, solvents, and methods of use, are described in the Pierce Chemical Co. Catalog, pages O-90 to O-110 (1995, Pierce Chemical Co., 3747 N. Meridian Rd., Rockford Ill., 61105, USA), which is incorporated herein by reference.

[0214] For example, DCC is a useful coupling agent and can be used to facilitate coupling of the alcohol NHS with chlorin e6 in DMSO to form an activated ester that can be crosslinked to polylysine. DCC is a carboxy-reactive crosslinker commonly used as a coupling agent in peptide synthesis and has a molecular weight of 206.32. Another useful crosslinker is SPDP, a heterobifunctional crosslinker that uses a primary amine group and a sulfhydryl group. SPDP has a molecular weight of 312.4, a spacer arm length of 6.8 angstroms, and is reactive with NHS-ester groups and pyridyldithio groups, and upon further reaction the agent is removed to produce a cleavable crosslink so that a photosensitizer can be directly linked to a backbone or targeting agent. Other useful conjugation agents are SATA to introduce blocked SH groups for a two-step crosslink that is deblocked with hydroxylamine-HCl, as well as sulfo-SMCC and sulfhydryl groups. Other crosslinking and coupling agents are also available from Pierce Chemical Co. Additional compounds and processes for conjugating proteins to other proteins or other compositions, such as reporter groups or chelating agents for labeling proteins with metal ions, particularly processes involving Schiff bases as intermediates, are disclosed in European Patent Publication EPO 243,929 A2 (published November 4, 1987).

[0215] Photosensitizers containing a carboxyl group can be coupled to lysine ε-amino groups in the target polypeptide either by preformed reactive esters (N-hydroxysuccinimide esters) or by esters conjugated in situ by carbodiimide-mediated reaction. The same applies to photosensitizers containing sulfonic acid groups, which can be converted to sulfonyl chlorides that react with amino groups. Photosensitizers with a carboxyl group can be coupled to amino groups on the polypeptide by the in situ carbodiimide method. Photosensitizers can also be attached to the hydroxyl groups of serine or threonine residues, or to the sulfhydryl groups of cysteine ​​residues.

[0216] Methods for linking multiple components of a conjugate, such as linking a polyamino acid chain bearing a photosensitizer to an antimicrobial polypeptide, may use heterobifunctional cross-linking reagents. These reagents link a functional group in one chain to a different functional group in the other chain. These functional groups are typically amino, carboxyl, sulfhydryl, and aldehyde groups. There are numerous combinations of suitable residues to react with these groups and with differently positioned structures to conjugate them to each other. See Pierce's catalog, and Merrifield, RB et al., Ciba Found Symp. 186:5-20 (1994).

[0217] The compounds or pharma- ceutically acceptable derivatives thereof may be packaged as an article of manufacture comprising: packaging material; and within the packaging material, a compound provided herein, or a pharma- ceutically acceptable derivative thereof, effective for modulating hyperproliferative tissue or neovascular activity, or for the treatment, prevention, or amelioration of one or more symptoms of a disease or disorder mediated by hyperproliferative tissue or angiogenesis, or a disease or disorder involving hyperproliferative tissue or angiogenic activity; and a label indicating that the compound or composition, or a pharma- ceutically acceptable derivative thereof, is used for modulating hyperproliferative tissue or angiogenic activity, or for the treatment, prevention, or amelioration of one or more symptoms of a disease or disorder mediated by hyperproliferative tissue or angiogenesis, or a disease or disorder involving hyperproliferative tissue or angiogenic activity.

[0218] The articles of manufacture provided herein include packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those skilled in the art. For example, see U.S. Pat. No. 5,323,907; U.S. Pat. No. 5,052,558 and U.S. Pat. No. 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. A wide range of formulations of the compounds and compositions provided herein are contemplated, as well as various treatments for possible diseases or disorders in which hyperproliferative tissue or neovascularization is involved as a mediator or contributor to the symptoms or causes.

[0219] In some embodiments, the compounds of the present invention can be photosensitizing compounds. The photosensitizing compounds can be administered to the target tissue, target composition and / or subject before the subject is exposed to illumination. The photosensitizing compounds can be administered as described elsewhere herein.

[0220] The dose of the photosensitizing compound may be clinically determined. Depending on the photosensitizing compound used, an equivalent optimal therapeutic level may need to be established. A certain time may be required for the circulating or locally administered photosensitizer to be taken up by the target tissue. Unbound photosensitizer is cleared from the circulation during this waiting period, but additional time may optionally be provided to clear unbound compound from non-target tissues. The waiting period is clinically determined and may vary depending on the compound.

[0221] After the waiting period is over, a laser or non-laser light source (including but not limited to an artificial light source, such as a fluorescent or incandescent lamp, or a natural light source, such as ambient sunlight) is used to activate the bound photosensitizer. The area of ​​illumination can be determined by the location and / or size of the pathological area to be detected, diagnosed, or treated. The duration of illumination depends on whether detection or treatment is being performed, and can be empirically determined. Any total or cumulative duration between about 4 minutes and about 72 hours can be used. In one embodiment, the illumination period can be from about 60 minutes to about 148 hours. In another embodiment, the illumination period can be from about 2 hours to about 24 hours.

[0222] In some embodiments, the total fluence or energy of the light used for irradiating, measured in Joules, may be from about 10 Joules to about 25,000 Joules; in some embodiments, from about 100 Joules to about 20,000 Joules; in some embodiments, from about 500 Joules to about 10,000 Joules. Light of a wavelength and fluence sufficient to produce a desired effect, whether for detection by luminescence (e.g., fluorescence or phosphorescence) or for therapeutic treatment to destroy or damage a target tissue or target composition, may be selected. Light having a wavelength corresponding at least in part to a characteristic light absorption wavelength of a photosensitizer may be used to irradiate a target tissue.

[0223] The intensity or power of the light used may be measured in watts, where each Joule is equal to one watt-second. Therefore, the intensity of the light used for illumination in the present invention is substantially in mW / cm. 2 The total fluence or energy of the light in Joules is divided by the total duration of exposure in seconds, so the longer the target is exposed to irradiation, the greater the total energy or fluence can be used without increasing the intensity of the light used. The present invention uses a total fluence of irradiation sufficient to activate the photosensitizer.

[0224] In one embodiment of using the compounds disclosed herein for photodynamic therapy, the compounds are injected into a mammal, e.g., a human, to be diagnosed or treated. The amount of injection can be about 0.1 to about 0.5 μmol / kg body weight. In the case of treatment, the area to be treated is injected with the desired wavelength and energy, e.g., about 10 to about 200 J / cm. 2 In the case of detection, emission is determined in response to exposure to light at a wavelength different from that used to irradiate the compound and at a wavelength sufficient to cause the compound to fluoresce and / or phosphoresce. The energy used in detection is sufficient to cause fluorescence and / or phosphorescence and is usually significantly lower than the energy required for treatment.

[0225] A kit comprising the composition, compound and / or particle of the present invention is also provided according to an embodiment of the present invention.In some embodiments, the kit comprises one or more (or all) total compositions that do not contain organic solvent.In some embodiments, the kit of the present invention comprises a first compound having a first absorption and emission spectrum comprising a first emission wavelength, and a second compound having a second absorption and emission spectrum comprising a second emission wavelength, where the first emission wavelength and the second emission wavelength are different and / or distinct, and the first compound and the second compound are both compounds of the present invention.In some embodiments, the first compound and the second compound are each excited by the same excitation wavelength.

[0226] Any one of the photosensitizing compounds or pharma- ceutically acceptable derivatives thereof disclosed herein may be provided in a kit with instructions for carrying out any of the methods disclosed herein.The instructions may be in any tangible form, such as a printed paper, a computer disk instructing a person how to carry out the method, a videocassette containing instructions on how to carry out the method, or a computer memory that receives data from a remote location and illustrates the instructions or otherwise provides instructions to a person (e.g., via the Internet).A person may be instructed on how to use the kit using any of the above instructions, or may be instructed by receiving instructions, for example, in a classroom, or, for example, during the course of treating a subject using any of the methods disclosed herein.

[0227] In some embodiments, methods of using the compounds of the present invention in photodynamic therapy (PDT) and / or photodynamic inactivation (PDI) are provided. Additional examples and specific examples of methods of using the compounds and compositions of the present invention include, but are not limited to, the following (i)-(xi):

[0228] (i) Treatment of opportunistic infections. The compounds, compositions and methods of the present invention can be useful for PDT of opportunistic infections, particularly soft tissue. For antimicrobial treatment (via PDT) of infections, particularly wound infections, infectious organisms can include (non-limiting examples) Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. In hospital-acquired infections, Pseudomonas aeruginosa causes 8% of surgical wound infections and 10% of bloodstream infections. In some embodiments, the subject is an immunocompromised subject, for example, a subject suffering from AIDS or a subject undergoing treatment with an immunosuppressant.

[0229] (ii) Treatment of burns. Infections by S. aureus and gram-positive bacteria in general are particularly prevalent in burns (Lambrechts, 2005). Multidrug resistance of S. aureus presents a significant medical challenge. In this regard, the compounds, compositions and methods of the present invention are useful for the treatment of opportunistic infections in burns.

[0230] (iii) Sepsis. The compounds, compositions and methods of the present invention are useful for PDT treatment of subjects suffering from opportunistic infections with Vibrio vulnificus. Vibrio vulnificus, a gram-negative bacterium, causes primary sepsis, wound infections, and gastrointestinal disease in humans.

[0231] (iv) Ulcers. The compounds, compositions and methods of the invention may be useful for PDT treatment of ulcer-causing bacteria (Helicobacter pylori). In the clinic, treatment may be effected in any suitable manner, for example, by insertion of a fiber optic cable (similar to an endoscope, but with provisions for delivery of red or near infrared light) into the stomach or affected area.

[0232] (v) Periodontal Disease. The compounds, compositions and methods of the present invention may be useful in PDT for the treatment of periodontal disease, such as those mentioned above, including gingivitis. Periodontal disease is caused by the overgrowth of bacteria, such as the gram-negative anaerobe Porphyromonas gingivalis. As with many PDT treatments, a targeting or solubilizing agent along with the photoactive species is essential to properly deliver the photoactive species to the desired cells. Oral pathogens of interest for targeting include Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Bacteroides forsythus, Campylobacter rectus, Eikenella corrodens, Fusobacterium nucleatum subsp. Polymorphum, Actinomyces viscosus, and streptococci. For such applications, the compounds or compositions of the present invention may be applied topically (eg, as a mouthwash or gargle) and then photoadministered using an external device, an intra-oral appliance, or a combination thereof.

[0233] (vi) Atherosclerosis. The compounds, compositions and methods of the present invention may be useful in PDT to treat vulnerable atherosclerotic plaques. Without wishing to be bound by any particular theory, it is believed that invading inflammatory macrophages secrete metalloproteases that degrade the thin layer of collagen in coronary arteries, resulting in often fatal thrombosis (Demidova and Hamblin, 2004). Bacteriochlorins that target such inflammatory macrophages may be useful in PDT of vulnerable plaques.

[0234] (vii) Cosmetic and dermatological applications. The compounds, compositions and methods of the present invention may be useful in PDT to treat a wide range of cosmetic dermatological problems, such as hair removal, treatment of psoriasis, or removal of skin discoloration. Ruby lasers are currently used for hair removal. In many laser treatments, melanin is the photosensitized chromophore. Such treatments are reasonably effective in fair-skinned individuals with dark hair. The compounds, compositions and methods of the present invention may be used as near-infrared sensitizers for hair removal, thereby allowing targeting of chromophores with more specific and sharper absorption bands.

[0235] (viii) Acne. The compounds, compositions and methods of the present invention are useful in PDT to treat acne. Acne vulgaris is caused by Propionibacterium acnes, which infects the sebaceous glands, and affects approximately 80% of young people. Again, increasing bacterial resistance to antibiotic treatments has led to a surge in difficult-to-treat acne. Current PDT treatments for acne typically rely on the addition of aminolevulinic acid, which is converted to free-base porphyrin in the hair follicle or sebaceous gland. The compounds and compositions of the present invention may be administered to a subject topically or parenterally (e.g., by subcutaneous injection), depending on the particular condition.

[0236] (ix) Infectious diseases. The compounds, compositions and methods of the present invention may be useful in PDT to treat infectious diseases. For example, cutaneous leishmaniasis and sub-cutaneous leishmaniasis, which occur widely in the Mediterranean and Middle Eastern regions, are currently treated with arsenic-containing compounds. PDT has recently been used in humans with reasonable success in at least one case. The use of the compounds and compositions of the present invention is similarly useful and potentially offers advantages, such as ease of synthesis and better spectral absorption properties.

[0237] (x) Tissue sealants. The compounds, compositions and methods of the present invention may be useful as tissue sealants in PDT in subjects in need of a tissue sealant. Light-activated tissue sealants are attractive for sealing wounds, adhering tissue, and closing defects in tissue. There are many applications where sutures or staples are undesirable, and the use of such mechanical methods of sealing often leads to infection and scarring.

[0238] (xi) Neoplastic diseases. The compounds, compositions and methods of the present invention may be useful in PDT to treat neoplastic diseases or cancers, such as those listed above, including skin cancer, lung cancer, colon cancer, breast cancer, prostate cancer, cervical cancer, ovarian cancer, basal cell carcinoma, leukemia, lymphoma, squamous cell carcinoma, melanoma, plaque stage cutaneous T-cell lymphoma, and Kaposi's sarcoma.

[0239] Furthermore, in the modern medical field, there are various procedures for diagnosing diseases, including magnetic resonance imaging (MRI). Detecting cancer at its early stage should improve the curative ability to remove cancerous tissue. Early diagnosis of precancerous regions and microcancers is a key challenge in modern cancer treatment. MRI has emerged as a powerful tool in clinical practice because it is non-invasive and gives accurate volume rendering of the object. Images are created by imposing one or more orthogonal magnetic field gradients on the object or specimen while exciting the nuclear spins with radio frequency pulses, as in a typical nuclear magnetic resonance (NMR) experiment. After data collection with various gradient fields, deconvolution provides one-, two-, or three-dimensional images of the specimen / object. Typically, the images are based on NMR signals from water protons, where the signal intensity in a given volume element is a function of the water concentration and relaxation time. Localized changes in these parameters provide the vivid contrast observed in MR images.

[0240] MRI contrast agents act by increasing the rate of relaxation, thereby increasing the contrast between water molecules at the site where the imaging agent adsorbs and water molecules elsewhere in the body. However, the action of the MRI contrast agent reduces both T1 and T2, resulting in higher contrast at the former and lower contrast at the latter. Thus, the phenomenon is concentration-dependent, and there is usually an optimal concentration of paramagnetic species for maximum effect. This optimal concentration varies with the particular agent used, the site of imaging, the mode of imaging, i.e., spin-echo, saturation-recovery, inversion-recovery, and / or various other T1- or T2-dependent imaging techniques, and the composition of the medium in which the agent is dissolved or suspended. These factors and their relative importance are known in the art. See, e.g., Pykett, Scientific American 246:78 (1982); Runge et al., Am. J. Radiol. 141:1209 (1983). When MRI contrast agents are used diagnostically, they can perfuse blood vessels, enhance vascular contrast, and report organ lesions and infiltration. However, labeling specific tissues for radiological diagnosis remains a challenging task for MRI. Efforts to develop cell- and tissue-specific MRI image-enhancing agents by improving existing immunological techniques have been the focus of much research in diagnostic radiology. For example, antibodies labeled with paramagnetic ions, commonly the gadolinium chelate Gd-DTPA, have been made and tested for their effect on MRI imaging of tumors and other tissues (U.S. Pat. No. 5,059,415). Unfortunately, the relaxant properties of antibody-bound Gd have been shown to be only slightly better than those of unbound Gd-DTPA (Paajanen et al., Magn. Reson. Med 13:38-43 (1990)).

[0241] MRI is generally used for in vivo 1 1H nuclei. However, MRI is not able to detect the NMR spectra of other nuclei, e.g. 13 C. 15 N, 31 P, and 19 NMR spectra of the above-mentioned other nuclei, including F, can be detected. 19 F is not abundant in the body. In the compositions provided herein, isotopes useful in MRI, such as 13 C. 15 N, 31 P, or 19 F., especially 19 By administration to a subject incorporating F, the compounds provided herein accumulate in the target tissue and, subsequently, for MR imaging, are coupled to an MRI recognizable isotope, e.g. 19 The presence of accumulated compounds having F produces NMR data having an enhanced signal from the target tissue or target composition. Thus, the disclosed compounds may be used as image enhancing agents and provide labeling of specific target tissues or target compositions for diagnostic radiology, such as those described above including MRI.

[0242] In some embodiments, the compositions of the present invention can be used to detect target cells, target tissues, and / or target compositions in a subject. Any type of cell, tissue, and / or composition (e.g., normal or healthy cells and / or tissues, diseased cells and / or tissues, cancer cells, hyperproliferative cells and / or tissues, benign tumors, malignant tumors, aneurysms, etc.) can be detected in a subject. In some embodiments, the compositions of the present invention can be used to detect the presence of target cells, target tissues, and / or target compositions in a subject. When a compound provided herein is to be used to detect a target tissue or target composition, the compound can be introduced into a subject and a sufficient time can be allowed for the compound to accumulate in the target tissue and / or associate with the target composition. The treatment site is then irradiated, typically with light of sufficient energy to cause the compound to luminesce (e.g., fluoresce or phosphoresce), and the energy used is usually significantly lower than the energy required for a photodynamic therapy treatment. Luminescence is determined upon exposure to light at the desired wavelength, and the amount of luminescence can be correlated to the presence of the compound, either qualitatively or quantitatively, by methods known in the art.

[0243] In some embodiments, the compositions of the present invention can be used to diagnose the presence and / or identity of an infectious agent in a subject. The compounds provided herein can be conjugated to one or more ligands specific for the infectious agent, such as an antibody or antibody fragment that selectively associates with the infectious agent, and after allowing sufficient time for the targeted compound to associate with the infectious agent and clear from non-target tissue, the compound can be visualized, for example, by exposing the tissue and / or the compound to light of sufficient energy to cause the compound to emit light, or by causing the generation of heat and / or ultrasound, or by imaging with diagnostic radiology, such as the diagnostic radiology described above, including MRI. As an example, any one of the compounds provided herein can be conjugated to an antibody targeted against a suitable Helicobacter pylori antigen and formulated into a pharmaceutical formulation that, when introduced into a subject, releases the conjugated compound to the gastric mucus / epithelial layer where the bacteria resides. After a sufficient amount of time has passed for the compound to selectively associate with the target infectious agent and for unbound compound to be removed from non-target tissues, the subject may be examined to determine whether Helicobacter pylori is present. 19 Detecting compounds that have accumulated due to the presence of F substituents can be done by MRI or by shining light, e.g., using fiber optics, on the suspected target area with light of sufficient energy to cause the compound to luminesce and detecting any luminescence of the targeted compound.

[0244] According to some embodiments of the present invention, the compounds of the present invention may be used as chromophores (also referred to as photosensitizers, or simply sensitizers) in solar cells, including but not limited to high surface area colloidal semiconductor film solar cells (Gratzel cells), as described, for example, in U.S. Pat. Nos. 5,441,827; 6,420,648; 6,933,436; 6,924,427; 6,913,713; 6,900,382; 6,858,158; and 6,706,963.

[0245] In some embodiments, the compounds of the present invention can be used as chromophores in light harvesting rods as described in U.S. Patent No. 6,407,330 and U.S. Patent No. 6,420,648 (incorporated herein by reference). The light harvesting rods can include one or more compounds of the present invention bound to one or two adjacent chromophores, depending on their location in the light harvesting rod. Such light harvesting rods can be utilized to fabricate light harvesting arrays as described in U.S. Patent No. 6,420,648, and solar cells as described in U.S. Patent No. 6,407,330.

[0246] In some embodiments, the compounds of the present invention are useful immobilized on substrates for the manufacture of charge storage molecules and information storage devices comprising them, individually or as linked polymers, and optionally additional compounds for adding additional oxidation states. Such charge storage molecules and information storage devices are known and are described, for example, in U.S. Patent No. 6,208,553 to Gryko et al.; U.S. Patent No. 6,381,169 to Bocian et al.; and U.S. Patent No. 6,324,091 to Gryko et al. The bacteriochlorins of the present invention may include members of sandwich coordination compounds in information storage molecules, such as those described in U.S. Patent No. 6,212,093 to Li et al. or U.S. Patent No. 6,451,942 to Li et al.

[0247] The invention is described in more detail in the following non-limiting experimental section.

[0248] Working Example

[0249] The labeling / numbering of the compounds provided in the Examples section pertains only to the Examples section and may not correspond to the labeling / numbering provided throughout the remainder of this application. Thus, the labeling / numbering of the compounds in the Examples section should not be confused with the labeling / numbering of the compounds throughout the remainder of this application (e.g., in the Abstract and Detailed Description sections and claims).

[0250] Abbreviations include: round-bottom flask (RBF), dichloromethane (DCM, or CH2Cl2), ethyl acetate (EtOAc), hexane (hex), methanol (MeOH), isopropanol (IPA), diethyl ether (Et2O), acetic acid (AcOH), 1-2-dichloroethane (1,2-DCE), tetrahydrofuran (THF), dimethylformamide (DMF), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine (TEA, or Et3N), cesium carbonate (Cs2CO3), sodium sulfate (Na2SO4), and silica (SiO2).

[0251] Example 1: P2-C1 dyad, methyl ester

[0252] [ka]

[0253] A sample of chlorin C1 (45.0 mg, 72 μmol), porphyrin P2 (57 mg, 80.5 μmol, 1.1 equiv.), Pd(PPh3)4 (25 mg, 21.4 μmol), and Cs2CO3 (70 mg, 214 μmol) was placed in an oven-dried Schlenk flask equipped with a stir bar (50 mL). The flask was evacuated for 1.0 h and degassed by three evacuation-backfill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / DMF (24 mL, 2:1) using an argon-filled syringe. The resulting mixture was stirred at 90 °C for 17.0 h. The reaction flask was removed from the heat and ∼112 mg of palladium scavenger was added and stirred at room temperature for 60 min. It was washed with EtOAc, brine, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified using a 12 g SiO2 column in a minimal amount of CH2Cl2 and eluted with 0-5% MeOH in CH2Cl2 for 20 min to give a dark brown solid in 77 mg (96%) yield.

[0254] Example 2: P2-C1 dyad, maleimide

[0255] [ka]

[0256] A sample of the P2-C1 dyad and methyl ester (77 mg, 68 μmol) in THF (10.0 mL) and MeOH (5.0 mL) was treated with 5N aqueous NaOH (5.0 mL). The reaction mixture was refluxed at 70 °C for 2.0 h. 1N aqueous HCl (50.0 mL) was added and stirred for 10 min. CHCl was then added, washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The resulting P2-C1 dyad carboxylic acid (76 mg, 68 μmol) and TSTU (31 mg, 102 μmol) were dissolved in 17 mL of DMF, and TEA (83 mg, 820 μmol, 114 μL) was added. The solution was stirred at room temperature in the dark under an argon atmosphere for 1.0 h. 2-Maleimidoethylamine HCl (18 mg, 102 μmol) was added and stirred overnight at room temperature under argon. The reaction mixture was quenched with CH2Cl2, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in a minimum amount of CH2Cl2 and silica caked. A 24 g SiO2 column was eluted with 0-75% EtOAc in hexanes for approximately 40 min to give a brown solid in 54 mg (64%) yield.

[0257] Example 3: P2~CuC1 dyad, maleimide

[0258] [ka]

[0259] The P2~C1 dyad, maleimide (12.6 mg, 10.2 μmol) in anhydrous DMF (4.0 mL) was treated with Cu(OAc)2 (18.4 mg, 101 μmol). After refluxing at 80 °C for 2 min, the brownish solution turned bright purple. After refluxing for 10 min, the reaction flask was removed from the heat and cooled to room temperature. The reaction mixture was quenched with EtOAc, washed with brine (2x), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in a minimal amount of CH2Cl2 and afforded a dark solid in 10.3 mg (77%) yield.

[0260] Example 4: P3-C1 dyad

[0261] [ka]

[0262] Chlorin C1 (10.0 mg, 16 μmol), porphyrin P3 (14 mg, 19 μmol, 1.2 equiv.), Pd(PPh3)4 (6.0 mg, 4.8 μmol), and Cs2CO3 (16 mg, 48 mol) were placed in an oven-dried Schlenk flask equipped with a stir bar (25 mL). The flask was evacuated for 1.0 h and degassed by three evacuation-backfill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / DMF (9.0 mL, 2:1) using an argon-filled syringe. The resulting mixture was stirred at 90° C. for 20.5 h. The reaction flask was removed from the heat and 255 mg of palladium scavenger was added and stirred at room temperature for 60 min. It was concentrated and redissolved in a minimal amount and eluted on a 12 g SiO2 column with 0-5% MeOH in CH2Cl2 for 20 min to give a dark brown solid in 15.3 mg (81%) yield.

[0263] Example 5: P4-C3 dyad

[0264] [ka]

[0265] Chlorin C3 (10 mg, 20 μmol), porphyrin P4 (16 mg, 24 μmol), Pd2(dba)3 (7.3 mg, 8.0 μmol), and P(o-tol)3 (7.3 mg, 24 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (10 mL). The flask was evacuated for 60 min and degassed by three evacuation-refill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / TEA (6 mL, 5:1) using an argon-filled syringe. The resulting mixture was stirred at 60 °C for 19.0 h. The reaction flask was removed from the heat and ∼150 mg of palladium scavenger was added and stirred at room temperature for 60 min. EtOAc was added to the reaction mixture (30 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in a minimum amount of CH2Cl2 and purified using a 12 g SiO2 column and eluted in 0-2% MeOH in CH2Cl2 for 15 min to give a dark red solid in ∼17 mg (76%) yield.

[0266] Example 6: P5-C3 dyad

[0267] [ka]

[0268] Chlorin C3 (10 mg, 20 μmol), porphyrin P5 (17 mg, 24 μmol), Pd2(dba)3 (7.3 mg, 8.0 μmol), and P(o-tol)3 (7.3 mg, 24 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (10 mL). The flask was evacuated for 60 min and degassed by three evacuation-backfill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / TEA (6 mL, 5:1) using an argon-filled syringe. The resulting mixture was stirred at 60 °C for 19.0 h. The reaction flask was removed from the heat and ∼150 mg of palladium scavenger was added and stirred at room temperature for 60 min. EtOAc was added to the reaction mixture (30 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in a minimum amount of CH2Cl2 and purified using a 12 g SiO2 column and eluted in 0-2% MeOH in CH2Cl2 for 15 min to give a dark red solid in ∼17 mg (73%) yield.

[0269] Example 7: P2-C2 dyad

[0270] [ka]

[0271] Chlorin C2 (15.0 mg, 27 μmol), porphyrin P2 (23 mg, 33 μmol, 1.2 equiv.), Pd(PPh3)4 (9.4 mg, 8.1 μmol), and Cs2CO3 (27 mg, 81 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (50 mL). The flask was evacuated for 1.0 h and degassed by three evacuation-backfill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / DMF (12 mL, 2:1) using an argon-filled syringe. The resulting mixture was stirred at 90 °C for 17.0 h. The reaction flask was removed from the heat and ∼150 mg of palladium scavenger was added and stirred at room temperature for 60 min. It was washed with EtOAc, brine, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by purification using a 12 g SiO column eluted with a minimal amount of CH2Cl2 and then eluted with 0-70% EtOAc in hexanes for 33 min to give a brown solid in 22 mg (77%) yield.

[0272] Example 8: P2-ZnC2 dyad

[0273] [ka]

[0274] The P2-C2 dyad (6.4 mg, 6.1 μmol) in CHCl3 / MeOH (5:1, 6.0 mL) was treated with Zn(OAc)2 (9.9 mg, 54 μmol, 9.0 equiv.). The resulting mixture was refluxed at 50 °C for 60 min. The brownish solution turned purple-blue after 10 min of reflux. The reaction flask was removed from the heat and cooled to room temperature, concentrated on a rotary evaporator, and the residue was dissolved in a minimum amount of CH2Cl2 and eluted on a 4 g SiO2 column with 0-70% EtOAc in hexanes for approximately 20 min to give a blue solid in 4.6 mg (68%) yield.

[0275] Example 9: P6-C3 dyad

[0276] [ka]

[0277] Chlorin C3 (10 mg, 20 μmol), porphyrin P6 (14 mg, 24 μmol), Pd2(dba)3 (7.3 mg, 8.0 μmol), and P(o-tol)3 (7.3 mg, 24 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (10 mL). The flask was evacuated for 60 min and degassed by three evacuation-refill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / TEA (6 mL, 5:1) using an argon-filled syringe. The resulting mixture was stirred at 60° C. for 19.0 h. The reaction flask was removed from the heat and 50 mg of palladium scavenger was added and stirred at room temperature for 60 min. EtOAc was added to the reaction mixture (20 mL), washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in a minimum amount of CH2Cl2 and purified using a 12 g SiO2 column and eluted with 0-40% EtOAc in CH2Cl2 for 30 min to give a brown solid in ∼3.5 mg (18%) yield.

[0278] Example 10: P7-C2 dyad

[0279] [ka]

[0280] Chlorin C2 (15 mg, 27 μmol), porphyrin P7 (~16 mg, 30 μmol, 1.1 equiv.), Pd2(dba)3 (10 mg, 11.0 μmol), and P(o-tol)3 (10 mg, 33 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (25 mL). The flask was evacuated for 60 min and degassed by three evacuation-backfill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / TEA (12 mL, 5:1) using an argon-filled syringe. The resulting mixture was stirred at 60 °C for 18.0 h. The reaction flask was removed from the heat and ~75 mg of palladium scavenger was added and stirred at room temperature for 60 min. EtOAc was added to the reaction mixture (30 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in a minimum amount of CH2Cl2 and purified using a 12 g SiO2 column and eluted in 0-60% EtOAc in hexanes for 25 min to give a brown solid in ∼20 mg (75%) yield.

[0281] Example 11: P8-C2 dyad, methyl ester

[0282] Porphyrin P8 (~57 mg, 119 μmol, 1.1 equiv.), chlorin C2 (60 mg, 108 μmol), Pd2(dba)3 (40 mg, 43.0 μmol), and P(o-tol)3 (40 mg, 130 μmol) were placed in an oven-dried (50 mL) Schlenk flask equipped with a stir bar. The flask was evacuated for 60 min and degassed by three evacuation-backfill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / TEA (24 mL, 5:1) using an argon-filled syringe. The resulting mixture was stirred at 60 °C for 18.0 h. The reaction flask was removed from the heat and ~55 mg of palladium scavenger was added and stirred at room temperature for 60 min. EtOAc was added to the reaction mixture, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in a minimum amount of CH2Cl2 and silica caked and purified using a 24 g SiO2 column and eluted with 0-50% EtOAc in hexanes for 40 min to give a brown solid in 53 mg (51%) yield.

[0283] Example 12: P8-C2 dyad, maleimide

[0284] [ka]

[0285] P8~C2 dyad and methyl ester (46 mg, 49 μmol) in THF (10.0 mL) and MeOH (5.0 mL) were treated with 5N aqueous NaOH (5.0 mL). The reaction mixture was refluxed at 70° C. for 2.0 h. 1N aqueous HCl (50.0 mL) was added and stirred for 10 min. Then, EtOAc was added, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. It was used as is for the next step. P8~C2 dyad acid (45 mg, 49 μmol), TSTU (22 mg, 73 μmol), and TEA (30 mg, 292 μmol, 41 μL) were dissolved in 12 mL of DMF and stirred at room temperature in the dark under argon atmosphere for 1.0 h. 2-Maleimidoethylamine hydrochloride (13 mg, 73 μmol) was added and stirred overnight at room temperature under argon. The reaction mixture was quenched with CH2Cl2, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in a minimum amount of CH2Cl2 and silica caked. A 24 g SiO2 column was eluted with 0-75% EtOAc in hexanes for approximately 42 min to give a brown solid in 44 mg (85%) yield.

[0286] Example 13: P8-ZnC2 dyad

[0287] [ka]

[0288] P8~C2 dyad, methyl ester (3.9 mg, 4.1 μmol) in CHCl3 / MeOH (5:1, 3.0 mL) was treated with Zn(OAc)2 (1.5 mg, 8.1 μmol, 2.0 equiv.). The resulting mixture was refluxed at 50 °C for 30 min. The brownish solution turned greenish after 10 min of reflux. The reaction flask was removed from the heat and cooled to room temperature, concentrated on a rotary evaporator, and the residue was dissolved in a minimum amount of CH2Cl2 and purified on a 4 g SiO2 column eluted with 0-100% EtOAc in hexanes for approximately 10 min to give a green solid in 2.6 mg (63%) yield.

[0289] Example 14: P9-C4 dyad

[0290] [ka]

[0291] Chlorin C4 (60.0 mg, 107 μmol), porphyrin P9 (78 mg, 129 μmol, 1.2 equiv.) Pd2(dba)3 (39 mg, 43.0 μmol), and P(o-tol)3 (39 mg, 129 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (50 mL). The flask was evacuated for 45 min and degassed by three evacuation-refill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / TEA (24 mL, 5:1) using an argon-filled syringe. The resulting mixture was stirred at 60° C. for 17.0 h. The reaction flask was removed from the heat and cooled to room temperature. EtOAc was added to the reaction mixture, which was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in a minimal amount of CH2Cl2 and purified using a 24 g SiO2 column and eluted with 0-100% CH2Cl2 in hexanes for 27 min, then switched to 50% EtOAc in CH2Cl2 for 5 min (total 32 min) to give a green-purple solid in 68 mg (58%) yield.

[0292] Example 15: P10-C5 dyad

[0293] [ka]

[0294] Chlorin C5 (40.0 mg, 81 μmol), porphyrin P10 (63 mg, 89 μmol, 1.1 equiv.) Pd(PPh3)4 (28 mg, 24 μmol), and CS2CO3 (79 mg, 242 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (50 mL). The flask was evacuated for 1.0 h and degassed by three evacuation-backfill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / TEA (24 mL, 5:1) using an argon-filled syringe. The resulting mixture was stirred at 90 °C for 20 h. The reaction flask was removed from the hot oil bath and cooled to room temperature. ∼78 mg of palladium scavenger was added and stirred at room temperature for 60 min. EtOAc was added to the reaction mixture, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in a minimum amount of CH2Cl2 and silica caked and purified using a 12 g SiO2 column and eluted with 0-3% MeOH in CH2Cl2 for 18 min to give a dark brown solid in 32 mg (40%) yield.

[0295] Example 16: P1-C6 dyad, methyl ester

[0296] Chlorin C6 (20.0 mg, 32 μmol), porphyrin P1 (29 mg, 70 μmol, 2.2 equiv.), and PdCl2(PPh3)2 (11.2 mg, 16.0 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (50 mL). The flask was evacuated for 1.0 h and degassed by three evacuation-backfill cycles. The mixture was dissolved by the addition of anhydrous toluene / TEA (15 mL, 2:1) purged with argon using an argon-filled syringe. The temperature was then increased to 100° C. and refluxed for 2.5 h. The reaction flask was removed from the heat and cooled to room temperature. EtOAc was added to quench, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in a minimal amount of CH2Cl2 and purified using a 24 g SiO2 column and eluted in 0-100% CH2Cl2 in hexanes for 39 min, then switched to 1% MeOH in CH2Cl2 for 8 min (47 min total) to give a red solid in 41 mg (100%) yield.

[0297] Example 17: P1-C6 dyad, maleimide

[0298] [ka]

[0299] A sample of JA28-141 (~41 mg, 68 μmol) in THF (8.0 mL) and MeOH (4.0 mL) was treated with 5N aqueous NaOH (4.0 mL). The reaction mixture was refluxed at 70 °C for 2.0 h. 5N aqueous HCl (5.0 mL) was added and stirred for 10 min. The reaction flask was removed from the heat and allowed to cool to room temperature. It was diluted with CH2Cl2, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude carboxylic acid (40 mg, 32 μmol), TSTU (14 mg, 47 μmol), and TEA (19 mg, 190 μmol, 27 μL) were dissolved in 8.0 mL of DMF and stirred at room temperature in the dark under argon for 1.5 h. 2-Maleimidoethylamine hydrochloride (8.4 mg, 47 μmol) was added and stirred at room temperature under argon overnight. CHCl was added to the reaction mixture, quenched with saturated aqueous NaHCO, washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was dissolved in a minimum amount of CHCl and eluted on a 4 g SiO column with 0-85% EtOAc in hexanes for 17 min to give a brown solid in 8.0 mg (18%) yield.

[0300] Example 18: P8-C6 dyad

[0301] [ka]

[0302] Chlorin C6 (10.0 mg, 16 μmol), porphyrin P8 (16.5 mg, 35 μmol, 2.2 equiv.), and PdCl2(PPh3)2 (2.8 mg, 4.0 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (25 mL). The flask was evacuated for 1.0 h and degassed by three evacuation-backfill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / TEA (9 mL, 2:1) using an argon-filled syringe. The resulting mixture was stirred at 100° C. for 22.5 h. The reaction flask was removed from the heat and cooled to room temperature. EtOAc was added to quench, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in a minimal amount of CH2Cl2 and purified using a 12 g SiO2 column and eluted in 0-100% CH2Cl2 in hexanes for 39 min, then switched to 1% MeOH in CH2Cl2 for 8 min (total 47 min) to give a red solid in 41 mg (100%) yield.

[0303] Example 19: General Procedure E (P8-BC2a)

[0304] [ka]

[0305] BC2 (0.2 g, 0.3 mmol), 4-methoxycarbonylphenylboronic acid pinacol ester (78 mg, 0.3 mmol), K2CO3 (0.41 g, 3 mmol), and Pd(PPh3)4 (69 mg, 0.06 mmol) were added to a Schlenk flask and placed under high vacuum for 1 h. Both anhydrous DMF and anhydrous toluene were degassed for 1 h using a strong stream of argon. The flask was degassed by three evacuation / backfilling argon cycles. Toluene (18 mL) and DMF (9 mL) were added and the flask was placed in a preheated oil bath at 80 °C for 16 h. The crude mixture was cooled to room temperature, diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was dried, filtered, and concentrated. The mixture was purified by flash chromatography and eluted with a gradient of hexane:EtOAc (69 mg, 32%).

[0306] Example 20: P8-BC2 dyad 1

[0307] Synthesized via general procedure E. The reaction was carried out using the following amounts: P8-BC2a (89 mg, 0.122 mmol), porphyrin P8 (83 mg, 0.175 mmol), Pd(PPh3)2Cl2 (8.55 mg, 0.0122 mmol), DMF (25 mL), and Et3N (12.5 mL). The crude product was purified by flash chromatography and eluted with a gradient of hexane:CH2Cl2 and CH2Cl2:MeOH. Subsequent purification by preparative TLC gave the preparative TLC in 78% yield.

[0308] [ka]

[0309] Example 21: P11-BC3 dyad

[0310] Synthesized via general procedure E. The reaction was carried out using the following amounts: BC3 (7.2 mg, 15.02 μmol), porphyrin P11 (9.2 mg, 18.02 μmol), K2CO3 (10 mg, 72.1 μmol), Pd(PPh3)4 (5.2 mg, 4.51 μmol), toluene (2 mL), and DMF (1 mL). The crude product was purified by flash chromatography and eluted with a gradient of hexane:CH2Cl2 to give a red / brown solid (6.6 mg, 56%).

[0311] [ka]

[0312] Example 21: P12-BC4 dyad

[0313] Synthesized via general procedure E. The reaction was carried out using the following amounts: BC4 (20 mg, 38 μmol), porphyrin P12 (17 mg, 32 μmol), K2CO3 (21 mg, 152 μmol), Pd(PPh3)4 (11 mg, 9.5 μmol), toluene (4 mL), and DMF (2 mL). The crude product mixture was purified by flash chromatography and eluted with a gradient of hexane:CH2Cl2 to give a red-brown solid (2.7 mg, 10%).

[0314] Example 22: P11-BC1-1a

[0315] [ka]

[0316] BC1 (50.0 mg, 90 μmol), 4-methoxycarbonylphenylboronic acid (24 mg, 90 μmol), Pd(PPh3)4 (20 mg, 18 μmol), and K2CO3 (124 mg, 896 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (50 mL). The flask was evacuated for 1.0 h and degassed by three evacuation-refill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / DMF (15.0 mL, 2:1) using an argon-filled syringe. The resulting mixture was stirred at 80 °C for 17.5 h. The reaction flask was removed from the heat and cooled to room temperature. EtOAc (20 mL) was added, washed with NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated. It was redissolved in a minimal amount of CH2Cl2 and eluted on a 12 g SiO2 column with 10-100% CH2Cl2 in hexanes to give a green solid in 34 mg (62%) yield.

[0317] Example 23: P11-BC1-1b

[0318] Porphyrin P11 (34 mg, 67 μmol, 1.2 equiv.), P11-BC1-1a (34 mg, 55 μmol), Pd(PPh3)4 (19 mg, 17.0 μmol), and CS2CO3 (54 mg, 166 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (50 mL). The flask was evacuated for 60 min and degassed by three evacuation-refill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / DMF (12 mL, 2:1) using an argon-filled syringe. The resulting mixture was stirred at 90 °C for 18.5 h. The reaction flask was removed from the heat and cooled to room temperature. EtOAc was added to the reaction mixture, which was washed with NaHCO3, aqueous brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in a minimal amount of CH2Cl2 and silica caked and purified using a 12 g SiO2 column and eluted with 10-100% CH2Cl2 in hexanes for 28 min to give a dark solid in 37 mg (72%) yield.

[0319] Example 24: P11-BC1-1c

[0320] P11-BC1-1b (30 mg, 33 μmol) in THF (8.0 mL) and MeOH (4.0 mL) was treated with 5N aqueous NaOH (4.0 mL). The reaction mixture was refluxed at 70° C. for 2.0 h. The reaction flask was removed from the heat and cooled to room temperature. 1N aqueous HCl (100.0 mL) was added and stirred for 10 min. CH2Cl2 was added, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. It was used as is for the next step.

[0321] Example 25: P11-BC1 dyad 1

[0322] P11-BC1-1c (30 mg, 33 μmol), TSTU (15 mg, 49 μmol), and TEA (20 mg, 197 μmol, 27 μL) were dissolved in DMF (8.0 mL) and stirred at room temperature in the dark under argon for 1.5 h. 2-Maleimidoethylamine hydrochloride (18 mg, 102 μmol) was added and stirred at room temperature under argon overnight. The reaction mixture was quenched with CHCl, washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was dissolved in a minimum amount of CHCl and silica caked. Elution on a 24 g SiO column with 10-100% CHCl in hexanes, then switched to 75% EtOAc in hexanes (total 42 min) gave a brown solid in 20 mg (59%).

[0323] Example 26: P11-BC1-2a

[0324] [ka]

[0325] BC1 (30.0 mg, 54 μmol), porphyrin P11 (33.0 mg, 65 μmol, 1.2 equiv.), Pd(PPh3)4 (19 mg, 16.0 μmol), and CS2CO3 (53 mg, 161 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (50 mL). The flask was evacuated for 1.0 h and degassed by three evacuation-refill cycles. The mixture was dissolved by the addition of anhydrous toluene / DMF (12.0 mL, 2:1) purged with argon using an argon-filled syringe. The resulting mixture was stirred at 80 °C for 18.5 h. The reaction flask was removed from the heat and cooled to room temperature. EtOAc (20 mL) was added, washed with NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated. It was redissolved in a minimal amount of CH2Cl2 and silica caked and eluted on a 12 g SiO2 column with 10-100% CH2Cl2 in hexanes for 25 min to give a brown solid in 29 mg (63%) yield.

[0326] Example 27: P11-BC1 dyad 2

[0327] P11-BC1-2a (29.0 mg, 34 μmol), 4-methoxycarbonylphenylboronic acid (11 mg, 40 μmol, 1.2 equiv.), Pd(PPh3)4 (7.8 mg, 6.7 μmol), and K2CO3 (46 mg, 336 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (50 mL). The flask was evacuated for 1.0 h and degassed by three evacuation-refill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / DMF (12.0 mL, 2:1) using an argon-filled syringe. The resulting mixture was stirred at 80° C. for 18.0 h. The reaction flask was removed from the heat and cooled to room temperature. EtOAc (20 mL) was added, washed with NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated, redissolved in a minimum amount of CH2Cl2, and loaded onto a 12 g SiO2 column, eluted with 10-100% CH2Cl2 in hexanes for 30 min to give a brown solid in 4.7 mg (15%) yield.

[0328] Example 28: P1-BC1a.

[0329] [ka]

[0330] BC1 (55.8 mg, 100.0 μmol), porphyrin P1 (43.1 mg, 105.0 μmol), tetrakis(triphenylphosphine)palladium(0), (11.6 mg, 10.0 μmol), and potassium carbonate (138.2 mg, 1.0 mmol) were added to an oven-dried, vacuum-cooled, Ar-flushed 25 mL Schlenk flask equipped with a stir bar. The flask was sealed with a septum, evacuated, and flushed with Ar (3X). DMF (10.0 mL) was added. The flask was evacuated for 1 min, then flushed with Ar, and placed in a preheated oil bath at 80° C. and stirred under low flow of Ar. After 16 h, the reaction was cooled, diluted with EtOAc (40 mL), and washed with water (4×50 mL), then brine, dried over sodium sulfate, filtered, and concentrated. The residue was loaded onto Celite (750 mg, then 150 mg) in DCM and eluted on a 24 g silica column with 10-75% DCM in hexane. The desired product was isolated as a solid, 24.3 mg (27%). Absorption maxima (Abs max) (toluene): 380, 405, 516, 740 nm; emission maxima (em max) (toluene): 745 nm.

[0331] Example 29: P1-BC1 dyad

[0332] P1-BC1a (20.7 mg, 23.3 μmol), methyl 4-ethynylbenzoate (7.5 mg, 46.6 μmol), and bis(triphenylphosphine)palladium(II) dichloride (1.6 mg, 2.3 μmol) were added to a 10 mL Schlenk flask equipped with a stir bar. The flask was evacuated and flushed with Ar (3X). DMF (4.8 mL) was added followed by triethylamine (2.4 mL). The flask was placed in an oil bath preheated to 80° C. and stirred under low flow of Ar. After 16 h, the reaction was cooled and diluted with EtOAc (30 mL). The organic layer was washed with water (4×40 mL) and brine, then washed with sodium sulfate, filtered, and concentrated. The residue was loaded onto Celite (300 mg) in DCM and the cake was eluted onto a 12 g silica column with 20-90% DCM in hexanes for 15 min. The desired major product was isolated as a brownish red solid, 9.6 mg (43%). Absorption maxima (Abs max) (toluene): 405, 529, 760; emission maxima (em max) (toluene): 765 nm.

[0333] Example 30: P1-BC2 dyad

[0334] [ka]

[0335] BC2 (20.0 mg, 29.7 μmol), porphyrin P1 (26.8 mg, 65.2 mg), and bis(triphenylphosphine)palladium(II) dichloride (6.2 mg, 8.9 μmol) were added to an oven-dried 25 mL Schlenk flask equipped with a stir bar. The flask was sealed with a septum and evacuated for 1 h. The flask was flushed with Ar, evacuated, and flushed again with Ar (2X). DMF (6.0 mL) was added, followed by triethylamine (3.0 mL). The flask was evacuated with stirring for 1 min, then flushed with Ar, and placed in a preheated oil bath at 80° C. Stirred under low flow of Ar. After 16 h, the reaction was diluted with EtOAc (50 mL) and the organic layer was washed with water (5 x 50 mL) and brine, then dried over sodium sulfate, filtered, and rinsed with DCM. The sample was loaded onto Celite and eluted with 0-38% EtOAc in hexanes for 10 min, subsequently increased to 80% EtOAc, then eluted with 0-3% MeOH in DCM for 8 min. 21.9 mg (55%) of the desired product was isolated. Absorption maxima (Abs max) (toluene): 405, 499, 795 nm; emission maxima (em max) (toluene): 804 nm.

[0336] Example 31: P1d, P8, and P1

[0337] [ka]

[0338] For the synthesis of P1a, see Org. Process Res. Dev. 2003, 7, 799. P1a was isolated as an off-white solid in 58% yield.

[0339] For the synthesis of P1b, see Tetrahedron 1994, 50, 11427. The crude P1b was purified by flash chromatography and eluted with a gradient of hexane:EtOAc to give a thick orange liquid that solidified under vacuum in 81% yield.

[0340] For the synthesis of P1c, see J. Porphyrins Phthalocyanines 2005, 9, 554. P1c was isolated in 91% yield as a thick brown / orange liquid and was used directly in the next step.

[0341] General Procedure A. For P1d, a solution of P1c (0.81 g, 2.16 mmol) in THF (10 mL) was treated with propylamine (3.9 mL, 47.4 mmol) and the solution was stirred at room temperature for 2 h. Concentrated to dryness and dried under high vacuum overnight. Isolated (0.99 g, 2.16 mmol, 100%). Step 1: Isolated material P1a (0.32 g, 2.16 mmol) and EtOH (216 mL) were treated with Zn(OAc)2 (3.96 g, 21.6 mmol). The mixture was refluxed open to air overnight, cooled to room temperature, and concentrated. The crude product was purified by flash chromatography and eluted with a gradient of hexane:CH2Cl2 to give a dark purple solid (0.43 g, 36%).

[0342] General Procedure B. For P8, K2CO3 (54 mg, 0.39 mmol) was added to a solution of P1d (0.18 g, 0.33 mmol) in THF:MeOH (1:1 v / v, 30 mL) and stirred at room temperature for 1.5 h. The mixture was diluted with CH2Cl2, washed with H2O and brine, dried, filtered, and concentrated to give a dark red / purple solid (0.16 g, 100%).

[0343] For general procedure C.P1, Zn porphyrin P8 (0.16 g, 0.33 mmol) was treated with 20% TFA in CH2Cl2 (20 mL) and stirred at room temperature until complete. The reaction was quenched by slowly pouring the crude mixture into a stirred solution of saturated aqueous NaHCO3. The pH was adjusted to neutral if necessary and the layers were separated. The aqueous layer was washed with CH2Cl2 and the combined organics were washed with brine, dried, filtered and concentrated. The crude product was purified by flash chromatography and eluted with a gradient of hexane:CH2Cl2 to give a purple solid (0.116 g, 86%).

[0344] Example 32: P2c, P2d, and P2

[0345] [ka]

[0346] For the synthesis of P2a, see Org. Process Res. Dev. 2003, 7, 799. P2a was isolated as a brown solid in 65% yield.

[0347] For the synthesis of P2b, see J. Porphyrins Phthalocyanines 2005, 9, 554. P2b was isolated as a green solid in 44% yield and used directly in the next step.

[0348] P2c was synthesized via general procedure A (see synthesis of P1d). The crude mixture was purified by flash chromatography and eluted with a gradient of hexane:CH2Cl2 to give a dark red / purple solid as a mixture of methyl and ethyl esters in 11% yield.

[0349] For P2d, a solution of porphyrin P2c (0.39 g, 0.77 mmol), MeOH (5 mL), and THF (10 mL) was treated with 5 M aqueous NaOH (5 mL) and refluxed for 1.5 h. Concentrated to remove MeOH and THF and acidified with 1 M aqueous HCl. The precipitate was collected by filtration, air-dried, and dried under high vacuum overnight to give a dark red solid (0.34 g, 90%).

[0350] General Procedure D. For P2, 4-methylmorpholine (100 mL, excess) was added to a solution of porphyrin P2d (100 mg, 0.20 mmol) in CHCl:THF (3:1 v / v, 20 mL) at room temperature and stirred for 15 min. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (43 mg, 0.243 mmol) was added and the mixture was stirred at room temperature for 1.5 h. After 1.5 h, 4-dimethylaminopyridine (DMAP, 27 mg, 0.22 mmol), 4-aminomethylphenylboronic acid pinacol ester (38 mg, 0.21 mmol), and CHCl (16 mL) were added and the mixture was stirred at room temperature for 1.5 h. Celite was added to the crude mixture and concentrated to dryness. The mixture was purified by flash chromatography and eluted with a gradient of CH2Cl2:MeOH to give a dark red solid (98.6 mg, 69%).

[0351] Example 33: P3b, P3c, P3d, and P3

[0352] [ka]

[0353] For the synthesis of P3a, see Org. Process Res. Dev. 2003, 7, 799.

[0354] P3b was synthesized via general procedure A. The crude product was purified by flash chromatography and eluted with a gradient of hexane:CH2Cl2 to give a dark solid in 18% yield.

[0355] P3c was synthesized via general procedure C. The red solid was isolated in 84% yield and used directly in the next step.

[0356] For the synthesis of P3d, porphyrin P3c (144.7 mg, 257.2 μmol) was added to a 100 mL RBF equipped with a stir bar. THF (12.8 mL) was added followed by MeOH (6.4 mL) and 5 M aqueous NaOH (6.4 mL) was added dropwise. The solution was heated at 70° C. for 5 h. The reaction was cooled to room temperature and placed in a cold water bath. 1 M aqueous HCl (27 mL) was added in portions and the aqueous layer was removed. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. 131.2 mg (93%) of a dark red solid was isolated. MS: [M+H] + Calculated 549.3; observed 549.4.

[0357] For the synthesis of P3, porphyrin P3d (60.0 mg, 109.4 μmol) was added to a flame-dried 100 mL RBF equipped with a stir bar. The flask was evacuated / flushed with Ar and 2:1 DCM / THF was added (10.9 mL) followed by 4-methylmorpholine (60.1 μL, 546.8 μmol) pipetted directly into the solution in one portion. After 15 min, 2-chloro-4,6-dimethoxy-1,3,5-triazine (23.0 mg, 131.2 μmol) was added. The reaction was stirred at room temperature under Ar. After 1 h, 4-dimethylaminopyridine (14.7 mg, 120.3 μmol) and 4-aminomethylphenylboronic acid pinacol ester (28.0 mg, 120.3 μmol) were added followed by additional DCM (10.9 mL). After 2 h, the crude reaction mixture was loaded onto Celite (540 mg) and the cake onto a 24 g silica column was eluted with 0-4% MeOH in DCM for 10 min. The product was dried to give 67.2 mg (80%). Absorption maximum (Abs max) (toluene): 409,503 nm; emission maximum (em max) (toluene): 633,702 nm.

[0358] Example 33: P4

[0359] [ka]

[0360] P4 was synthesized via general procedure D. The crude mixture was purified by flash chromatography and eluted with a gradient of CH2Cl2:MeOH to give a dark red solid in 90% yield.

[0361] Example 34: P5

[0362] [ka]

[0363] Porphyrin P3d (60.0 mg, 109.4 μmol) was added to a flame-dried 100 mL RBF equipped with a stir bar. The flask was evacuated / flushed with Ar and 2:1 DCM / THF was added (10.9 mL) followed by 4-methylmorpholine (60.1 μL, 546.8 μmol) pipetted all at once directly into the solution. After 15 min, 2-chloro-4,6-dimethoxy-1,3,5-triazine (23.0 mg, 131.2 μmol) was added. The reaction was stirred at room temperature under argon. After 1 h, 4-dimethylaminopyridine (14.7 mg, 120.3 μmol) and 4-bromobenzylamine (22.4 mg, 120.3 μmol) were added followed by DCM (10.9 mL). After 2 h, the crude reaction mixture was loaded onto Celite (540 mg) and the cake onto a 24 g SiO2 column was eluted with 0-4% MeOH in DCM for 12 min. The product was dried to give 69.7 mg (71%, 80% pure).

[0364] Example 35: P6

[0365] [ka]

[0366] For the synthesis of P6a, see Bioconjugate Chem. 2006, 17, 638. P6a was isolated as a brown solid in 91% yield.

[0367] For the synthesis of P6b, see Bioconjugate Chem. 2006, 17, 638. P6b was isolated as a brown foam in 92% yield and used directly in the next step.

[0368] P6c was synthesized via general procedure A. The crude product was purified by flash chromatography and eluted with a gradient of hexane:CH2Cl2 to give a red solid in 13% yield.

[0369] P6 was synthesized via general procedure C. The red solid was isolated in 80% yield and used directly in the next step.

[0370] Example 36: P7

[0371] [ka]

[0372] For P7a, porphyrin P6 (50 mg, 86 μmol), Pd2(dba)3 (24 mg, 26 μmol), and P(o-tol)3 (65 mg, 214 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (25 mL). The flask was evacuated for 1 h and degassed by three evacuation-backfill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / TEA (12 mL, 5:1) using an argon-filled syringe. A sample of trimethylsilylacetylene (36 uL, 257 μmol) was added, and the resulting mixture was stirred at 60° C. overnight. After 18.0 h, the reaction was removed from the heat and EtOAc was added to quench, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under high vacuum rotary evaporation to give a reddish solid in ∼52 mg (100%) yield.

[0373] For P7, porphyrin P7a (52 mg, 87 μmol) in THF / MeOH (20 mL, 1:1) was treated with K2CO3 (14 mg, 104 μmol) for 30 min. The crude reaction mixture was diluted with CHCl2, washed with water, brine, extracted, and dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by dissolving in a minimum amount of CHCl2 and eluting with 0-40% CHCl2 in hexanes on a 12 g SiO2 column to give a dark green solid in 44 mg (80%) yield.

[0374] Example 37: P8

[0375] [ka]

[0376] P8 was formed in the manner described for porphyrin P1.

[0377] Example 38: P9

[0378] [ka]

[0379] P9a was synthesized via general procedure A. The crude product was purified by flash chromatography and eluted with 1:1 hexane:CH2Cl2 to 100% CH2Cl2 to 95:5 CH2Cl2:MeOH to give a dark red / purple solid as a mixture of methyl and ethyl esters in 40% yield.

[0380] P9 was synthesized via general procedure B. The crude product was purified by flash chromatography and eluted with a gradient of hexane:CH2Cl2 to give a red solid in 38% yield.

[0381] Example 39: P10

[0382] [ka]

[0383] For the synthesis of P10a, see Bioconjugate Chem. 2006, 17, 638. The crude P10a was triturated with hexane and the yellow / brown solid was collected by filtration, dried under high vacuum, and isolated in 81% yield.

[0384] P10 was synthesized via general procedure A. The crude product was purified by flash chromatography and eluted with a gradient of hexanes:CH2Cl2 to give a pink / purple solid as a mixture of methyl and ethyl esters in 8% yield.

[0385] Example 40: P11

[0386] [ka]

[0387] For the synthesis of P11a, see Bioconjugate Chem. 2006, 17, 638. The crude brown foam was isolated in 77% yield and used directly in the next step.

[0388] P11b was synthesized via general procedure A. The crude product was purified by flash chromatography and eluted with a gradient of hexanes:CH2Cl2 to give a red / brown solid in 11% yield.

[0389] P11 was synthesized via general procedure B. The crude product was purified by flash chromatography and eluted with a gradient of hexane:CH2Cl2 to give an orange solid in 49% yield.

[0390] Example 41: P12

[0391] [ka]

[0392] For P12a, see Bioorg. Med. Chem. 2003, 11, 2695. The crude product was purified by flash chromatography and eluted with a gradient of hexane:CH2Cl2 to give a thick, pale orange liquid that solidified upon freezing in 61% yield.

[0393] P12b was synthesized via general procedure A. The crude mixture was purified by flash chromatography and eluted with a gradient of hexane:CH2Cl2 to give a purple solid in 14% yield.

[0394] P12 was synthesized via general procedure C. A dark solid was isolated in 74% yield.

[0395] Example 42: P13

[0396] [ka]

[0397] P13a was synthesized via general procedure A. The crude mixture was purified by flash chromatography and eluted with a gradient of hexanes:CH2Cl2 to give a red / brown solid in 17% yield.

[0398] P13 was synthesized via general procedure B. The crude mixture was purified by flash chromatography and eluted with a gradient of hexane:CH2Cl2 to give a purple solid in 59% yield.

[0399] Example 43: C1

[0400] [ka]

[0401] For C1b, compound C1a (prepared as described in J. Porph. Phthal, 2009, 13, 1098-1110) (1.24 g, 2.93 mmol), Ph-Bpin (1.20 g, 5.86 mmol), Pd(PPh3)4 (1.02 g, 0.879 mmol), and Cs2CO3 (2.86 g, 8.79 mmol) were placed in an oven-dried (200 mL) Schlenk flask equipped with a stir bar. The flask was evacuated for 1.5 h and degassed by three evacuation-refill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / DMF (60 mL, 2:1) using an argon-filled syringe. The resulting mixture was stirred at 90° C. for 17.0 h. The reaction flask was removed from the heat and .about.112 mg of palladium scavenger was added and stirred at room temperature for 60 min. It was washed with EtOAc, brine, and water, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on a 40 g SiO2 column, eluted with a minimal amount of CH2Cl2 and 0-25% EtOAc in hexanes for 42 min to give a yellow solid in 0.818 g (67%) yield.

[0402] For C1c, compound C1b (818 mg, 1.95 mmol) was dissolved in MeOH (37 mL) and THF (37 mL). Aqueous KOH (5N, 37 mL) was added and the reaction mixture was refluxed at 100 °C overnight. The reaction flask was removed from the heating oil bath and cooled to room temperature. EtOAc was added and washed with water and brine. The aqueous layer was extracted with additional EtOAc (3x). The combined organic layers were dried (Na2SO4), filtered, concentrated, and dried under high vacuum to give 282 mg (54%) of compound C1c as a light brown solid.

[0403] In general procedure F (used for C1e), a suspension of compound C1c (0.342 g, 1.28 mmol) and compound C1d (prepared as described in J. Org. Chem, 2013, 78, 10678-10691) (0.598 g, 1.28 mmol) in CHCl (37 mL) was treated with p-toluenesulfonic acid monohydrate (1.22 g, 6.42 mmol) in methanol (8.6 mL) and stirred at room temperature for 40 min. The resulting mixture was treated with 2,2,6,6-tetramethylpiperidine (2.2 mL, 10 equiv.) for 5-10 min. The reaction mixture was concentrated on a rotary evaporator, and the resulting brown solid was suspended in acetonitrile (128 mL) and treated with zinc acetate (3.53 g, 19.3 mmol), 2,2,6,6-tetramethylpiperidine (5.4 mL, 25 equiv.), and silver trifluoromethanesulfonate (0.99 g, 3.85 mmol). The resulting suspension was refluxed for 16.5 h. The flask was removed from the heating oil bath and cooled to room temperature. Concentration on a rotary evaporator formed a dark solid. The residue was dissolved in ethyl acetate (300 mL) and filtered through a bed of silica gel on a glass frit, washed with excess EtOAc (300 mL) until the eluate was clear, and concentrated. The residue was redissolved in CH2Cl2 and prepared as a silica cake. The cake was loaded onto a 40 g SiO column and eluted with 0-30% EtOAc in hexanes for 25 min. The major green fractions were combined, concentrated, and dried under high vacuum to give a green solid in 439 mg (49%) yield.

[0404] For C1, C1e (408 mg, 589 μmol) was placed in a round-bottom flask. A mixture of CH2Cl2 (42.1 mL) and TFA (841 μL) was added and the reaction was stirred at room temperature for 1.5 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (85 mL), washed with brine (85 mL), dried (Na2SO4), filtered, and concentrated. Recrystallization in MeOH / CH2Cl2 (20 mL) gave compound C1 (284 mg, 76%) as a dark solid powder.

[0405] Example 44: C2

[0406] [ka]

[0407] For C2b (prepared as described in J. Org. Chem, 2013, 78, 10678-10691), a solution of p-toluenesulfonic acid hydrate (p-TsOH-HO, 4.45 g, 23.4 mmol) in MeOH (32 mL) was added to a suspension of C2a (prepared as described in Org. Process Res. Dev. 2005, 9, 651-659) (0.89 g, 4.68 mmol) and C1d (prepared as described in J. Org. Chem, 2013, 78, 10678-10691) (2.18 g, 4.68 mmol) in DCM (140 mL). The mixture was stirred at room temperature for 40 min, and 2,2,6,6-tetramethylpiperidine (TMP, 8.77 mL, 52 mmol) was added. The mixture was concentrated to dryness. The residue was suspended in CH3CN (500 mL) and treated with zinc acetate (Zn(OAc)2, 12.88 g, 70.2 mmol), copper triflate (AgOTf, 3.61 g, 14.04 mmol), and TMP (20 mL, 119 mmol). The mixture was refluxed overnight, cooled to room temperature, and concentrated. The crude product was purified by column chromatography with a hexane:EtOAc gradient to give a blue / green solid (0.464 g, 16%).

[0408] For general procedure G (used to prepare C2) (prepared as described in J. Org. Chem, 2013, 78, 10678-10691), zinc chlorin C2b (0.296 g, 0.48 mmol) was treated with a solution of trifluoroacetic acid (TFA, 4 mL) in DCM (50 mL). The solution was stirred at room temperature for 2 h and washed with saturated aqueous NaHCO3 and H2O. The organic layer was dried, filtered, and concentrated. The residue was purified by column chromatography (silica gel dry load; 24 g column; 100% hexane to 3:2 hexane:DCM) to give a green solid (0.1 g, 38%).

[0409] Example 45: C3

[0410] [ka]

[0411] For C3a, chlorin C2 (100 mg, 181 μmol), Pd2(dba)3 (50 mg, 54 μmol), and P(o-tol)3 (138 mg, 452 μmol) were placed in an oven-dried Schlenk flask equipped with a stir bar (50 mL). The flask was evacuated for 1 h and degassed by three evacuation-refill cycles. The flask was evacuated for 1 h and degassed by three evacuation-refill cycles. The mixture was dissolved by the addition of argon-purged anhydrous toluene / TEA (18 mL, 5:1) using an argon-filled syringe. A sample of trimethylsilylacetylene (75 uL, 542 μmol) was added, and the resulting mixture was stirred at 60° C. overnight. After 17.5 h it was removed from the heat and palladium scavenger (44 mg) was added and stirred at room temperature for 1 h. It was concentrated under high vacuum rotary evaporation and dissolved in a minimum amount of CH2Cl2 to give a silica cake. It was loaded onto a 12 g SiO2 column and eluted with 0-50% hexane in CH2Cl2 to give a green solid in 70 mg (68%) yield.

[0412] For C3, chlorin C3a (70 mg, 123 μmol) in THF / MeOH (28 mL, 1:1) was treated with K2CO3 (20 mg, 147 μmol) for 30 min. The reaction mixture was diluted with CHCl2, washed with water (20 mL) and brine (20 mL), extracted, dried over anhydrous Na2SO4, filtered, and concentrated. It was dissolved in a minimum amount of CHCl2 and silica caked. It was eluted on a 12 g SiO2 column with 0-40% EtOAc in hexanes for 21 min to give a dark green solid in 44 mg (72%) yield.

[0413] Example 46: C4

[0414] [ka]

[0415] C4 was prepared as described in Chem PhotoChem, 2020, 4, 601-611.

[0416] Example 47: C5

[0417] [ka]

[0418] C5 was prepared as described in Chem PhotoChem, 2020, 4, 601-611.

[0419] Example 48: C6

[0420] [ka]

[0421] C6b was prepared by general procedure F from C6a (prepared as described in J. Porph. Phthal, 2009, 13, 1098-1110) and C1d.

[0422] C6 was prepared by general procedure G.

[0423] Example 49: BC1

[0424] [ka]

[0425] BC1 was prepared as described in J. Org. Chem., 2010, 75, 1016-1039.

[0426] Example 50: BC2

[0427] [ka]

[0428] BC2 was prepared as described in Org. Biomol. Chem., 2014, 12, 86-103.

[0429] Example 51: BC3

[0430] [ka]

[0431] Compound BC3a (prepared as described in J. Org. Chem., 2010, 75, 1016-1039) (40.6 mg, 101.37 mmol) in THF (40 mL) was treated with a solution of NBS (18 mg, 101.37 mmol) in THF (1 mL) at room temperature. Stirred at room temperature for 1 h, diluted with CHCl, and washed with saturated aqueous NaHCO. The organic layer was dried, filtered, and concentrated. The crude mixture was purified by flash chromatography and eluted with a gradient of hexane:CHCl to give a green solid (33.8 mg, 70%).

[0432] Example 52: BC4

[0433] [ka]

[0434] BC4 was prepared as described in Org. Lett., 2016, 18, 4590. Bacteriochlorin BC3 (33.8 mg, 70.5 mmol) and Pd(PPh3)2Cl2 (5 mg, 7.05 mmol) were placed in a Schlenk flask and placed under high vacuum for 1 h. 1,2-Dichloroethane was degassed with a stream of argon for 1 h. After 1 h under high vacuum, the solid was subjected to three argon fill / drain cycles. 1,2-DCE (14 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (102 mL, 1420 mmol), and NEt3 (200 mL, 1420 mmol) were added to the flask. The flask was placed in a preheated oil bath and heated at 90 °C for 17 h. After 17 h, the crude mixture was cooled to room temperature, concentrated, and purified by flash chromatography and eluted with a gradient of hexanes:CH2Cl2 to give a green solid (33.5 mg, 90%).

[0435] Example 53: Dyad Photophysical Data

[0436] The photophysical properties of the samples were tested in toluene at room temperature and excited at 405 nm, and the results are shown in Table 1 below.

[0437] [Table 1]

[0438] Example 54: Comparative Example Porphyrin Photophysical Data

[0439] The photophysical properties of the samples were tested in toluene at room temperature and excited at 405 nm, and the results are shown in Table 2 below.

[0440] [Table 2]

[0441] Example 55: Effect of Linking Groups at P3-C1 and P5-C3 on Photophysical Properties

[0442] FIG. 5 shows the fluorescence spectrum of compound P3-C1 (Example 4). P3-C1 shows no residual emission from the porphyrin. FIG. 6 shows the fluorescence spectrum of compound P5-C3 (Example 6). Emission spectra were collected at room temperature in toluene. For P5-C3, the emission of the porphyrin is evident, indicating reduced energy transfer. P5-C3 contains a more rigid linker between the chlorine and porphyrin than P3-C1, resulting in greater spatial separation of the two components and lower energy transfer.

[0443] Figure 7 shows the fluorescence emission spectra of P3-C1 and P5-C3 at the same sample concentration. The brightness of P3-C1 is significantly increased relative to P5-C3. Brightness (molar extinction coefficient x fluorescence quantum yield): 84,700 (P3-C1), 13,900 (P5-C3).

[0444] Example 56: Effects of Beta Linkage and Meso Linkage on P11-BC3

[0445] Without being bound to a particular theory, the effect of the linkage position between the porphyrin and hydroporphyrin may affect the photophysical properties of the compound, as shown in Figure 8. Emission spectra were collected using 0.5 μM solutions in toluene. Brightness (molar extinction coefficient x fluorescence quantum yield): 19,900 (P11-BC3 meso), 45,100 (P11-BC1 beta). Thus, P11-BC1 with beta linkages produced significantly brighter emission than P11-BC1 with meso linkages.

[0446] Example 57: Comparison of brightness between hydroporphyrin monomers and porphyrin-hydroporphyrin dyads

[0447] The brightness was calculated using an excitation wavelength of 405 nm for hydroporphyrin monomers with emission wavelengths of about 660, about 680, about 715, or about 800 nm, and for fluorescent compounds containing porphyrin and hydroporphyrin structurally similar to the hydroporphyrin monomers. The brightness was calculated as the product of the molar extinction coefficient at 405 nm and the fluorescence quantum yield in toluene at room temperature. Table 3 provides the emission wavelengths of the hydroporphyrin monomers and the corresponding dyads, the brightness of the hydroporphyrin monomers excited at 405 nm, the brightness of the dyads excited at 405 nm, and the fold change in brightness of the hydroporphyrin monomers compared to the brightness of the dyads.

[0448] [Table 3]

[0449] As shown in Table 3, the brightness of the dyads was significantly increased over the hydroporphyrin monomers alone. The absorbance maximum of the dyads was shifted toward 405 nm relative to that of the corresponding monomers. The full width half maximum (FWHM), a measure of the narrowness of the emission peak, was maintained or improved for the dyads compared to the structurally related monomers. In some cases, the fluorescence quantum yield of the dyads was greater than that of the corresponding monomers.

[0450] The foregoing is illustrative of the present invention and is not to be construed as limiting the present invention. The present invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

1. A fluorescent compound comprising: a first porphyrin; and First Hydroporphyrin Including, wherein said first porphyrin is attached to said first hydroporphyrin.

2. 2. The compound of claim 1, wherein the first porphyrin has the structure of one of Formulas Ia or Ib: 【Chemistry 1】 or 【Chemistry 2】 Where: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently a group selected from the group consisting of a hydrogen atom, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkylalkyl, a cycloalkylalkenyl, a cycloalkylalkynyl, a heterocyclo, a heterocycloalkyl, a heterocycloalkenyl, a heterocycloalkynyl, an aryl, an aryloxy, an arylalkyl, an arylalkenyl, an arylalkynyl, a heteroaryl, a heteroarylalkyl, a heteroarylalkenyl, a heteroarylalkynyl, an alkoxy, a halogen atom, a mercapto, an azido, a cyano, a formyl, a carboxylic acid, a hydroxyl, a nitro, an acyl, an alkylthio, an amino, an alkylamino, an arylalkylamino, a disubstituted amino, an acylamino, an acyloxy, an ester, an amide, a sulfoxyl, a sulfonyl, a sulfonate, a sulfonic acid, a sulfonamide, a urea, an alkoxyl acylamino, an aminoacyloxy, a hydrophilic group, a linking group, a bioconjugable group, a surface attachment group, and a targeting group; R 3 and R 5 taken together represent a fused aromatic or heteroaromatic ring system; or R 4 and R 7 taken together represent a fused aromatic or heteroaromatic ring system; or R 9 and R 10 taken together represent a fused aromatic or heteroaromatic ring system; or R 10 and R 11 together represent a fused aromatic or heteroaromatic ring system, and M 1 is a metal atom, if present, Here, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 At least one of is a direct bond to the first hydroporphyrin or a bond to a linking group attached to the first hydroporphyrin.

3. The compound according to claim 1 or 2, wherein the first hydroporphyrin is a chlorin.

4. The compound according to claim 1 or 2, wherein the first hydroporphyrin is a bacteriochlorin.

5. 3. The compound of claim 1 or 2, wherein the first hydroporphyrin has a structure of one of Formulas IIa to IId: 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 or 【Chemistry 6】 Where: R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 are each independently a group selected from the group consisting of a hydrogen atom, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkylalkyl, a cycloalkylalkenyl, a cycloalkylalkynyl, a heterocyclo, a heterocycloalkyl, a heterocycloalkenyl, a heterocycloalkynyl, an aryl, an aryloxy, an arylalkyl, an arylalkenyl, an arylalkynyl, a heteroaryl, a heteroarylalkyl, a heteroarylalkenyl, a heteroarylalkynyl, an alkoxy, a halogen atom, a mercapto, an azido, a cyano, a formyl, a carboxylic acid, a hydroxyl, a nitro, an acyl, an alkylthio, an amino, an alkylamino, an arylalkylamino, a disubstituted amino, an acylamino, an acyloxy, an ester, an amide, a sulfoxyl, a sulfonyl, a sulfonate, a sulfonic acid, a sulfonamide, a urea, an alkoxyl acylamino, an aminoacyloxy, a hydrophilic group, a linking group, a bioconjugable group, a surface attachment group, and a targeting group; R 20 and R 21 taken together are =O or spiroalkyl; or R 22 and R 23 taken together are =O or spiroalkyl; or R 28 and R 33 taken together are =O or spiroalkyl; or R 29 and R 33 taken together are =O or spiroalkyl; or R 24 and R 25 taken together represent a fused aromatic or heteroaromatic ring system; or R 25 and R 26 taken together represent a fused aromatic or heteroaromatic ring system; or R 26 and R 27 taken together represent a fused aromatic or heteroaromatic ring system; or R 30 and R 31 taken together represent a fused aromatic or heteroaromatic ring system; or R 31 and R 32 taken together represent a fused aromatic or heteroaromatic ring system; or R 32 and R 33 taken together represent a fused aromatic or heteroaromatic ring system; and M 2 is a metal atom, if present, Here, R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34 At least one of is a direct bond to the first hydroporphyrin or a bond to a linking group attached to the first hydroporphyrin.

6. the first hydroporphyrin has the structure of Formula Ia or Formula Ib, R 32 is a direct bond to the first hydroporphyrin or a bond to a linking group attached to the first hydroporphyrin, and R 30 The compound of claim 5 , wherein:

7. 3. The compound of claim 1 or 2, wherein the first porphyrin is attached to the first hydroporphyrin via a direct bond between the first porphyrin and the first hydroporphyrin.

8. 3. The compound of claim 1 or 2, further comprising a linking group between the first porphyrin and the first hydroporphyrin, the linking group attaching the first porphyrin to the first hydroporphyrin.

9. 3. The compound according to claim 1 or 2, wherein the linking group is selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a heterocyclo group, a heteroaryl group, an amino group, an amido group, or a peptidyl group, which may be substituted or unsubstituted.

10. 3. The compound according to claim 1, wherein the linking group is selected from the group consisting of an ethyne group, an ethane group, a p-phenylene group, a 4,4'-biphenyl group, a 4,4"-terphenyl group, a 1,4-diphenylethyne group, a phenylethyne group, a thienyl group, or a peptidyl group, which may be substituted or unsubstituted.

11. 3. The compound of claim 1, wherein the linking group comprises at least one substituent that modifies the maximum emission wavelength of the compound.

12. 3. The compound of claim 1 or 2, wherein the linking group comprises at least one site for a bioconjugation reaction.

13. 3. The compound of claim 1 or 2, wherein the compound further comprises a water-solubilizing group.

14. 3. The compound of claim 1 or 2, wherein the compound is excited at wavelengths in the violet region of the visible light spectrum.

15. 3. The compound of claim 1 or 2, wherein the compound comprises one or more additional porphyrins.

16. The compound of claim 1 or 2, wherein the compound further comprises a second porphyrin.

17. 17. The compound of claim 16, wherein the first hydroporphyrin is between the first porphyrin and the second porphyrin.

18. 17. The compound of claim 16, wherein the second porphyrin is between the first porphyrin and the first hydroporphyrin.

19. 3. The compound of claim 1 or 2, wherein the first porphyrin and / or the second porphyrin have a structure of Formula Ia and / or the first hydroporphyrin has a structure of Formula IIa or IIc.

20. 3. The compound of claim 1 or 2, wherein the first porphyrin and / or the second porphyrin has a structure of formula Ib and / or the first hydroporphyrin has a structure of formula IIb or IId.

21. the first hydroporphyrin has a structure of Formula IIa or Formula IIb, and R 20 , R 21 , R 22 , and R 23 The compound according to claim 1 or 2, wherein each is independently a hydrogen atom or alkyl.

22. the first hydroporphyrin has a structure of Formula IIc or Formula IId, and R 20 , R 21 , R 22 , R 23 , R 28 , R 29 , R 33 , and R 34 The compound according to claim 1 or 2, wherein each is independently a hydrogen atom or alkyl.

23. The compound of claim 1 or 2, wherein the compound further comprises at least one bioconjugable group.

24. 24. The compound of claim 23, wherein the compound further comprises an attachment moiety between the first porphyrin and / or the first hydroporphyrin and the at least one bioconjugable group.

25. The compound of claim 1 or 2, wherein the compound further comprises an auxochrome.

26. 26. The compound of claim 25, wherein the auxochrome is selected from the group consisting of acyl, acyloxy, ester, carboxylic acid, cyano, sulfonyl, sulfoxyl, alkene, alkyne, arene, amino, nitro, hydroxy, mercapto, and / or alkoxy groups, which may be substituted or unsubstituted.

27. The compound of claim 1 or 2, wherein the compound further comprises at least one additional chromophore.

28. 3. The compound of claim 1 or 2, wherein the lowest energy singlet excited state of the first porphyrin is greater than the lowest energy singlet excited state of the first hydroporphyrin.

29. The compound of claim 1 or 2, further comprising a biomolecule.

30. 3. The compound according to claim 1 or 2, wherein the compound is excited at a wavelength of 405 nm.

31. 3. The compound according to claim 1 or 2, wherein the compound emits at wavelengths in the red and / or near infrared region of the visible light spectrum.

32. 3. The compound of claim 1 or 2, wherein the compound has increased brightness compared to the brightness of the hydroporphyrin alone.

33. The compound is 10,000M -1 cm -1 Over 110,000, 200,000, 300,000, 400,000 or 500,000M -1 cm -1 Brightness at maximum absorbance in the range of 8,000M -1 cm -1 More than 90,000, 100,000, 200,000, 300,000, 400,000 or 500,000M -1 cm -1 3. The compound according to claim 1 or 2, having a brightness at absorbance at 405 nm in the following range:

34. The compound according to claim 1 or 2, wherein the compound has a reduced luminescence intensity for the first porphyrin compared to the luminescence intensity of the first porphyrin alone, or has no luminescence intensity for the first porphyrin.

35. 3. The compound of claim 1 or 2, wherein the compound has a fluorescence quantum yield of energy transfer from the first porphyrin to the first hydroporphyrin of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%.

36. 3. The compound of claim 1 or 2, wherein energy transfer from the first porphyrin to the first hydroporphyrin is less than about 100 picoseconds.

37. 3. The compound of claim 1 or 2, wherein the compound has an absorption and emission spectrum that includes an emission peak from the first hydroporphyrin having a second intensity, and wherein there are no additional emission peaks or emission peaks having an intensity greater than the second intensity between the excitation wavelength and the emission peak of the compound.

38. 3. The compound of claim 1 or 2, wherein the first hydroporphyrin of the compound has an emission wavelength having a full width at half maximum of the emission peak of about 14 nm to about 50 nm.

39. The first porphyrin alone has a molecular weight of at least about 200,000 M -1 cm -1 The compound according to claim 1 or 2, having a molar extinction coefficient of

40. The compound according to claim 1 or 2, wherein the compound has a molar extinction coefficient and / or a fluorescence quantum yield greater than the molar extinction coefficient and / or the fluorescence quantum yield, respectively, of the first hydroporphyrin alone.

41. 3. The compound of claim 1 or 2, wherein the compound has a fluorescence quantum yield at 405 nm of about 0.04 to about 0.

34.

42. The compound has an absorbance maximum of about 120,000 or more, about 450,000, about 750,000, about 1,000,000, or about 1,250,000 M -1 cm -1 and having a molar extinction coefficient in the range of about 115,000 or more, about 350,000, about 450,000, about 750,000, about 1,000,000, or about 1,250,000M -1 cm -1 3. The compound according to claim 1 or 2, having a molar extinction coefficient at 405 nm in the following range:

43. 3. The compound of claim 1 or 2, wherein the compound has a second lowest (Qx) energy absorption band that is red-shifted relative to the excitation wavelength of the first porphyrin.

44. 3. The compound of claim 1 or 2, wherein the compound has a peak emission wavelength and a peak excitation wavelength, and the difference between the peak emission wavelength and the peak excitation wavelength is at least 50 nm or 80 nm.

45. 3. The compound of claim 1 or 2, wherein the compound has an emission wavelength from a first porphyrin that does not overlap with an emission wavelength from the first hydroporphyrin.

46. 3. The compound according to claim 1 or 2, wherein the compound has a brightness greater than that of the first porphyrin alone and / or a brightness greater than that of the first hydroporphyrin alone.

47. A particle comprising the compound of claim 1.

48. 48. The particle of claim 47, wherein the particle is a microparticle or a nanoparticle.

49. 49. The particle of claim 47 or 48, wherein the particle comprises a shell and a core, and the compound is present in the core.

50. 49. The particle of claim 47 or 48, wherein the compound is encapsulated in a polymer, and the polymer forms the shell.

51. The compound is attached to a polymer represented by Formula IIIa or Formula IIIb: ABC (IIIa), or CAB (IIIb) Where: A is the compound; B is the polymer; C is any bioconjugated group as described above; 51. The particle of claim 50.

52. 49. The particle of claim 47 or 48, wherein the compound is attached to the surface of the particle.

53. 49. The particle of claim 47 or 48, wherein the particle is soluble in water or an aqueous solution.

54. 13. A composition or kit comprising a compound according to claim 1 and / or particles comprising a compound according to claim 1.

55. 55. The composition or kit of claim 54, wherein the composition or kit further comprises water and the compound and / or the particles are present in water.

56. 55. The composition or kit of claim 54, wherein the composition or kit is free of organic solvents.

57. A composition or kit comprising: a first compound having a first absorption and emission spectrum that includes a first emission wavelength; and a second compound having a second absorption and emission spectrum including a second emission wavelength. Including, wherein the first emission wavelength and the second emission wavelength are different and / or distinct, and the first compound and the second compound are compounds according to claim 1 or 2. The composition or kit.

58. 58. The composition or kit of claim 57, wherein the first compound and the second compound are each excited by the same excitation wavelength.

59. Use of a compound according to claim 1, a particle comprising a compound according to claim 1, or a composition or kit comprising a compound according to claim 1 and / or a particle comprising a compound according to claim 1 in flow cytometry.

60. 1. A method for detecting cells and / or particles using flow cytometry, comprising: Labeling cells and / or particles with a compound according to claim 1, a particle comprising a compound according to claim 1, or a composition comprising a particle comprising a compound according to claim 1; and detecting said compounds by flow cytometry, thereby detecting cells and / or particles; Including, The method.

61. An agent for use in detecting a tissue and / or an agent in a subject, comprising: The agent comprises a compound according to claim 1, a particle comprising the compound according to claim 1, or a composition comprising a particle comprising the compound according to claim 1; and said compound is detected in said subject, thereby detecting said tissue and / or said agent; The agent.

62. 1. An agent for use in treating cells and / or tissues in a subject in need thereof, comprising: The agent comprises a compound according to claim 1, a particle comprising the compound according to claim 1, or a composition comprising a particle comprising the compound according to claim 1; and The subject or a portion thereof is irradiated with light of a wavelength and intensity sufficient to treat cells and / or tissue. The agent comprising:

63. The method of claim 62, wherein the cells and / or tissue are hyperproliferative tissue.

64. 13. Use of a compound according to claim 1, a particle comprising a compound according to claim 1, or a composition or kit comprising a particle comprising a compound according to claim 1 in imaging and / or microscopy.

65. 1. An agent for use in imaging tissues and / or agents in a subject, comprising: The agent comprises a compound according to claim 1, a particle comprising the compound according to claim 1, or a composition or kit comprising a particle comprising the compound according to claim 1; and The compound is detected in the subject, thereby imaging the tissue and / or the agent. The agent.

66. 66. The method of claim 65, wherein detecting the compound in the subject comprises illuminating the subject or a portion thereof with light of a wavelength and intensity sufficient to generate ultrasound.

67. 66. The method of claim 65, wherein detecting the compound in the subject comprises detecting ultrasound.

68. The method of claim 65, wherein the method of imaging the tissue and / or the agent in the subject comprises photoacoustic imaging of the tissue and / or the agent.

69. 13. Use of a compound according to claim 1, a particle comprising a compound according to claim 1, or a composition or kit comprising a particle comprising a compound according to claim 1 in an assay.

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