Diarylpiperidone hybrid conjugates and methods of use thereof

Abstract

Curcumin-based compounds are described herein. The disclosed compounds contain a curcumin mimic moiety linked to an anti-inflammatory drug via an amino acid linker. These compounds show anticancer and / or anti-inflammatory activities, and may have a higher potency compared to the free curcumin mimic alone and / or the free anti-inflammatory drug alone. Pharmaceutical compositions containing the compounds and methods of using the compounds or pharmaceutical composition thereof for treating cancer and / or inflammation diseases / disorders are also described.

Description

[0001] DIARYLPIPERIDONE HYBRID CONJUGATES AND METHODS OF USE THEREOF

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims the benefit and priority to U.S. Application No. 63 / 569,533, filed March 25, 2024, the disclosure of which is incorporated herein by reference.

[0004] FIELD OF THE INVENTION

[0005] This invention is generally in the field of curcumin-based compounds and methods of use thereof.

[0006] BACKGROUND OF THE INVENTION

[0007] Drug development is a challenging task. Among various resources, natural products are considered the most reliable source to identify lead compounds. In the past, many designs of therapeutics were inspired by biologically active natural compounds. Curcumin is a natural compound (isolated from Curcuma longa) that has gained tremendous interest because of its diverse pharmacological properties. However, this natural product suffers in clinical applications due to its low bioavailability. Further, the traditional “one molecule, one target” drug discovery paradigm is not adequately effective for diseases with complexities, such as cancers.

[0008] There remains a need to develop curcumin-based compounds that present multiple biological activities.

[0009] Therefore, it is the object of the present invention to provide curcumin-based compounds.

[0010] It is a further object of the present invention to provide curcumin-based compounds that present multiple biological activities.

[0011] It is a further object of the present invention to provide curcumin-based compounds with high potency.

[0012] It is a further object of the present invention to provide methods of using the curcumin- based compounds for treating complex diseases, such as cancer.

[0013] It is a further object of the present invention to provide methods of using the curcumin- based compounds for cancer therapy.

[0014] SUMMARY OF THE INVENTION

[0015] Curcumin-based compounds (also referred to herein as “curcumin mimics hybrid conjugates” or “compounds”) are described herein. The disclosed compounds contain a curcumin mimic moiety linked to a drug moiety, such as an anti-inflammatory drug moiety, via an amino acid linker. Preferably, the curcumin mimic moiety of the compounds is a diarylpiperidone moiety. Preferably, the drug moiety (e.g., an anti-inflammatory drug moiety) contains a -(C=O)- group that is converted from a carboxylic acid group of the corresponding drug.

[0016] In some forms, the disclosed compounds show both anti-cancer and anti-inflammatory properties. In some forms, the compounds can have a higher potency compared to a corresponding curcumin mimic alone and / or a corresponding anti-inflammatory drug alone. For example, the compounds show an anti-cancer activity that is higher than a corresponding curcumin mimic alone and / or a corresponding anti-inflammatory drug alone. For example, the compounds show an antiinflammatory activity that is higher than a corresponding curcumin mimic alone and / or a corresponding anti-inflammatory drug alone. For example, the compounds show an anti-cancer activity that is higher than a corresponding curcumin mimic alone and / or a corresponding antiinflammatory drug alone; and / or an anti-inflammatory activity that is higher than a corresponding curcumin mimic alone and / or a corresponding anti-inflammatory drug alone.

[0017] In some forms, the disclosed compounds can have the structure of Formula I: wherein: (i) each occurrence of R is independently hydrogen, a halide (e.g., F, Cl, Br, etc.), an unsubstituted Ci-G, alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.), an alkoxyl (e.g., methoxy, ethoxy, etc.), -(C=O)H, -(C=O)Ri, (C=O)OH, -(C=O)ORi, - (C=O)X1, -NH2, -NHR1, -NR1R2, -CF3, -CN, -(S=O)OH, -NO2, -SH, -OH, -(CGO)NHRi , - (C=0)NR]R2; (ii) each occurrence of R’ is independently hydrogen or a side chain of an amino acid (e.g., a naturally occurring amino acid); (iii) n is an integer from 1 to 6, from 1 to 5, from 1 to 4, or from 1 to 3; and (iv) jsan anti-inflammatory drug moiety. Optionally, the -(C=O)- group of the anti-inflammatory drug moiety is converted from a carboxylic acid group of the corresponding drug.

[0018] In some forms, Ri and R2can be independently hydrogen or an unsubstituted Ci-Ce alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.).

[0019] In some forms, the disclosed compounds can have the structure of Formula II:

[0020] wherein R, R’, n, and are as defined above for Formula T.

[0021] In some forms, each occurrence of R is independently hydrogen, a halide (e.g., F, Cl, Br, etc.), an unsubstituted C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, etc.), an alkoxyl (e.g., methoxy, ethoxy, etc.). In some forms, each occurrence of R is independently hydrogen, F, Cl, CH3, or OCH3.

[0022] In some forms, each occurrence of R’ is independently hydrogen or a side chain of a naturally occurring amino acid (e.g., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine). In some forms, each occurrence of R’ is independently hydrogen or an unsubstituted C1-C4 alkyl. In some forms, each occurrence of R’ is independently hydrogen or -CH3. In some forms, R’ is hydrogen.

[0023] In some forms, is a non-steroidal anti-inflammatory drug (NSAID) moiety, such as an ibuprofen moiety, a naproxen moiety, a diclofenac moiety, a mefenamic acid moiety, an indomethacin moiety, or an aspirin moiety, where the carboxylic acid group of the free drug has been converted to the -(C=O)- of . in some forms, the anti-inflammatory drug moiety is an inflammatory drug moiety is a dichloroacetic acid moiety having the structure of Exemplary compounds are shown below.

[0024]

[0025]

[0026] In some forms, the compounds have a corresponding curcumin mimic having the structure of Formula III; and a corresponding anti-inflammatory drug having the structure of Formula IV, wherein R and can be in any forms described herein.

[0027] Pharmaceutical compositions containing one or more of the compounds and optionally one or more pharmaceutically acceptable excipients are disclosed. The pharmaceutical compositions can be formulated for administration via a variety of routes, such as oral administration, intranasal administration, intramuscular administration, intravenous administration, intraperitoneal administration, subcutaneous administration, topical administration, or a combination thereof.

[0028] Optionally, the pharmaceutical composition further contains one or more additional active agent(s), such as one or more additional anticancer agent(s) and / or anti-inflammatory agent(s). Methods of using the compounds or pharmaceutical compositions containing the compounds for treating cancer and / or anti-inflammatory disease / disorder are also disclosed. In some forms, the compounds are particularly useful for treating cancer, such as breast cancer and / or colon cancer. Generally, the method for treating cancer includes a step of administering the compounds or pharmaceutical composition thereof to a subject in need thereof. In some forms, the cancer is a solid cancer, such as breast cancer or colon cancer. Typically, following the administration step, an effective amount of the compounds is administered to the subject to ameliorate one or more symptoms associated with the cancer in the subject. In some forms, the treatment effect is achieved by the anticancer property of the compounds, such as by killing cancer cells and / or reducing or preventing growth or proliferation of the cancer cells. In some forms, the treatment effect is achieved by the anti-inflammatory property of the compounds, such as by inhibiting one or more inflammation markers, e.g., COX-1, COX-2, TNF-a, NO, and / or IL-6. In some forms, the treatment effect is achieved by both the anticancer property and the antiinflammatory property of the compounds.

[0029] In some forms, the effective amount of compounds administered to the subject is from about 0.1 pg to about 1000 pg, from about 0.1 pg to about 500 pg, from about 0.1 pg to about 200 pg, from about 0.1 pg to about 100 pg, from about 0.5 pg to about 50 pg, from about 1 pg to about 1000 pg, from about 1 pg to about 500 pg, from about 1 pg to about 100 pg, from about 1 pg to about 50 pg, from about 1 pg to about 25 pg, from about 1 pg to about 10 pg, from about 0.1 pg to about 50 pg, from about 5 pg to about 50 pg, or from about 0.1 pg to about 20 pg per g of the subject. Optionally, the method further includes administering an additional active agent prior to, during, and / or subsequent to the administration of the pharmaceutical composition containing the compounds, optionally wherein the active agent is an anticancer agent or an anti-inflammatory agent, or a combination of both.

[0030] BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1A are bar graphs showing relative O.D of MCF10A cell lines at different concentrations of compounds NCMC1-NCMC5, respectively. Figure IB are bar graphs showing relative O.D of MCF7 cell lines at different concentrations of compounds NCMC1-NCMC5, respectively. Figure 1C are bar graphs showing relative O.D of MB231 cell lines at different concentrations of compounds NCMC1-NCMC5, respectively.

[0032] Figure 2 shows a general chemical structure of exemplary compounds composed of ibuprofen, an amino acid linker, and a curcumin mimic.

[0033] Figure 3 is a bar graph showing percent inhibition of COX-1, COX-2, IL-6, NO, and TNF-a using compounds J1-J17 and reference compounds, Ibuprofen and Indomethin, at a concentration of 10 pM.

[0034] Figure 4 is a bar graph showing percent inhibition of human mouse double minute 2 (MDM2-p53) binding protein homolog using compounds JLJ17 at a concentration of 10 pM. Figure 5 is a bar graph showing percent viability of 5637 cell line tested using Ibuprofen, 1ST- 5ST, and compounds J1-J5, at different concentrations (5pM and 10 pM), respectively.

[0035] Figure 6 is a bar graph showing percent viability of 5637 WT cell line tested using Ibuprofen, 1ST- 5ST, and compounds J1-J5, at different concentrations (5pM, IpM, 0.5pM, and O.lpM), respectively.

[0036] Figure 7 is a bar graph showing percent viability of MDA-MB231LUC cell line tested using Ibuprofen, 1ST- 5ST, and compounds J1-J5, at different concentrations (5pM and lOpM), respectively.

[0037] Figure 8 is a bar graph showing percent viability of MB231LUC cell line tested using Ibuprofen, 1ST- 5ST, and compounds J1-J5, at different concentrations (5pM, IpM, 0.5pM, and O. lpM), respectively.

[0038] Figure 9 is a bar graph showing percent viability of MCF-7 cell line tested using Ibuprofen, 1ST- 5ST, and compounds J1-J5, at different concentrations (5pM, IpM, 0.5pM, and O.lpM), respectively.

[0039] Figure 10 is a bar graph showing percent viability of MCF-12 cell line tested using compounds, Ibuprofen, 1ST- 5ST, and compounds J 1-J5, at different concentrations (5pM, IpM, 0.5pM, and O. lpM), respectively.

[0040] Figures 11A and 11B shows the NMR spectra of compound 10J using1H-NMR (Figure 11A) andnC-NMR (Figure 11B).

[0041] DETAILED DESCRIPTION OF THE INVENTION

[0042] It is to be understood that the disclosed compounds, compositions, and methods are not limited to specific synthetic methods, specific analytical techniques, or to particular reagents unless otherwise specified, and, as such, may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular forms and embodiments only and is not intended to be limiting.

[0043] “Substituted,” as used herein, refers to all permissible substituents of the compounds or functional groups described herein. In the broadest sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic groupings containing any number of carbon atoms, preferably 1-14 carbon atoms, and optionally include one or more heteroatoms such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats. Representative substituents include a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted aralkyl, a halogen, a hydroxyl, an alkoxy, a phenoxy, an aroxy, a silyl, a thiol, an alkylthio, a substituted alkylthio, a phenylthio, an arylthio, a cyano, an isocyano, a nitro, a substituted or unsubstituted carbonyl, a carboxyl, an amino, an amido, an oxo, a sulfinyl, a sulfonyl, a sulfonic acid, a phosphonium, a phosphanyl, a phosphoryl, a phosphonyl, an amino acid. Such a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted phenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted poly heteroaryl, a substituted or unsubstituted aralkyl, a halogen, a hydroxyl, an alkoxy, a phenoxy, an aroxy, a silyl, a thiol, an alkylthio, a substituted alkylthio, a phenylthio, an arylthio, a cyano, an isocyano, a nitro, a substituted or unsubstituted carbonyl, a carboxyl, an amino, an amido, an oxo, a sulfinyl, a sulfonyl, a sulfonic acid, a phosphonium, a phosphanyl, a phosphoryl, a phosphonyl, and an amino acid can be further substituted.

[0044] Heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is understood that “substitution” or “substituted” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e.. a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0045] “Alkyl,” as used herein, refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl, and cycloalkyl (alicyclic). In some forms, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30for branched chains), 20 or fewer, 15 or fewer, or 10 or fewer. Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, / -butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. Likewise, a cycloalkyl is a non-aromatic carbon-based ring composed of at least three carbon atoms, such as a nonaromatic monocyclic or nonaromatic polycyclic ring containing 3-30 carbon atoms, 3-20 carbon atoms, or 3-10 carbon atoms in their ring structure, and have 5, 6 or 7 carbons in the ring structure. Cycloalkyls containing a polycyclic ring system can have two or more non-aromatic rings in which two or more carbons are common to two adjoining rings (i.e., “fused cycloalkyl rings”). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, etc. "Substituted alkyl” refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can be any substituents described above, e.g., halogen (such as fluorine, chlorine, bromine, or iodine), hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), aryl, alkoxyl, aralkyl, phosphonium, phosphanyl, phosphonyl, phosphoryl, phosphate, phosphonate, a phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, oxo, sulfhydryl, thiol, alkylthio, silyl, sulfinyl, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, an aromatic or heteroaromatic moiety. -NRR’, wherein R and R’ are independently hydrogen, alkyl, or aryl, and wherein the nitrogen atom is optionally quatemized; -SR, wherein R is a phosphonyl, a sulfinyl, a silyl a hydrogen, an alkyl, or an aryl; -CN; -NO2; -COOH; carboxylate; -COR, -COOR, or -CON(R)2, wherein R is hydrogen, alkyl, or aryl; imino, silyl, ether, haloalkyl (such as -CF3, -CH2-CF3, -CCI3); -CN; -NCOCOCH2CH2;-NCOCOCHCH; and -NCS; and combinations thereof.

[0046] It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, aralkyl, azido, imino, amido, phosphonium, phosphanyl, phosphoryl (including phosphonate and phosphinate), oxo, sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), haloalkyls, -CN and the like. Cycloalkyls can be substituted in the same manner.

[0047] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.

[0048] “Heteroalkyl,” as used herein, refers to straight or branched chain, or cyclic carbon-containing alkyl radicals, or combinations thereof, containing at least one heteroatom on the carbon backbone. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quatemized. For example, the term “heterocycloalkyl group” is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulphur, or phosphorus.

[0049] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms and structural formula containing at least one carbon-carbon double bond. Alkenyl groups include straight-chain alkenyl groups, branched-chain alkenyl, and cycloalkenyl. A cycloalkenyl is a non-aromatic carbon-based ring composed of at least three carbon atoms and at least one carbon-carbon double bond, such as a nonaromatic monocyclic or nonaromatic polycyclic ring containing 3-30 carbon atoms and at least one carbon-carbon double bond, 3-20 carbon atoms and at least one carbon-carbon double bond, or 3-10 carbon atoms and at least one carbon-carbon double bond in their ring structure, and have 5, 6 or 7 carbons and at least one carbon-carbon double bond in the ring structure. Cycloalkenyls containing a polycyclic ring system can have two or more non-aromatic rings in which two or more carbons are common to two adjoining rings (i.e., “fused cycloalkenyl rings”) and contain at least one carbon-carbon double bond. Asymmetric structures such as (AB)C=C(C’D) are intended to include both the E and Z isomers. This may be presumed in structural formulae herein wherein an asymmetric alkene is present, or it may be explicitly indicated by the bond symbol C. The term "alkenyl" as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkenyls" and "substituted alkenyls,” the latter of which refers to alkenyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. The term “alkenyl” also includes “heteroalkenyl.”

[0050] The term “substituted alkenyl” refers to alkenyl moieties having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, oxo, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0051] “Heteroalkenyl,” as used herein, refers to straight or branched chain, or cyclic carbon-containing alkenyl radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term “heterocycloalkenyl group” is a cycloalkenyl group where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulphur, or phosphorus.

[0052] The term “alkynyl group” as used herein is a hydrocarbon group of 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond. Alkynyl groups include straight-chain alkynyl groups, branched-chain alkynyl, and cycloalkynyl. A cycloalkynyl is a non-aromatic carbon-based ring composed of at least three carbon atoms and at least one carbon-carbon triple bond, such as a nonaromatic monocyclic or nonaromatic polycyclic ring containing 3-30 carbon atoms and at least one carbon-carbon triple bond, 3-20 carbon atoms and at least one carbon-carbon triple bond, or 3-10 carbon atoms and at least one carbon-carbon triple bond in their ring structure, and have 5, 6 or 7 carbons and at least one carbon-carbon triple bond in the ring structure. Cycloalkynyls containing a polycyclic ring system can have two or more non-aromatic rings in which two or more carbons are common to two adjoining rings (i.e., “fused cycloalkynyl rings”) and contain at least one carbon-carbon triple bond. Asymmetric structures such as (AB)C=C(C”D) are intended to include both the E and Z isomers. This may be presumed in structural formulae herein wherein an asymmetric alkyne is present, or it may be explicitly indicated by the bond symbol C. The term "alkynyl" as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkynyls" and "substituted alkynyls,” the latter of which refers to alkynyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. The term “alkynyl” also includes “heteroalkynyl.”

[0053] The term “substituted alkynyl” refers to alkynyl moieties having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxy 1, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0054] “Heteroalkynyl,” as used herein, refers to straight or branched chain, or cyclic carbon-containing alkynyl radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term “heterocycloalkynyl group” is a cycloalkynyl group where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulphur, or phosphorus.

[0055] “Aryl,” as used herein, refers to C4-C26-membered aromatic rings or fused ring systems containing one aromatic ring and optionally one or more non-aromatic rings. Examples of aryl groups are benzene, tetralin, indane, etc. The term “substituted aryl” refers to an aryl group, wherein one or more hydrogen atoms on one or more aromatic rings are substituted with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (such as a ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as CF3, -CH2-CF3, -CCI3), -CN, aryl, heteroaryl, and combinations thereof.

[0056] “Heterocyclo” and “heterocyclyl” are used interchangeably, and refer to a cyclic radical attached via a ring carbon or nitrogen atom of a monocyclic ring or polycyclic ring system containing 3-30 ring atoms, 3-20 ring atoms, 3- 10 ring atoms, or 5-6 ring atoms, where the polycyclic ring system contains one or more non-aromatic rings and optionally one or more aromatic rings, where at least one non-aromatic ring contains carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O, C1-C10 alkyl, phenyl or benzyl, and optionally containing 1-3 double bonds and optionally substituted with one or more substituents. Heterocyclyl are distinguished from heteroaryl by definition. Heterocycles can be a heterocycloalkyl, a heterocycloalkenyl, a heterocycloalkynyl, etc, such as piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, dihydrofuro[2,3-£>]tetrahydrofuran, morpholinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl, 2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl, 6H-l,2,5-thiadiazinyl. Heterocyclic groups can optionally be substituted with one or more substituents as defined above for alkyl and aryl.

[0057] The term “heteroaryl” refers to C3-C26-membered aromatic rings or fused ring systems containing one aromatic ring and one or more non-aromatic rings, in which one or more carbon atoms on the aromatic ring structure have been substituted with a heteroatom. Suitable heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen. Examples of heteroaryl groups pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Examples of heteroaryl rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl and xanthenyl. One or more of the rings can be substituted as defined below for “substituted heteroaryl.”

[0058] The term “substituted heteroaryl” refers to a heteroaryl group in which one or more hydrogen atoms on one or more heteroaromatic rings are substituted with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (such as a ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as CF3, -CH2-CF3, -CCI3), -CN, aryl, heteroaryl, and combinations thereof.

[0059] The term “polyaryl” refers to a fused ring system that includes two or more aromatic rings and optionally one or more non-aromatic rings. Examples of polyaryl groups are naphthalene, anthracene, phenanthrene, chrysene, pyrene, corannulene, coronene, etc. When a fused ring system containing two or more aromatic rings and optionally one or more non-aromatic rings, in which one or more carbon atoms on one or more aromatic ring structures have been substituted with a heteroatom, the fused ring system can be referred to as a “heteropolyaryl” or “polyheteroaryl”. The terms “heteropolyaryl” and “polyheteroaryl” are used interchangeably herein.

[0060] The term “substituted polyaryl” refers to a polyaryl in which one or more of the aryls are substituted, with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (or quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof. When a polyheteroaryl is involved, the chemical moiety can be referred to as a “substituted polyheteroaryl.” The term “cyclic,” “cyclic ring” or “cyclic group” refers to a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted polycyclic ring (such as those formed from single or fused ring systems), such as a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted cycloalkynyl, or a substituted or unsubstituted heterocyclyl, that have from three to 30 carbon atoms, as geometric constraints permit. The substituted cycloalkyls, cycloalkenyls, cycloalkynyls, and heterocyclyls are substituted as defined above for the alkyls, alkenyls, alkynyls, and heterocyclyls, respectively.

[0061] The term “aralkyl” as used herein is an aryl group or a heteroaryl group having an alkyl, alkynyl, or alkenyl group as defined above attached to the aromatic group, such as an aryl, a heteroaryl, a polyaryl, or a polyheteroaryl. An example of an aralkyl group is a benzyl group.

[0062] The terms “alkoxyl” or “alkoxy,” “aroxy” or “aryloxy,” generally describe compounds represented by the formula -ORV, wherein Rvincludes, but is not limited to, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocycloalkenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted alkylaryl, a substituted or unsubstituted alkylheteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted carbonyl, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, and an amino. Exemplary alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. A “lower alkoxy” group is an alkoxy group containing from one to six carbon atoms. An “ether” is two functional groups covalently linked by an oxygen as defined below. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O- arakyl, -O-aryl, -0-heteroaryl, -O-polyaryl, -O-polyheteroaryl, -O-heterocyclyl, etc.

[0063] The term “substituted alkoxy” refers to an alkoxy group having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the alkoxy backbone. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, oxo, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

[0064] The term “ether” as used herein is represented by the formula A2OA', where A2and A1can be, independently, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, a substituted or unsubstituted carbonyl, an alkoxy, an amido, or an amino, described above.

[0065] The term “polyether” as used herein is represented by the formula: where A3can be, independently, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a phosphonium, a phosphanyl, a substituted or unsubstituted carbonyl, an alkoxy, an amido, or an amino, described above; g can be a positive integer from 1 to 30.

[0066] The term “phenoxy” is art recognized and refers to a compound of the formula -ORVwherein Rvis C(,Hs (z.e., -O-CeHs). One of skill in the art recognizes that a phenoxy is a species of the aroxy genus.

[0067] The term “substituted phenoxy” refers to a phenoxy group, as defined above, having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the phenyl ring. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxy 1, phosphonium, phosphanyl, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

[0068] The terms “aroxy” and “aryloxy,” as used interchangeably herein, are represented by -O-aryl or -0-heteroaryl, wherein aryl and heteroaryl are as defined herein.

[0069] The terms “substituted aroxy” and “substituted aryloxy,” as used interchangeably herein, represent -O-aryl or -O-heteroaryl, having one or more substituents replacing one or more hydrogen atoms on one or more ring atoms of the aryl and heteroaryl, as defined herein. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxy 1, phosphonium, phosphanyl, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0070] The term "amino" as used herein includes the group (tertiary amino), and (quaternary amino), wherein, E is absent, or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted poly heteroaryl, substituted or unsubstituted heterocyclyl, wherein independently of E, Rx, RX1, and Rxneach independently represent a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted poly heteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, an amino, or -(CH2)m-R ”; R ” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. The term “quaternary amino” also includes the groups where the nitrogen, Rx, RX1, and Rxnwith the N+to which they are attached complete a heterocyclyl or heteroaryl having from 3 to 14 atoms in the ring structure. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1 ,4-phenylene, cyclohexane- 1,2-diyl). The terms “amide” or “amido” are used interchangeably, refer to both “unsubstituted amido” and “substituted amido” and are represented by the general formula: wherein, E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, or a substituted or unsubstituted heterocyclyl, wherein independently of E, R and R’ each independently represent a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, an amino, or -(CH2)m-R’”, or R and R’ taken together with the N atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. In some forms, when E is oxygen, a carbamate is formed. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1 ,2-diyl, 1,4-phenylene, cyclohexane- 1 ,2-diyl).

[0071] “Carbonyl,” as used herein, is art-recognized and includes such moieties as can be represented by the general formula: wherein X is a bond, or represents an oxygen or a sulfur, and R represents a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, an amido, an amino, or (CH2)m-R”, or a pharmaceutical acceptable salt; E” is absent, or E” is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl; R’ represents a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, an amido, an amino, or -(CH2)m-R”; R” represents a hydroxyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E” groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1 ,4-phenylene, cyclohexane- 1,2-diyl). Where X is oxygen and R is defined as above, the moiety is also referred to as a carboxyl group. When X is oxygen and R is hydrogen, the formula represents a “carboxylic acid.” Where X is oxygen and R’ is hydrogen, the formula represents a “formate.” Where X is oxygen and R or R’ is not hydrogen, the formula represents an "ester.” In general, where the oxygen atom of the above formula is replaced by a sulfur atom, the formula represents a “thiocarbonyl” group. Where X is sulfur and R or R’ is not hydrogen, the formula represents a “thioester.” Where X is sulfur and R is hydrogen, the formula represents a “thiocarboxylic acid.” Where X is sulfur and R’ is hydrogen, the formula represents a “thioformate.” Where X is a bond and R is not hydrogen, the above formula represents a “ketone.” Where X is a bond and R is hydrogen, the above formula represents an “aldehyde.”

[0072] The term “phosphanyl” is represented by the formula wherein, E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, wherein independently of E, RV1and Rvueach independently represent a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g., a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, an amino, or -(CH2)m-R’”, or RV1and R™ taken together with the P atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1,2-diyl, 1,4- phenylene, cyclohexane- 1 ,2-diyl) .

[0073] The term “phosphonium” is represented by the formula wherein, E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, wherein independently of E, RV1, Rvn, and RVI" each independently represent a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, an amino, or -(CH2)m-R ”, or RV1, R™, and Rvintaken together with the P+atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, poly heteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1 ,2-diyl, 1,4-phenylene, cyclohexane- 1,2-diyl). The term “phosphonyl” is represented by the formula wherein E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl (e.g., a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted poly heteroaryl, a substituted or unsubstituted heterocyclyl, oxygen, alkoxy, aroxy, or substituted alkoxy or substituted aroxy, wherein, independently of E, RV1and R™ are independently a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a silyl, a thiol, an amido, an amino, or -(CHilm-R ’, or RV1and R™ taken together with the P atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1 ,4-phenylene, cyclohexane- 1,2-diyl). The term “phosphoryl” defines a phosphonyl in which E is absent, oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and independently of E, RV1and R™ are independently hydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above. When E is oxygen, the phosphoryl cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art. When E, RV1and Rvnare substituted, the substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1,2-diyl, 1,4- phenylene, cyclohexane- 1 ,2-diyl).

[0074] The term “sulfinyl” is represented by the formula wherein E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl (e.g., a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, wherein independently of E, R represents a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsuhstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted poly heteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, a phosphonyl, a silyl, a thiol, an amido, an amino, or -(CH2)m-R ”, or E and R taken together with the S atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1,2-diyl, 1,4- phenylene, cyclohexane- 1 ,2-diyl).

[0075] The term “sulfonyl” is represented by the formula wherein E is absent, or E is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl (e.g., a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, wherein independently of E, R represents a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted poly heteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, an amido, an amino, or -(CH2)m-R’”, or E and R taken together with the S atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R’” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1,2-diyl, 1,4- phenylene, cyclohexane- 1 ,2-diyl).

[0076] The term “sulfonic acid” refers to a sulfonyl, as defined above, wherein R is hydroxyl, and E is absent, or E is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted poly aryl, a substituted or unsubstituted polyheteroaryl, or substituted or unsubstituted heteroaryl. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1 ,4-phenylene, cyclohexane- 1,2-diyl).

[0077] The term “sulfate” refers to a sulfonyl, as defined above, wherein E is absent, oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and R is independently hydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above. When E is oxygen, the sulfate cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1,2-diyl, 1,4- phenylene, cyclohexane- 1 ,2-diyl) .

[0078] The term “sulfonate” refers to a sulfonyl, as defined above, wherein E is oxygen, alkoxy, aroxy, substituted alkoxy or substituted aroxy, as defined above, and R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, -(CH2)m-R’”, R’” represents a hydroxy group, substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, an amido, an amino, or a poly cycle; and m is zero or an integer ranging from 1 to 8. When E is oxygen, sulfonate cannot be attached to another chemical species, such as to form an oxygen-oxygen bond, or other unstable bonds, as understood by one of ordinary skill in the art. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1 ,4-phenylene, cyclohexane- 1,2-diyl).

[0079] The term “sulfamoyl” refers to a sulfonamide or sulfonamide represented by the formula wherein E is absent, or E is substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aralkyl (e.g., a substituted or unsubstituted alkylaryl, a substituted or unsubstituted cycloalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, wherein independently of E, R and R’ each independently represent a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbonyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted heterocyclyl, a hydroxyl, an alkoxy, a phosphonium, a phosphanyl, an amido, an amino, or -(CH2)m-R”’, or R and R’ taken together with the N atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R'” represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It is understood by those of ordinary skill in the art, that the E groups listed above are divalent (e.g., methylene, ethane- 1 ,2-diyl, ethene- 1,2-diyl, 1,4- phenylene, cyclohexane- 1 ,2-diyl).

[0080] The term “silyl group” as used herein is represented by the formula -SiRR’R,” where R, R’, and R” can be, independently, a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted carbonyl, a phosphonium, a phosphanyl, a phosphonyl, a sulfinyl, a thiol, an amido, an amino, an alkoxy, or an oxo, described above. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quartemized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0081] The terms “thiol” are used interchangeably and are represented by -SR, where R can be a hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl (e.g. a substituted or unsubstituted alkylaryl, a substituted or unsubstituted arylalkyl, etc.), a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, a substituted or unsubstituted carbonyl, a phosphonium, a phosphanyl, an amido, an amino, an alkoxy, an oxo, a phosphonyl, a sulfinyl, or a silyl, described above. Such substituents can be any substituents described above, e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), silyl, ether, ester, thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (e.g. quarternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0082] The disclosed compounds and substituent groups, can, independently, possess two or more of the groups listed above. For example, if the compound or substituent group is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can be substituted with a hydroxyl group, an alkoxy group, etc. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (z.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an ester group,” the ester group can be incorporated within the backbone of the alkyl group. Alternatively, the ester can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0083] The compounds and substituents can be substituted, independently, with the substituents described above in the definition of “substituted.”

[0084] The numerical ranges disclose individually each possible number that such a range could reasonably encompass, as well as any sub-ranges and combinations of sub-ranges encompassed therein. For example, in a given range carbon range of C3-C9, the range also discloses C3, C4, C5, Ce, C7, Cs, and C9, as well as any subrange between these numbers (for example, C4 -Ce), and any possible combination of ranges possible between these values. In yet another example, a given temperature range may be from about 25 °C to 30 °C, where the range also discloses temperatures that can be selected independently from about 25, 26, 27, 28, 29, and 30 °C, as well as any range between these numbers (for example, 26 to 28 °C), and any possible combination of ranges between these values.

[0085] Use of the term "about" is intended to describe values either above or below the stated value, which the term “about” modifies, to be within a range of approximately + / - 10%. When the term "about" is used before a range of numbers (i.e., about 1-5) or before a series of numbers (i.e., about 1, 2, 3, 4, etc.) it is intended to modify both ends of the range of numbers and / or each of the numbers recited in the entire series, unless specified otherwise.

[0086] The disclosed compounds and substituent groups, can, independently, possess two or more of the groups listed above. For example, if the compound or substituent group is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can be substituted with a hydroxyl group, an alkoxy group, etc. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an ester group,” the ester group can be incorporated within the backbone of the alkyl group. Alternatively, the ester can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0087] The compounds and substituents can be substituted with, independently, with the substituents described above in the definition of “substituted.”

[0088] II. Compositions

[0089] Described are curcumin-based compounds (also referred to herein as “curcumin mimics hybrid conjugates” or “compounds”). The disclosed compounds contain a curcumin mimic moiety linked to a drug moiety, such as an anti-inflammatory drug moiety, via an amino acid linker. Preferably, the curcumin mimic moiety of the compounds is a diarylpiperidone moiety. Preferably, the drug moiety (e.g., an anti-inflammatory drug moiety) contains a -(C=O)- group that is converted from a carboxylic acid group of the corresponding drug. The term “corresponding drug” refers to the drug in free form that can react with a first functional group of the amino acid linker, such as a primary amino group of the amino acid linker, and be converted to the drug moiety of the compound.

[0090] In some forms, the disclosed compounds show both anti-cancer and anti-inflammatory properties. In some forms, the compounds show an anti-cancer activity that is higher than a corresponding curcumin mimic alone and / or a corresponding anti-inflammatory drug alone. The term “corresponding curcumin mimic” refers to the curcumin mimic in free form that can react with a first functional group of the amino acid linker, such as a carboxylic acid group of the amino acid linker, and be converted to the curcumin mimic moiety of the compound. The term “corresponding anti-inflammatory drug” refers to the anti-inflammatory drug in free form that can react with a second functional group of the amino acid linker, such as a primary amino group of the amino acid linker, and be converted to the anti-inflammatory drug moiety of the compound. In some forms, the compounds show an anti-inflammatory activity that is higher than a corresponding curcumin mimic alone and / or a corresponding anti-inflammatory drug alone. In some forms, the compounds show an anti-cancer activity that is higher than a corresponding curcumin mimic alone and / or a corresponding anti-inflammatory drug alone; and / or an anti-inflammatory activity that is higher than a corresponding curcumin mimic alone and / or a corresponding anti-inflammatory drug alone.

[0091] Pharmaceutical formulations containing the compounds are also disclosed.

[0092] A. Curcumin-Based Compounds

[0093] In some forms, the disclosed compounds can have the structure of Formula I: wherein: (i) each occurrence of R is independently hydrogen, a halide (e.g., F, Cl, Br, etc.), an unsubstituted Ci-Cs alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.), an alkoxyl (e.g., methoxy, ethoxy, etc.), -(C=O)H, -(C=O)Ri, -(C=O)OH, -(C=O)ORi, - (C=O)X1, -NH2, -NHR], -NR1R2, -CF3, -CN, -(S=O)OH, -NO2, -SH, -OH, -(C=O)NHRi, - (C=O)NRIR2; (ii) each occurrence of R’ is independently hydrogen or a side chain of an amino acid (e.g., a naturally occurring amino acid); (iii) n is an integer from 1 to 6, from 1 to 5, from 1 to 4, or from 1 to 3; and (iv) is an anti-inflammatory drug moiety. Optionally, the -(C=O)- group of the anti-inflammatory drug moiety is converted from a carboxylic acid group of the corresponding drug.

[0094] In some forms, Ri and R2can be independently hydrogen or an unsubstituted Ci-Ce alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.).

[0095] In some forms, the disclosed compounds can have the structure of Formula II:

[0096] wherein R, R’, n, and are as defined above for Formula T.

[0097] In some forms, each occurrence of R is independently hydrogen, a halide (e.g., F, Cl, Br, etc.), an unsubstituted Ci-Ce alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, etc.), an alkoxyl (e.g., methoxy, ethoxy, etc.). In some forms, each occurrence of R is independently hydrogen, F, Cl, CH3, or OCH3.

[0098] In some forms, each occurrence of R’ is independently hydrogen or a side of a naturally occurring amino acid (i.e., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine). In some forms, each occurrence of R’ is independently hydrogen or an unsubstituted C1-C4 alkyl. In some forms, each occurrence of R’ is independently hydrogen or - CH3. In some forms, R’ is hydrogen.

[0099] In some forms, is a non-steroidal anti-inflammatory drug (NSAID) moiety, such as an ibuprofen moiety, a naproxen moiety, a diclofenac moiety, a mefenamic acid moiety, an indomethacin moiety, or an aspirin moiety, where the carboxylic acid group of the free drug has been converted to the -(C=O)- o . in some forms, the anti-inflammatory drug moiety is an inflammatory drug moiety is a dichloroacetic acid moiety having the structure of Exemplary compounds are shown below.

[0100]

[0101]

[0102] In some forms, the compounds have a corresponding curcumin mimic having the structure of Formula III; and a corresponding anti-inflammatory drug having the structure of Formula IV, wherein R and can be in any forms described above.

[0103] The compounds described herein may be neutral or may be one or more pharmaceutically acceptable salts, crystalline forms, non-crystalline forms, hydrates, or solvates, or a combination thereof. References to the compounds may refer to the neutral molecule, and / or those additional forms thereof collectively and individually from the context. Pharmaceutically acceptable salts of the compounds include the acid addition and base salts thereof.

[0104] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

[0105] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0106] Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

[0107] The compounds described herein may be in a prodrug form. The term "prodrug" refers to a pharmacologically inactive substance that is converted in the body (e.g., via enzymatic or non- enzymatic action, including pH dependent bioactivation) into a pharmacologically active drug. Exemplary groups that can convert the disclosed compounds to a prodrug form include, but are not limited to, hydroxyl, carboxyl, amine, phosphate, phosphonate, amidine, guanine and / or carbohydrate. These can be attached to any suitable position of the disclosed compounds to form a prodrug of the compounds.

[0108] The in vitro and in vivo inhibitory activity, anticancer effect, and anti-inflammatory effect of the compounds disclosed herein can be evaluated by using methods known in the art. Specific examples for evaluating the activity and effects of the compounds are described in the Examples below.

[0109] B. Pharmaceutical Composition Containing Curcumin-Based Compounds

[0110] Pharmaceutical compositions that contain one or more of the compounds described herein in a form suitable for in vitro or in vivo applications (such as administration to a mammal), are disclosed. The pharmaceutical composition may include one or more pharmaceutically acceptable carriers and / or one or more pharmaceutically acceptable excipients. For example, the pharmaceutical composition may be in the form of a liquid, such as a solution or a suspension, and contain a plurality of the disclosed compounds in an aqueous medium and, optionally, one or more suitable excipients for the liquid composition. Optionally, the pharmaceutical composition is in a solid form, and contains a plurality of the disclosed compounds and one or more suitable excipients for a solid composition.

[0111] 1. Carriers and Excipients

[0112] Suitable pharmaceutically acceptable carriers and excipients are generally recognized as safe (GRAS), and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. Representative carriers and excipients include solvents (including buffers), diluents, pH modifying agents, preservatives, antioxidants, suspending agents, wetting agents, viscosity modifiers, tonicity agents, and stabilizing agents, and a combination thereof.

[0113] Excipients can be added to a liquid or solid pharmaceutical composition (for in vivo or in vitro applications) to assist in sterility, stability (e.g. shelf-life), integration, and to adjust and / or maintain pH or isotonicity of the compounds in the pharmaceutical composition, such as diluents, pH modifying agents, preservatives, antioxidants, suspending agents, wetting agents, viscosity modifiers, tonicity agents, and stabilizing agents, and a combination thereof.

[0114] Compounds for administering to a subject in need thereof, such as a mammal, can be dissolved or suspended in a suitable carrier to form a liquid pharmaceutical formulation, such as sterile saline, phosphate buffered saline (PBS), balanced salt solution (BSS), viscous gel, or other pharmaceutically acceptable carriers for administration. The pharmaceutical formulation may also be a sterile solution, suspension, or emulsion in a nontoxic, parenterally acceptable diluent or solvent.

[0115] 2. Forms for Administration

[0116] The disclosed RhoA inhibitors can be formulated into a pharmaceutical composition, in a liquid form or a solid form, as a liquid formulation or a solid formulation for oral administration, mucosal administration (e.g. intravaginal administration, pulmonary administration, and / or administration to other mucosal surfaces), parenteral administration (e.g. intramuscular administration, intravenous administration, intraperitoneal administration, and subcutaneous administration), and / or topical administration to a subject. a. Oral Formulations

[0117] The pharmaceutical composition containing one or more of the disclosed compounds may be provided in a form suitable for oral administration to a subject, such as a mammal (i.e., an oral composition). Oral administration may involve swallowing, so that the compounds, optionally including additional active agent(s) in the pharmaceutical composition, enter the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compounds enter the blood stream directly from the mouth.

[0118] Compositions suitable for oral administration include solid compositions such as tablets, capsules containing particulates, liquids, powders, lozenges (including liquid-filled lozenges), chews, multi- and nano-particulates, gels, solid solutions, liposomes, films, ovules, sprays, and liquid compositions.

[0119] Liquid compositions for oral administration include suspensions, solutions, syrups, and elixirs. Such oral compositions may be employed as fillers in soft or hard capsules and can contain one or more suitable carriers and / or excipients, for example, water, ethanol, polyethylene glycol, propylene glycol, chitosan polymers and chitosan derivatives (e.g. N-trimethylene chloride chitosan, chitosan esters, chitosan modified with hydrophilic groups, such as amino groups, carboxyl groups, sulfate groups, etc.), methylcellulose, a suitable oil, one or more emulsifying agents, and / or suspending agents. Liquid compositions for oral administration may also be prepared by the reconstitution of a solid, for example, from a sachet.

[0120] Optionally, the compounds are included in a fast-dissolving and / or fast-disintegrating dosage form.

[0121] For tablet or capsule dosage forms, in addition to the compounds described herein, tablets generally contain disintegrants, binders, diluents, surface active agents, lubricants, glidants, antioxidants, colourants, flavoring agents, preservatives, or taste masking agents, or a combination thereof.

[0122] Examples of suitable disintegrants for forming a table or capsule dosage form containing the compounds include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant can have a concentration in a range from about 1 wt% to about 25 wt%, from about 5 wt% to about 20 wt% of the tablet or capsule dosage form containing the compounds.

[0123] Binders are generally used to impart cohesive qualities to a tablet composition containing the compounds. Suitable binders for forming a tablet or capsule formulation containing the compounds include, but are not limited to, microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, chitosan polymers and chitosan derivatives (e.g. N-trimethylene chloride chitosan, chitosan esters, chitosan modified with hydrophilic groups, such as amino groups, carboxyl groups, sulfate groups, etc.), hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

[0124] Suitable diluents for forming a table or capsule composition containing the compounds include, but are not limited to, lactose (as, for example, the monohydrate, spray-dried monohydrate or anhydrous form), chitosan polymers and chitosan derivatives (e.g. N-trimethylene chloride chitosan, chitosan esters, chitosan modified with hydrophilic groups, such as amino groups, carboxyl groups, sulfate groups, etc.), N-sulfonated derivatives of chitosan, quatemarized derivatives of chitosan, carbosyalkylated chitosan, microcrystalline chitosan, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablet or capsule composition containing the compounds may also contain surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc, in the coating. When present, surface active agents can have a concentration in a range from about 0.2 wt% to 5 wt% of the tablet or capsule formulation.

[0125] Tablet or capsule compositions containing the compounds also generally contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants can have a concentration in a range from about 0.25 wt% to 10 wt%, from about 0.5 wt% to about 3 wt% of the tablet or capsule composition.

[0126] Other possible excipients included in a tablet or capsule formulation containing the compounds include glidants (e.g. Talc or colloidal anhydrous silica at about 0.1 wt% to about 3 wt% of the table or capsule formulation), antioxidants, colourants, flavouring agents, preservatives and taste-masking agents. When present, glidants can have a concentration in a range from about 0.2 wt% to 1 wt% of the tablet or capsule composition.

[0127] An exemplary tablet composition contains up to about 80 wt% of the compounds described herein, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt % lubricant.

[0128] Tablet or capsule blends, including the compounds and one or more suitable excipients, may be compressed directly or by roller to form tablets. Tablet or capsule blends or portions of the blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final table or capsule composition may contain one or more layers and may be coated or uncoated; it may even be encapsulated in a particle, such as a polymeric particle or a liposomal particle.

[0129] Solid formulations containing the compounds for oral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations. b. Mucosal Formulation

[0130] The disclosed compounds can be formulated for pulmonary or mucosal administration. The administration can include delivery of the composition to the lungs, nasal, oral (sublingual, buccal), vaginal, or rectal mucosa.

[0131] For example, the compounds can also be administered intranasally or by oral inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (optionally an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as water, ethanol -water mixture, 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal or oral inhalation use, the powder may contain a bioadhesive agent, for example, chitosan or cyclodextrin. The term “aerosol” as used herein refers to any preparation of a fine mist of particles, which can be in solution or a suspension, whether or not it is produced using a propellant. Aerosols can be produced using standard techniques, such as ultrasonication or high-pressure treatment.

[0132] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of one or more of the compounds including, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

[0133] Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compounds described herein, a suitable powder base such as lactose or starch and a performance modifier such as 1 -leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0134] A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 pg to 20 mg of one or more of the compounds per actuation and the actuation volume may vary from 1 pl to 100 pl. A typical formulation may contain a plurality of the compounds disclosed herein, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used instead of propylene glycol include glycerol and polyethylene glycol.

[0135] Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations intended for inhaled / intranasal administration.

[0136] Formulations for inhaled / intranasal administration may be formulated to be immediate and / or modified release using for example, PGLA. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release formulations.

[0137] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the compounds are typically arranged to administer a metered dose or "puff". The overall daily dose will be administered in a single dose or, more usually, as divided doses throughout the day.

[0138] In some forms, the compounds can be formulated for pulmonary delivery, such as intranasal administration or oral inhalation. Carriers for pulmonary formulations can be divided into those for dry powder formulations and for administration as solutions. Aerosols for the delivery of therapeutic agents to the respiratory tract are known in the art. For administration via the upper respiratory tract, the compounds can be formulated into an aqueous solution, e.g., water or isotonic saline, buffered or un-buffered, or as an aqueous suspension, for intranasal administration as drops or as a spray. Such aqueous solutions or suspensions may be isotonic relative to nasal secretions and of about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7.0. Buffers should be physiologically compatible and include, simply by way of example, phosphate buffers. One skilled in the art can readily determine a suitable saline content and pH for an innocuous aqueous solution for nasal and / or upper respiratory administration.

[0139] In some forms, the aqueous solution is water, physiologically acceptable aqueous solutions containing salts and / or buffers, such as phosphate buffered saline (PBS), or any other aqueous solution acceptable for administration to an animal or human. Such solutions are well known to a person skilled in the art and include, but are not limited to, distilled water, de-ionized water, pure or ultrapure water, saline, phosphate-buffered saline (PBS). Other suitable aqueous vehicles include, but are not limited to, Ringer’s solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

[0140] In some forms, solvents that are low toxicity organic (i.e. nonaqueous) class 3 residual solvents, such as ethanol, acetone, ethyl acetate, tetrahydrofuran, ethyl ether, and propanol may be used for the formulations. The solvent is selected based on its ability to readily aerosolize the formulation. The solvent should not detrimentally react with the compounds. An appropriate solvent should be used that forms a suspension of the compounds. The solvent should be sufficiently volatile to allow formation of an aerosol of the solution or suspension. Additional solvents or aerosolizing agents, such as freons, can be added as desired to increase the volatility of the solution or suspension.

[0141] In some forms, the pharmaceutical formulations may contain minor amounts of surfactants or other excipients well known to those of the art. In this context, “minor amounts” means no excipients are present that might affect or mediate penetration of the compounds in tissues and that the excipients that are present in amount that do not adversely affect penetration of the compounds in tissues.

[0142] In some forms, the pharmaceutical formulations containing one or more of the compounds can be administered directly to the mucous membranes (including the surface membranes of the nose, lungs and mouth), such that compounds cross the mucosal layer and enters the underlying tissues.

[0143] Such formulations for direct application on the mucous membrane generally contain a dermatologically acceptable carrier that is suitable for application to the mucous membrane, has good aesthetic properties, is compatible with the active agents and any other components, and will not cause any untoward safety or toxicity concerns.

[0144] The carrier can be in a wide variety of forms. For example, emulsion carriers, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions, are useful herein. These emulsions can cover a broad range of viscosities, e.g., from about 100 cps to about 200,000 cps. These emulsions can also be delivered in the form of sprays using either mechanical pump containers or pressurized aerosol containers using conventional propellants. These carriers can also be delivered in the form of a mousse or a transdermal patch. Other suitable topical carriers include anhydrous liquid solvents such as oils, alcohols, and silicones (e.g., mineral oil, ethanol isopropanol, dimethicone, cyclomethicone, and the like); aqueous-based single phase liquid solvents (e.g., hydro- alcoholic solvent systems, such as a mixture of ethanol and / or isopropanol and water); and thickened versions of these anhydrous and aqueous-based single phase solvents (e.g. where the viscosity of the solvent has been increased to form a solid or semi-solid by the addition of appropriate gums, resins, waxes, polymers, salts, and the like). Examples of topical carrier systems useful in the present formulations are described in the following four references all of which are incorporated herein by reference in their entirety: “Sun Products Formulary” Cosmetics & Toiletries, vol. 105, pp. 122-139 (December 1990); “Sun Products Formulary,” Cosmetics & Toiletries, vol. 102, pp. 117-136 (March 1987); U.S. Pat. No. 5,605,894 to Blank et al., and U.S. Pat. No. 5,681,852 to Bissett.

[0145] Formulations for direct application on the mucous membrane may be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations. Thus, the compounds may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active agents. Examples of such formulations include drug-coated stents. c. Parenteral Formulations

[0146] Optionally, the pharmaceutical composition containing one or more of the disclosed compounds is in a form suitable for administration directly into the blood stream, into muscle, or into an internal organ. Suitable routes for such parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, epidural, intracerebroventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous delivery. Suitable means for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0147] For example, the pharmaceutical formulation containing one or more of the compounds is in a form suitable for intramuscular administration, intravenous administration, intraperitoneal administration, or subcutaneous administration, or a combination thereof.

[0148] Parenteral formulations containing the compounds described herein are typically aqueous solutions which can contain excipients such as salts, carbohydrates and buffering agents (e.g., from about pH 6.5 to about pH 8.0, from about pH 6.5 to about pH 7.4, from about pH 6.5 to about pH 7.0, from about pH 7.0 to pH 8.0, or from about pH 7.0 to about pH 7.4), but, for some applications, they may be more suitably formulated as a sterile aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

[0149] The liquid compositions containing the compounds for parenteral administration may be a solution, a suspension, or an emulsion.

[0150] The liquid pharmaceutically acceptable carrier forming the parenteral composition containing the compounds can include one or more physiologically compatible buffers, such as a phosphate buffers. One skilled in the art can readily determine a suitable saline content and pH for an aqueous carrier for administration (e.g., from about pH 6.5 to about pH 8.0, from about pH 6.5 to about pH 7.4, from about pH 6.5 to about pH 7.0, from about pH 7.0 to pH 8.0, or from about pH 7.0 to about pH 7.4).

[0151] Liquid compositions containing the compounds for parenteral administration may include one or more suspending agents, such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone, gum tragacanth, or lecithin. The liquid compositions may also include one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate.

[0152] Optionally, the liquid composition containing the compounds contains one or more solvents that are low toxicity organic (i.e., nonaqueous) class 3 residual solvents, such as ethanol, acetone, ethyl acetate, tetrahydofuran, ethyl ether, and propanol, and a combination thereof. Any such solvents included in the liquid formulation should not detrimentally react with the compounds or any additional active agents in the liquid composition. Solvents such as freon, alcohol, glycol, polyglycol, or fatty acid, can also be included in the liquid composition containing the compounds as desired to increase the volatility of the solution or suspension.

[0153] Liquid compositions containing the compounds for parenteral administration may also contain minor amounts of polymers, surfactants, or other pharmaceutically acceptable excipients known to those in the art. In this context, "minor amounts" means an amount that is sufficiently small to avoid adversely affecting uptake of the compounds by the targeted cells, such as pituitary gonadotrophs.

[0154] The preparation of parenteral compositions containing the compounds is typically under sterile conditions, for example, by lyophilisation, which can be accomplished using standard pharmaceutical techniques known to those skilled in the art.

[0155] Compositions for parenteral administration containing the compounds may be formulated to provide immediate and / or modified release of the active agent. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations. d. Topical Formulations

[0156] The compounds can be administered directly to the external surface of the skin or the mucous membranes (including the surface membranes of the nose, lungs and mouth), such that the compounds can cross the external surface of the skin or mucous membrane and enters the underlying tissues.

[0157] Formulations for topical administration generally contain a dermatologically acceptable carrier that is suitable for application to the skin, has good aesthetic properties, is compatible with the active agents and any other components, and will not cause any untoward safety or toxicity concerns.

[0158] The carrier can be in a wide variety of forms. For example, emulsion carriers, including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions, are useful herein. These emulsions can cover a broad range of viscosities, e.g., from about 100 cps to about 200,000 cps. These emulsions can also be delivered in the form of sprays using either mechanical pump containers or pressurized aerosol containers using conventional propellants. These carriers can also be delivered in the form of a mousse or a transdermal patch. Other suitable topical carriers include anhydrous liquid solvents such as oils, alcohols, and silicones (e.g., mineral oil, ethanol isopropanol, dimethicone, cyclomethicone, and the like); aqueous-based single phase liquid solvents (e.g., hydro- alcoholic solvent systems, such as a mixture of ethanol and / or isopropanol and water); and thickened versions of these anhydrous and aqueous-based single phase solvents (e.g. where the viscosity of the solvent has been increased to form a solid or semi-solid by the addition of appropriate gums, resins, waxes, polymers, salts, and the like). Examples of topical carrier systems useful in the present formulations are described in the following four references all of which are incorporated herein by reference in their entirety: “Sun Products Formulary” Cosmetics & Toiletries, vol. 105, pp. 122-139 (December 1990); “Sun Products Formulary,” Cosmetics & Toiletries, vol. 102, pp. 117-136 (March 1987); U.S. Pat. No. 5,605,894 to Blank et al., and U.S. Pat. No. 5,681,852 to Bissett.

[0159] Formulations containing the compounds for topical administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release formulations. Thus, the compounds may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the compounds. Examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres. e. Amount of Curcumin-Based Compounds

[0160] Pharmaceutical compositions typically contain an effective amount of the compound(s) and one or more pharmaceutically acceptable carriers and / or excipients. As used herein, the term “effective amount” means any amount of the compounds that is sufficient to achieve the desired therapeutic, prophylactic, and / or diagnostic effect on a biological sample or in a subject to which it is administered. Depending on the specific condition to be treated and / or the route of administration, such an effective amount of the compounds can be from about 0.01 mg / kg to about 250 mg / kg body weight, from about 0.1 mg / kg to about 250 mg / kg body weight, from about 0.01 mg / kg to about 200 mg / kg body weight, from about 0. 1 mg / kg to about 200 mg / kg body weight, from about 0.01 mg / kg to about 150 mg / kg body weight, from about 0.1 mg / kg to about 150 mg / kg body weight, from about 0.01 mg / kg to about 100 mg / kg body weight, from about 0.1 mg / kg to about 100 mg / kg body weight, from about 0.01 mg / kg to about 50 mg / kg body weight, from about 0. 1 mg / kg to about 50 mg / kg body weight, from about 0.01 mg / kg to about 10 mg / kg body weight, from about 0.1 mg / kg to about 10 mg / kg body weight, from about 0.2 mg / kg to about 20 mg / kg body weight, or from about 0.5 mg / kg to about 50 mg / kg body weight, of the subject per day, which can be administered as a single daily dose, divided over one or more daily doses.

[0161] For example, the effective amount of the compounds is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, about 130 mg / kg, about 140 mg / kg, about 150 mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg, about 200 mg / kg, about 210 mg / kg, about 220 mg / kg, about 230 mg / kg, about 240 mg / kg, or about 250 mg / kg, of the subject per day, which can be administered as a single daily dose, divided over one or more daily doses. The amount of the compounds administered, the route of administration, and the further treatment regimen can be determined by the treating clinician or testing technologies, depending on factors such as the age, gender and general condition of the subject, the nature and severity of the disease / symptoms being prevented, treated, or diagnosed, and / or the samples being tested.

[0162] In some forms, the pharmaceutical composition is in a unit dosage form, and can be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable singledose or multi-dose holder or container (which can be properly labeled); optionally with one or more leaflets containing product information and / or instructions for use. Generally, such unit dosages can contain from 0.01 to 1000 mg, such as from 0.01 to 500 mg, from 0.01 to 100 mg, from 0.01 to 50 mg, from 0.01 to 10 mg, from 0.01 to 1 mg, from 0.1 to 500 mg, from 0.1 to 100 mg, from 0.1 to 50 mg, from 0.1 to 10 mg, or from 0.1 to 1 mg, of the disclosed compounds, e.g., about 0.1, 0.2, 0.5, 1, 5, 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage. f. Additional Active Agent

[0163] In some forms, the pharmaceutical composition containing the compounds also contains one or more additional active agent(s), such as one or more additional anticancer agent(s) and / or antiinflammatory agents. For example, one or more additional active agents is formulated into the same pharmaceutical composition containing one or more of the compounds described herein as a single dosage unit or as multiple dosage units for coordinated, combination, or concomitant administration, or into separate pharmaceutical compositions for combinational therapy.

[0164] Alternatively, the one or more additional active agents may be formulated as separate pharmaceutical compositions, for example, as a single dosage unit or as multiple dosage units, for co-administration with the pharmaceutical composition containing one or more of the compounds described herein. When formulated into a pharmaceutical composition that is separated from the pharmaceutical composition containing the disclosed compounds, the one or more additional active agents may be formulated in various formulations, for example, injectable formulations, lyophilized formulations, liquid formulations, or oral formulations. The formulation can be selected based upon the suitable administration route.

[0165] Examples of anticancer agents that can be used in the pharmaceutical compositions containing the compounds or a separate pharmaceutical composition include, but are not limited to, temozolomide, carmustine, bevacizumab, procarbazine, lomustine, vincristine, gefitinib, erlotinib, cisplatin, carboplatin, oxaliplatin, 5 -fluorouracil, gemcitabine, tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, vinblastine, vindesine, vinorelbine, paclitaxel, taxol, docetaxel, etoposide, teniposide, amsacrine, topotecan, camptothecin, bortezomib, anagrelide, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, fulvestrant, bicalutamide, flutamide, nilutamide, cyproterone, goserelin, leuprorelin, buserelin, megestrol, anastrozole, letrozole, vorozole, exemestane, finasteride, marimastat, trastuzumab, cetuximab, dasatinib, imatinib, combretastatin, thalidomide, azacitidine, azathioprine, capecitabine, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, doxifluridine, epothilone, irinotecan, mechlorethamine, mercaptopurine, mitoxantrone, pemetrexed, tioguanine, valrubicin and / or lenalidomide or combinations thereof such as cyclophosphamide, methotrexate, 5-fluorouracil (CMF); doxorubicin, cyclophosphamide (AC); mustine, vincristine, procarbazine, prednisolone (MOPP); sdriamycin, bleomycin, vinblastine, dacarbazine (ABVD); cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP); bleomycin, etoposide, cisplatin (BEP); epirubicin, cisplatin, 5-fluorouracil (ECF); epirubicin, cisplatin, capecitabine (ECX); and methotrexate, vincristine, doxorubicin, cisplatin (MV AC); and combinations thereof. Additional anticancer agents are described in U.S. Patent No. 10,393,736, the disclosure of which is incorporated herein by reference in its entirety.

[0166] Examples of anti-inflammatory agents that can be used in the pharmaceutical compositions containing the compounds or a separate pharmaceutical composition include, but are not limited to, ibuprofen, naproxen sodium, aspirin, naproxen sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, piroxicam, indomethacin, meloxicam, fenoprofen, naproxen, esomeprazole, diclofenac, diflunisal, etodolac, ketorolac tromethamine, katoprofen, meclofenamate, nabumetone, salsalate, tolmetin, and steroids, such as corticosteroids (e.g. hydrocortisone, cortisone, ethamethasoneb, prednisone, prednisolone, triamcinolone, methylprednisolone, and dexamethasone) and mineralocorticoids (e.g. fludrocortisone), and a combination thereof. Additional anti-inflammatory agents that can be included in the pharmaceutical compositions or formulations are described, for example, on WebMD, “Anti-inflammatory Drugs,” web site webmd.com / arthritis / anti- inflammatory -drugs; Barnes, Nature, 402(6760): 31-38 (1999); and Rainsford, Inflammation in the pathogenesis of chronic diseases 3:27 (2007).

[0167] III. Methods of Use

[0168] The disclosed compounds are suitable for use in treating cancer and / or anti-inflammatory disease / disorder. In some forms, the compounds are particularly useful in cancer therapy. In some forms, the cancer being treated using the disclosed method is a solid cancer, such as breast cancer and / or colon cancer.

[0169] “Treatment” or “treating” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder, such as a cancer. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, such as a cancer; and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder, such as a cancer. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder, such as a cancer; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder, such as a cancer; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder, such as a cancer.

[0170] Generally, the method for treating cancer includes a step of administering the compounds or pharmaceutical composition thereof to a subject in need thereof.

[0171] The administration in step (i) can be performed using any suitable technique, such as oral administration, intranasal administration, intramuscular administration, intravenous administration, intraperitoneal administration, subcutaneous administration, or topical administration, or a combination thereof.

[0172] Step (i) (administration of the pharmaceutical composition) of the disclosed method may occur one or more times. When more than one administration step is performed, each administration can be performed regularly every 5 mins, every 10 mins, every 20 mins, every 30 mins, every hour, every 2 hours, every day, every two days, every 3 days, every week, every two weeks, every month, etc.; or irregularly with a time interval of 5 mins, 10 mins, 20 mins, 30 mins, 1 hour, 2 hours, 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, etc. The specific number of treatment and time interval for the treatment can be determined by the treating clinician or testing technologies, depending on factors such as the age, gender and general condition of the subject, the nature and severity of the disease / symptoms being prevented, treated, or diagnosed, and / or the samples being tested.

[0173] In some forms, following the administration step or all of the administration steps, an effective amount of the compounds in the pharmaceutical formulation is administered to the subject to ameliorate one or more symptoms associated with the cancer in the subject. In some forms, the treatment effect is achieved by the anticancer property of the compounds, such as by killing cancer cells and / or reducing or preventing growth or proliferation of the cancer cells. In some forms, the treatment effect is achieved by the anti-inflammatory property of the compounds, such as by inhibiting one or more inflammation markers, e.g., COX-1, COX-2, TNF-a, NO, and / or IL-6. In some forms, the treatment effect is achieved by both the anticancer property and the antiinflammatory property of the compounds. In some forms, the disclosed compounds are more effective in treating the cancer compared to a corresponding curcumin mimic alone and / or a corresponding anti-inflammatory drug alone.

[0174] For example, following the administration step or all of the administration steps (if the administration occurs more than one time), an effective amount of the compounds is administered to the subject, such that the tumor weight (such as a breast cancer or a colon cancer) and / or tumor volume in the subject is at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% less than a control that is administered with the pharmaceutical formulation but contains the corresponding curcumin mimic alone.

[0175] For example, following the administration step or all of the administration steps (if the administration occurs more than one time), an effective amount of the compounds is administered to the subject, such that one or more symptoms associated with a cancer-related inflammation in the subject is at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% less severe than a control that is administered with the pharmaceutical formulation but contains the corresponding anti-inflammatory drug alone.

[0176] In some forms, following the administration step or all of the administration steps, the effective amount of the compounds administered to the subject is from about 0.1 pg to about 1000 pg, from about 0.1 pg to about 500 pg, from about 0.1 pg to about 100 pg, from about 0.5 pg to about 50 pg, from about 1 pg to about 1000 pg, from about 1 pg to about 500 pg, from about 1 pg to about 100 pg, from about 1 pg to about 50 pg, from about 1 pg to about 25 pg, from about 1 pg to about 10 pg, from about 2 pg to about 20 pg, or from about 5 pg to about 50 pg, per g of the subject.

[0177] The cancer treatment effect as described above can occur within 3 days, within 5 days, within 7 days, within 10 days, within 2 weeks, within one month, within three months, or within six months following the administration step or all of the administration steps. Optionally, the cancer treatment effect occurs without any observable toxicity to the subject, as indicated by body vital measurements (e.g., body weight), standard hematology markers, and / or blood biochemical parameters compared to a control administered with the pharmaceutically acceptable carrier / excipients alone.

[0178] In some forms, the disclosed method can further include administering one or more additional active agent(s), such as one or more additional anticancer agent(s) and / or antiinflammatory agent(s) described above, to the subject before step (i) administering a pharmaceutical composition containing the compounds, simultaneously with step (i), or after step (i), or a combination thereof. The disclosed compositions and methods can be further understood through the following enumerated paragraphs.

[0179] 1. A compound having a structure of: wherein:

[0180] (i) each occurrence of R is independently hydrogen, a halide (e.g., F, Cl, Br, etc.), an unsubstituted C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.), an alkoxyl (e.g., methoxy, ethoxy, etc.), -(C=O)H, -(C=O)Ri, -(C=O)OH, -(C=O)ORi, -(C=O)Xi, - NH2, -NHRI, -NR1R2, -CF3, -CN, -(S=O)OH, -NO2, -SH, -OH, -(C=O)NHRb-(C=O)NRIR2;

[0181] (ii) Ri and R2are independently hydrogen or an unsubstituted Ci-Ce alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.);

[0182] (iii) each occurrence of R’ is independently hydrogen or a side chain of an amino acid (e.g., a naturally occurring amino acid);

[0183] (iv) n is an integer from 1 to 6, from 1 to 5, from 1 to 4, or from 1 to 3; and

[0184] (v) is an anti-inflammatory drug moiety.

[0185] 2. The compound of paragraph 1, having a structure of: 3. The compound of paragraph 1 or 2, wherein each occurrence of R is independently hydrogen, a halide (e.g., F, Cl, Br, etc.), an unsubstituted Ci-Ce alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.), an alkoxyl (e.g., methoxy, ethoxy, etc.).

[0186] 4. The compound of any one of paragraphs 1-3, wherein each occurrence of R is independently hydrogen, F, Cl, CH3, or OCH3.

[0187] 5. The compound of any one of paragraphs 1-4, wherein each occurrence of R’ is independently hydrogen or a side of a naturally occurring amino acid (e.g., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine).

[0188] 6. The compound of any one of paragraphs 1-5, wherein each occurrence of R’ is independently hydrogen or an unsubstituted C1-C4 alkyl, optionally wherein each occurrence of R’ is independently hydrogen or CH3.

[0189] 7. The compound of any one of paragraphs 1-6, wherein is a non-steroidal anti inflammatory drug (NSAID) moiety, such as an ibuprofen moiety, a naproxen moiety, a diclofenac moiety, a mefenamic acid moiety, an indomethacin moiety, or an aspirin moiety.

[0190] 8. The compound of any one of paragraphs 1-7, wherein the anti-inflammatory drug moiety is an ibuprofen moiety having the structure of

[0191] 9. The compound of any one of paragraphs 1-7, wherein the anti-inflammatory drug moiety is a dichloroacetic acid moiety having the structure of

[0192] 10. The compound of any one of paragraphs 1-9, wherein the compound is any one of the following:

[0193]

[0194]

[0195] 11. A pharmaceutical composition comprising the compound of any one of paragraphs 1- 10, and optionally one or more pharmaceutically acceptable excipients.

[0196] 12. The pharmaceutical composition of paragraph 11, further comprising a second active agent, optionally wherein the second active agent is an anticancer agent or anti-inflammatory agent, or a combination thereof.

[0197] 13. The pharmaceutical composition of paragraph 11 or 12, wherein the compound in the pharmaceutical composition is in an amount ranging from about 0.1 pM to about 1 mM, from about 0.1 pM to about 500 pM, from about 0.1 pM to about 200 pM, from about 0.1 pM to about 100 pM, from about 0.1 pM to about 50 pM, or from about 0. 1 pM to about 20 pM.

[0198] 14. A method for treating cancer using the pharmaceutical composition of any one of paragraphs 11-13 comprising:

[0199] (i) administering the pharmaceutical composition to a subject in need thereof, wherein step (i) occurs one or more times.

[0200] 15. The method of paragraph 14, wherein the pharmaceutical composition is administered by oral administration, intramuscular administration, intravenous administration, intraperitoneal administration, subcutaneous administration, or topical administration, or a combination thereof.

[0201] 16. The method of paragraph 14 or 15, wherein in step (i), the dosage of the compound administered is from about 0.1 pg to about 1000 pg, from about 0.1 pg to about 500 pg, from about 0.1 pg to about 100 pg, from about 0.5 pg to about 50 pg, from about 1 pg to about 1000 pg, from about 1 pg to about 500 pg, from about 1 pg to about 100 pg, from about 1 pg to about 50 pg, from about 1 pg to about 25 pg, from about 1 pg to about 10 pg, from about 0.1 pg to about 50 pg, from about 5 pg to about 50 pg, or from about 0.1 pg to about 20 pg per g of the subject.

[0202] 17. The method of any one of paragraphs 14-16, wherein the cancer is a solid cancer.

[0203] 18. The method of any one of paragraphs 14-17, wherein the cancer is a breast cancer or colon cancer, or a combination thereof.

[0204] 19. The method of any one of paragraphs 14-18, wherein more than one administration step is performed, and wherein each administration is performed regularly every 5 mins, every 10 mins, every 20 mins, every 30 mins, every hour, every 2 hours, every day, every two days, every 3 days, every week, every two weeks, or every month, etc.; or irregularly with a time interval of 5 mins, 10 mins, 20 mins, 30 mins, 1 hour, 2 hours, 1 day, 2 days, 3 days, 5 days, 1 week, or 2 weeks.

[0205] 20. The method of any one of paragraphs 14-19, further comprising administering an active agent prior to, during, and / or subsequent to step (i), optionally wherein the active agent is an anticancer agent or anti-inflammatory agent, or a combination hereof.

[0206] The present invention will be further understood by reference to the following non-limiting examples.

[0207] Examples

[0208] Example 1. Molecular hybridization of bioactive moieties such as curcumin mimic 4- piperidone, dichloroacetic acid, and amino acids for breast cancer treatment

[0209] Materials and Methods

[0210] Scheme 1. Molecular hybridization of 4-piperidone, dichloroacetic acid, and amino acids Scheme 2. Synthesis of DCA-AA Conjugates

[0211] Scheme 3. Synthesis of DCA-AA-Cur Mimic Conjugates.

[0212] Synthesis of dichloroacetic-benzotriazole III

[0213] 3.5 equivalences (eq) of Benzotriazole was added in pure DCM in a round-bottom flask (RBF) and was stirred until dissolved. Upon the solid dissolving, the RBF was placed into an ice bath and upon being cooled, 2.0 eq thionyl chloride was added, turning the reaction a bright yellow. The reaction was stirred for 45 minutes, upon which 1.0 eq dichloroacetic acid was added to the reaction mixture. The reaction was left to proceed overnight. Upon returning, fresh DCM was added to the reaction to dilute thionyl chloride concentration and the reaction was filtered and washed with DCM. The filtrate was then subsequently washed with 20% Na2CO3, ddH2O, and 4N HC1, before drying over sodium sulfate. The solution was then rotovapped under reduced pressure to give a beige solid.

[0214] Synthesis of dichloroacetic-amino acid conjugate IVa-c

[0215] 1.0 eq of compound III was dissolved in acetonitrile in a flask. Meanwhile, 2.0 eq of chosen amino acid (glycine, P-alanine, or y- Aminobutyric acid) was dissolved in ddH2O in a RBF before adding 2.5 eq TEA. Upon stirring for 15 minutes, the dissolved compound III acetonitrile solution was added to the RBF. The reaction was monitored for 30 minutes and fresh ddH2O or acetonitrile was added as needed to keep the solution mixture clear. The reaction was then allowed to stir overnight. Upon returning, acetonitrile was rotovapped under reduced pressure. The remaining solution was then extracted with ethyl acetate. The organic layer was then washed with ddH2O) and 4N HC1. The organic layer was then dried over sodium sulfate prior to rotovapping. The resulting solution was then dried on a vacuum line to ensure formation of the solid, which was then filtered and washed with DCM to obtain the fluffy white solid. Synthesis of 4-piperidone CUR mimics Vla-e

[0216] To a RBF was added 2.5eq of a desired aldehyde in ethanol. The mixture was then heated and stirred in a water bath for 30 minutes. After heating, leq of 4-piperidone V was added along with 10% NaOH and the reaction was allowed to stir down to room temperature overnight. Upon returning, liquid was decanted from the RBF before addition of fresh ice and ddtUO and the mixture was then stirred for 30 minutes. The remaining water was then decanted before adding methanol and stirring for 30 minutes. Solid was then collected via vacuum filtration and washed with methanol.

[0217] Synthesis of dichloroacetic-amino acid-Cur mimic conjugates DHl-3a-e l.Oeq of compound Vla-e was added to a RBF and dissolved in pure DCM and placed into an ice bath. Upon cooling, 1.5 eq EDC and 0.5eq DMAP were added with continuous stirring. After the solution became clear, l.leq of IVa-c was added to the reaction and was allowed to stir overnight. Upon returning, DCM was rotovapped and to the pasty solid was added fresh ice, NazCCh. and ether, and was stirred. Upon the formation of collectable solid (15 minutes-2 hours), the solid was vacuum filtered and washed with fresh ddfUO and ether.

[0218] Instrumental Methods

[0219] Melting points were determined on a Stanford Research Systems DigiMelt equipped with a digital thermometer and were uncorrected. NMR spectra were recorded in CDCI3 or DMSO-cfe on a Bruker spectrometer operating at 500 MHz for 'H (with TMS as an internal standard) and13C using the NMR facility at the Chemical and Biomolecular Analysis core in the Department of Chemistry and Physics, Faculty of Science and Mathematics, Augusta University, Augusta, GA, USA. IR spectra (KBr, cm-1) were recorded on a Bruker Alpha II compact FT-IR spectrometer at the Chemical and Biomolecular Analysis core in the Department of Chemistry and Physics, Faculty of Science and Mathematics, Augusta University, Augusta, GA, USA. Computational data was obtained using STARDROP software and SwissADME.

[0220] Biological Testing

[0221] MTT proliferation assays were performed using a standard protocol62, with chosen compounds tested against human normal immortalized mammary epithelial cell line (MCF-10A), human ER+ BC cells (MCF-7), and TNBC cells (MDA-MB-231) at varying concentrations (0, 0.01, 0.0316, 0.1, 0.316, 1, 3.16, 10, and 31.6 pM). Instrumental Data for synthesized compounds

[0222] 2,2-Dichloro-N-(2-( 3, 5-di( ( E fbenzylidene )-4-oxopiperidin-l -yl )-2-oxoethyl )acetamide

[0223] (DHla)

[0224] Yellow tan solid, mp: 164-167 °C, yield: 75%. IR: Vmax / cm-13361, 2987, 1689, 1644, 1605,

[0225] 1574, 1474, 1432, 1270, 1174, 986, 947, 866, 805, 763, 690. ’H NMR (500 MHz, CDCh) 8: 7.92 (s, 1H), 7.89 (s, 1H), 7.50-7.37 (m, 11H), 5.89 (s, 1H), 4.96 (s, 2H), 4.70 (s, 2H), 3.97 (d, 7 = 3.4 Hz, 2H).13C NMR (500 MHz, CDCh) 8: 186.0, 166.0, 164.1, 139.3, 139.0, 134.6, 134.1, 130.8, 130.7, 130.5, 130.3, 130.0, 129.4, 129.3, 129.1 , 66.2, 45.6, 44.0, 41.6.

[0226] N-(2-( 3,5-Bis( (E)-4 -chlorobenzylidene )-4-oxopiperidin-l-yl )-2-oxoethyl)-2,2- dichloroacetamide (DHlb)

[0227] Yellow tan solid, mp: 177-183 °C, yield: 88%. IR: Vmax / cm13359, 2986, 1688, 1644, 1605, 1574, 1474, 1432, 1269, 1236, 1173, 986, 946, 866, 805, 762, 689. ’H NMR (500 MHz, CDCh) 8: 7.85 (s, 1H), 7.82 (s, 1H), 7.49-7.31 (m, 9H), 5.91 (s, 1H), 4.91 (s, 2H), 4.67 (s, 2H), 4.00 (d, J =

[0228] 4.0 Hz, 2H).13C NMR (500 MHz, CDCh) 8: 185.5, 166.0, 164.5, 138.0, 137.8, 136.7, 136.3, 132.9, 132.5, 131.9, 131.6, 131.1, 130.7, 129.8, 129.5, 66.2, 45.6, 43.8, 41.6. N-(2-( 3, 5-Bis( (E)-4-fluorobenzylidene )-4-oxopiperidin-l -yl )-2-oxoethyl )-2,2- dichloroacetamide (DHlc)

[0229] Yellow tan solid, mp: 158-162 °C, yield: 64%. IR: Vmax / cm-13357, 2989, 1650, 1599, 1507, 1231, 1157, 988, 832.1H NMR (500 MHz, CDCh) 8: 7.88 (s, 1H), 7.84 (s, 1H), 7.49 (s, 1H), 7.47-

[0230] 7.45 (m, 2H), 7.40-7.37 (m, 2H), 7.22-7.14 (m, 4H), 5.90 (s, 1H), 4.93 (s, 2H), 4.68 (s, 2H), 4.00 (d, J = 5.25 Hz, 2H).nC NMR (500 MHz, CDC13) 8: 185.7, 166.1, 164.7, 164.1, 162.6, 138.0, 132.8, 132.4, 130.7, 130.4, 130.3, 130.1, 116.8, 116.6, 116.3, 66.2, 45.6, 43.8, 41.6.

[0231] N-(2-( 3,5-Bis( (E)-4-methylbenzylidene )-4-oxopiperidin- 1 -yl )-2-oxoethyl )-2, 2- dichloroacetamide (DHld)

[0232] Pale yellow solid, mp: 179-183 °C, yield: 87%. IR: vlt1i / cnr 3359, 2989, 1687, 1673, 1647, 1600, 1508, 1474, 1432, 1236, 1158, 988, 807, 766.]H NMR (500 MHz, CDCI3) 8: 7.89 (s, 1H), 7.86 (s, 1H), 7.51 (s, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.28-7.25 (m, 6H), 5.89 (s, 1H), 4.95 (s, 2H), 4.68 (s, 2H), 3.98 (d, J = 4.0 Hz, 2H), 2.43 (s, 3H), 2.40 (s, 3H).13C NMR (500 MHz, CDCh) 8:

[0233] 186.0, 166.0, 164.1, 140.9, 140.5, 139.2, 138.9, 131.9, 131.4, 130.9, 130.5, 130.2, 130.1, 129.8, 129.7, 66.2, 45.7, 44.1, 41.7, 21.7. N-(2-( 3,5-Bis( (E)-4 -methoxyb en-y Helene )-4-oxopiperidin-l -yl )-2-oxoethyl)-2,2- dichloroacetamide (DHle)

[0234] Bright yellow solid, mp: 177-179 °C, yield: 77%. IR: Vmax / cm’13358, 2988, 1687, 1673, 1647, 1600, 1573, 1508, 1474, 1432, 1235, 1158, 988, 806, 765.!H NMR (500 MHz, CDCh) 5:

[0235] 7.86 (s, 1H), 7.83 (s, 1H), 7.60 (s, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.3 Hz), 7.01-6.96 (m, 4H), 5.94 (s, 1H), 4.94 (s, 2H), 4.69 (s, 2H), 4.03 (d, 7 = 3.6 Hz, 2H), 3.89 (s, 3H), 3.87 (s, 3H).13C NMR (500 MHz, CDCh) 8: 185.8, 165.9, 164.1, 161.3, 161.1, 138.8, 138.6, 132.8, 132.5, 128.8, 128.4, 127.4, 126.8, 1 15.0, 1 14.7, 66.2, 55.7, 55.6, 45.7, 44.0, 41.6. 2,2-Dichloro-N-(3-(3,5-di((E)-benzylidene)-4-oxopiperidin-l-yl)-3-oxopropyl)acetamide

[0236] (DH2a)

[0237] Yellow solid, mp: 138-139 °C, yield: 55%. IR: Vmax / cm’13357, 2989, 1688, 1673, 1646, 1599, 1507, 1473, 1432, 1233, 1158, 987, 806, 767. ’H NMR (500 MHz, CDC13) 8: 7.91 (s, 1H), 7.86 (s, 1H), 7.51-7.36 (m, 11H), 5.85 (s, 1H), 4.94 (s, 2H), 4.68 (s, 2H), 3.50 (q, J = 5.85 Hz, 2H),

[0238] 2.41 (t, 7 = 5.35 Hz).13C NMR (500 MHz, CDCh) 8: 186.5, 170.2, 164.2, 139.0, 138.1 , 134.7, 134.3, 131.5, 131.3, 130.8, 130.3, 130.1, 129.9, 129.2, 129.1, 66.6, 46.3, 43.8, 35.9, 32.1. N-( 3-( 3, 5-Bis( (E)-4 -chlorobenzylidene )-4-oxopiperidin-l-yl )-3 -oxopropyl )-2,2- dichloroacetamide (DH2b)

[0239] Yellow solid, mp: 166-168 °C, yield: 42%. IR: v^ / cm'13297, 2989, 1673, 1646, 1606, 1434, 1408, 1271, 1228, 1172, 1090, 988, 809, 765.1H NMR (500 MHz, CDCh) 8: 7.85 (s, 1H),

[0240] 7.81 (s, 1H), 7.49-7.32 (m, 9H), 5.87 (s, 1H), 4.91 (s, 2H), 4.68 (s, 2H), 3.54 (dd, J = 5.70 Hz, 2H), 2.41 (t, J = 5.25 Hz).13C NMR (500 MHz, CDCh) 8: 186.1, 170.2, 164.3, 137.8, 137.0, 136.4, 136.2, 133.1, 132.7, 132.0, 131.8, 131.6, 131.5 129.6, 129.4, 66.5, 46.3, 43.6, 35.9, 32.1.

[0241] N-(3-(3,5-Bis((E)-4-fliiorobenzylidene)-4-oxopiperidin-l-yl)-3-oxopropyl)-2,2- dichloroacetamide (DH2c)

[0242] Yellow solid, mp: 164-167 °C, yield: 69%. IR: Vmax / cm’13302, 3063, 1706, 1620, 1507, 1475, 1430, 1221, 1159, 983, 833, 811, 788. *H NMR (500 MHz, CDCh) 8: 7.84 (s, 1H), 7.80 (s, 1H), 7.48-7.46 (m, 2H), 7.38-7.35 (m, 2H), 7.36 (s, 1H), 7.20-7.13 (m, 4H), 5.86 (s, 1H), 4.90 (s, 1H), 4.67 (s, 2H), 3.51 (q, J = 5.9 Hz, 2H), 2.4009 (t, J = 5.40 Hz, 2H).13C NMR (500 MHz,

[0243] CDCh) 8: 186.2, 170.2, 164.6, 164.3, 162.6, 137.8, 137.0, 132.8, 132.4, 131.0, 130.9, 130.4, 116.7, 116.4, 116.2, 66.5, 46.2, 43.6, 35.9, 32.1. N-( 3-( 3, 5-Bis( (E)-4-methylbenzylidene )-4-oxopiperidin-l-yl )-3-oxopropyl )-2, 2- dichloroacetamide (DH2d)

[0244] Yellow solid, mp: 183-184 °C, yield: 93%. IR: v^ / cm'13295, 2990, 1702, 1673, 1644, 1605, 1585, 1559, 1435, 1271, 1228, 1172, 1090, 989, 809, 766. ’H NMR (500 MHz, CDCh) 8: 7.87 (s, 1H), 7.82 (s, 1H), 7.38 (d, J = 7.85 Hz, 2H), 7.29-7.25 (m, 7H), 5.84 (s, 1H), 4.93 (s, 2H), 4.67 (s, 2H), 3.50 (q, J = 5.80 Hz, 2H), 2.43 (s, 3H), 2.40 (s, 3H), 2.37 (t, J = 5.25 Hz, 2H).13C NMR (500 MHz, CDCh) 8: 186.5, 170.2, 164.2, 140.5, 140.3, 138.9, 138.0, 132.0, 131.5, 130.9, 130.7, 130.5, 130.4, 129.9, 129.8, 66.6, 46.2, 43.8, 35.9, 32.1, 21.7.

[0245] N-(3-( 3,5-Bis( ( E }-4-methoxybenzylidene )-4-oxopiperidin-l -yl )-3 -oxopropyl )-2, 2- dichloroacetamide (DH2e)

[0246] Bright yellow solid, mp: 168-170 °C, yield: 96%. IR: Vmax / cm13292, 2994, 1703, 1673, 1646, 1605, 1558, 1435, 1269, 1228, 1167, 1090, 986, 835, 809, 766. ’H NMR (500 MHz, CDCh) 8: 7.85 (s, 1H), 7.80 (s, 1H), 7.46 (d, J = 8.60 Hz, 2H), 7.42 (s, 1H), 7.33 (d, J = 8.55 Hz), 7.00-6.96 (m, 4H), 5.86 (s, 1H), 4.93 (s, 2H), 4.68 (s, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.51 (q, J = 5.75 Hz, 2H), 2.41 (t, J = 5.25 Hz, 2H).13C NMR (500 MHz, CDCh) 8: 186.2, 170.1, 164.2, 161.0, 160.9, 138.3, 137.5, 132.8, 132.3, 129.4, 129.3, 127.5, 126.9, 114.7, 114.5, 66.5, 55.6, 55.5, 46.3, 43.7, 35.9, 32.1. 2,2-Dichloro-N-(4-( 3, 5-di( ( E )-benzylidene )-4-oxopiperidin-l -yl )-4-oxobutyl )acetamide

[0247] (DH3a)

[0248] Yellow solid, mp: 116-119 °C, yield: 35%. IR: v.Jcm13288, 3063, 1704, 1672, 1645, 1606, 1576, 1548, 1445, 1272, 1225, 1174, 988, 811, 762. *H NMR (500 MHz, CDCh) S: 7.90 (s, 1H), 7.84 (s, 1H), 7.49-7.38 (m, 10H), 7.16 (s, 1H), 5.82 (s, 1H), 4.94 (s, 2H), 4.72 (s, 2H), 3.23 (q, 7 = 6.10 Hz, 2H), 2.24 (t, J = 6.40 Hz, 2H), 1.80 (quint, J = 6.55 Hz, 2H).13C NMR (500 MHz, CDCh) 8: 186.7, 171.4, 164.5, 138.9, 137.8, 134.7, 134.5, 131.6, 130.8, 130.7, 130.3, 130.0, 129.8, 129.2, 129.0, 66.6, 46.4, 43.9, 40.3, 30.5, 23.5.

[0249] N-(4-(3,5-Bis((E)-4-chlorobenzylidene)-4-owpiperidin-l-yl)-4-oxobutyl)-2,2- dichloroacetamide (DH3b)

[0250] Yellow solid, mp: 168-171 °C, yield: 63%. IR: VnJcm'13292, 3058, 1703, 1672, 1645, 1606, 1576, 1551, 1445, 1272, 1173, 987, 811, 762.]H NMR (500 MHz, CDCh) 8: 7.83 (s, 1H), 7.78 (s, 1H), 7.47-7.31 (m, 8H), 7.10 (s, 1H), 5.83 (s, 1H), 4.89 (s, 2H), 4.69 (s, 2H), 3.27 (q, J = 6.10 Hz, 2H), 2.26 (t, 7 = 6.30 Hz, 2H), 1.83 (quint, 7 = 6.40 Hz, 2H).13C NMR (500 MHz, CDCh) 8: 186.2, 171.4, 164.5, 137.6, 136.7, 136.3, 136.0, 133.1, 132.8, 131.9, 131.8, 131.7, 131.5, 129.6, 129.3, 66.7, 46.5, 43.7, 40.4, 30.5, 23.5. N-(4-(3, 5-Bis( ( E )-4-fluorobenzylidene )-4-oxopiperidin-l -yl )-4-oxobutyl )-2,2- dichloroacetamide (DH3c)

[0251] Pale yellow solid, mp: 174-177 °C, yield: 63%. IR: v.^ / cnT13289, 3061, 1702, 1673, 1644, 1605, 1575, 1558, 1509, 1445, 1272, 1226, 1173, 1090, 988, 811, 762. *H NMR (500 MHz, CDCh) 8: 7.84 (s, 1H), 7.80 (s, 1H), 7.49-7.47 (m, 2H), 7.39-7.37 (m, 2H), 7.20-7.11 (m, 5H), 5.83 (s, 1H), 4.90 (s, 2H), 4.69 (s, 2H), 3.26 (q, J = 6.10 Hz, 2H), 2.26 (t, J = 6.35 Hz, 2H), 1.83 (quint, J = 6.40 Hz, 2H).nC NMR (500 MHz, CDCh) 8: 186.2, 171.2, 164.3, 162.3, 137.5, 136.6, 132.6, 132.4, 132.2, 131.1, 130.7, 130.4, 116.4, 116.2, 116.0, 66.5, 46.3, 43.5, 40.2, 30.3, 23.3.

[0252] N-(4-(3,5-Bis((E)-4-methylbenzylidene)-4-oxopiperidin-l -yl)-4-oxobutyl)-2,2- dichloroacetamide (DH3d)

[0253] Pale yellow solid, mp: 177-179 °C, yield: 47%. %. IR: v^ / cm'13287, 3062, 1704, 1672, 1645, 1605, 1574, 1549, 1447, 1271, 1225, 1197, 1173, 990, 812, 769.]H NMR (500 MHz, CDCh) 8: 7.86 (s, 1H), 7.81 (s, 1H), 7.39 (d, J = 7.75 Hz, 2H), 7.28-7.24 (m, 6H), 7.16 (s, 1H), 5.81 (s, 1H), 4.93 (s, 2H), 4.71 (s, 2H), 3.23 (q, J = 6.10 Hz, 2H), 2.42 (s, 3H), 2.40 (s, 3H), 2.25 (t, 7 = 6.40 Hz, 2H), 1.80 (quint, 7 = 6.45 Hz, 2H).13C NMR (500 MHz, CDCh) 8: 186.7, 171.4, 164.4, 140.5, 140.3, 138.8, 137.7, 132.1, 131.8, 130.9, 130.8, 130.5, 129.9, 129.8, 129.5, 66.7, 46.5, 44.0, 40.4, 30.6, 23.5, 21.7. N-(4-(3,5-Bis((E)-4-methoxybenzylidene)-4-oxopiperidin-l-yl)-4-oxobutyl)-2,2- dichloroacetamide (DH3e)

[0254] Bright yellow solid, mp: 142-146 °C, yield: 49%. IR: Vmax / cm’13281, 3073, 1697, 1596, 1562, 1510, 1466, 1440, 1303, 1256, 1166, 1027, 806.:H NMR (500 MHz, CDCL) 8: 7.84 (s, 1H), 7.90 (s, 1H), 7.46 (d, J = 7.75 Hz, 2H), 7.35 (d, J = 8.40 Hz, 2H), 7. 18 (s, 1H), 7.01-6.96 (m, 4H), 5.82 (s, 1H), 4.93 (s, 2H), 4.71 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.25 (q, J = 6.15 Hz, 2H), 2.28 (t, J = 6.35 Hz, 2H), 1.82 (quint, 7 = 6.55 Hz, 2H). ).13C NMR (500 MHz, CDCI3) 8: 186.6, 171.4, 164.5, 161.0, 161.0, 138.4, 137.3, 132.9, 132.3, 129.8, 129.7, 127.6, 127.2, 114.7, 114.6, 66.7, 55.6, 46.6, 43.9, 40.4, 30.6, 23.5.

[0255] Results

[0256] Characterization ofN-( 2-( 3, 5-Bis( (E)-4-methylbenzylidene )-4-oxopiperidin-l -yl )-2-oxoethyl )- 2,2-dichloroacetamide ( DHld)

[0257] The structure of DHld was first confirmed with]H-NMR (Data not shown). There are 24 total protons, which is expected from the structure of the compound. The two alkene protons can be seen furthest downfield at 7.89 and 7.86 ppm. These peaks are shifted far downfield due to their position in being on the P-carbon of an a,P-unsaturated ketone. The amide N-H proton can be seen as a broad singlet at 7.51 ppm. The 8 aromatic protons can be seen in the 7.37 to 7.25 ppm range. The presence of the DCA proton can be seen as a singlet at 5.89 ppm. The two sets of piperidone alkane protons can be seen as two singlets at 4.95 and 4.68 ppm. The protons present from the amino acid glycine can be seen as a doublet at 3.98 ppm. Lastly, the presence of the methyl substituents can be seen as two singlets at 2.43 and 2.40 ppm. A13C-NMR spectra was then taken to confirm the identity and location of carbons in compound DHld (Data not shown). The spectra contained 20 unique carbons, which is in agreement with the expected number as the two carbons ortho to the methyl group and the two carbons meta to the methyl are equivalent carbons on their respective rings. The carbon for the ketone in the piperidone ring can be seen at 186.0 ppm. The two amide carbonyl carbons can be seen at 166.0 and 164.1 ppm. The DCA carbon attached to the chlorines can be seen at 66.2 ppm. The two carbons corresponding to the two alkane carbons in the piperidone ring can be seen at 45.7 and 44.1 ppm. The amino acid alkane carbon can be seen at 41.7 ppm. Lastly, the methyl substituent carbons show up as an identical carbon at 21.7 ppm.

[0258] Physical characteristics began with IR spectroscopy (Data not shown). The N-H stretch can be seen at 3295 cm1. The presence of alkane carbons can be seen in the C-H stretch at 2990 cm1. The C=C stretch can be identified at 1702 cm1. The presence of the amide C=O can be seen at the peak at 1644 cm1. The ketone stretch for the a, P-unsaturated ketone C=O stretch is seen at 1605 cm1. The C-N stretch can be seen at 1172 cm1. Lastly, the stretch corresponding to the C-Cl bond can be seen at 809 cm1. The compound was synthesized in an excellent yield of 87% and had a melting point range of 179-183 °C.

[0259] Characterization of N-(3-( 3, 5-Bis( ( E )-4-methoxybenzylidene )-4-oxopiperidin-l -yl )-3- oxopropyl)-2,2-dichloroacetamide (DH2e)

[0260] The spectra obtained of1H-NMR were similar to that of all the other spectra obtained, with again 26 protons similar to DH2d (Data not shown). The methoxy protons were visible as two singlets 3.89 and 3.86 ppm. The13C-NMR was again similar to that of the other spectra with 22 total carbon peaks present, containing an extra carbon due to the methoxy carbons showing up as non-equivalent similar to the glycine compound DHle, which can be seen at 55.6 and 55.5 ppm (Data not shown).

[0261] The IR spectra obtained contained all the functional groups present as seen in the other compounds’ spectra (Data not shown). The product was obtained in an excellent yield of 96% and had a melting point range of 168-170 °C. Characterization of N-( 4-(3, 5-Bis( ( E )-4-methylbenzylidene)-4-oxopiperidin-l -yl)-4- oxobutyl )-2,2-dichloroacetamide (DH3d)

[0262] The characterizations of DH3d began with1H-NMR in which 28 total protons were present due to the use of y- Aminobutyric acid for this compound (Data not shown). The proton signals were again in agreement with the other spectra, and the protons from the use of y- Aminobutyric acid can be seen as a quartet at 3.23 ppm being split by the two protons on the middle alkane chain carbon and the proton attached to the nitrogen. The next signal from the amino acid was seen as a triplet at 2.25 ppm, which was being split by the two protons on the middle alkane carbon. The final peak from the amino acid is for the middle alkane carbon and appeared as a quintet at 1.80 ppm, being split by the 4 total protons on the carbons adjacent to it. The13C-NMR spectra contained 22 total carbons as expected (Data not shown). The shifts were similar to those of all the spectra obtained, with the carbons from the amino acid being seen at 40.4, 30.6, and 23.5 ppm. Additionally, the methyl carbons were again equivalent and were at 21.7 ppm.

[0263] The IR spectra shared the same commonalities as the IR from all the other compounds (Data not shown). The compound was obtained in a yield of 47% and had a melting point range of 177- 179 °C.

[0264] Biological Data

[0265] From the synthesized compounds, a set of compounds prepared from the CUR-mimic scaffold, DCA, and glycine (DHla-e, NCMC1-5), were chosen for the initial biological investigation. The antitumor potential of NCMC1-5 drug candidates was tested in a human normal immortalized mammary epithelial cell line (MCF-10A), human ER+ BC cells (MCF-7), and TNBC cells (MDA-MB-231) using MTT proliferation assays, as discussed above. The results indicated that the candidates inhibited cell proliferation at sub micromolar concentrations in MCF-7 and MDA-MB-231 cells while they did not inhibit cell proliferation in MCF-10A cells (Figures 1A- 1C). MTT assay was carried out in MCF-10A (A), MCF-7 (B), and MDA-MB-231 (C) cells with NCMC1-5 at different concentrations (0, 0.01, 0.0316, 0.1, 0.316, 1, 3.16, 10, and 31.6 pM). Values are expressed as a mean ± SD of six replicates.

[0266] IC50 values were then obtained from the biological data for the compounds which can be seen in Table 1.

[0267] Table 1. IC50 values for DHla-e against two BC cell lines

[0268] As shown in the data, the activity of the compounds with the fluorine and methoxy substituents (DHlc & DHle) was greater than the other compounds tested. In the case of the methoxy group, it can be theorized that this is due to some hydrogen bond accepting interaction of the oxygen in the binding pocket, as the methoxy substituent is retained from the original structure of CUR. Fluorine can be beneficial as a substituent for multiple reasons, and is present in around 20% of all FDA approved pharmaceuticals. Firstly, fluorine is highly electronegative, which can lead to increased dipole interactions while also improving metabolic stability. Additionally, fluorine is relatively small, with a comparable radius to that of a hydrogen atom, and thus will not be likely to cause any steric hinderance with interactions in the binding pocket. Lastly, fluorine’s ability to act as a hydrogen bond acceptor could be contributing to its activity against the cell lines, similar to the hydrogen bond acceptor present in natural CUR.

[0269] Biological Studies of Compounds JI to J 17

[0270] Overall, the proposed products composed of ibuprofen, an amino acid linker, and a curcumin mimic (Figure 2) is a formidable approach to the formation of the new generation of NSAIDs. By linking these residues each with a benefit of its own, the end goal of producing a compound with higher selectivity (thus, lower side effects) and higher potency than chemotherapeutic drugs available in the market is within reach. Scheme 4. Synthesis of Ibuprofen-amino acid conjugates

[0271] Scheme 5. Synthesis of Curcumin mimic-ibuprofen conjugates with an amino acid as a linker

[0272] The chemical structures of compounds J1-J17 are shown below. Characterization of compound 10J using 1H-NMR and 13C-NMR is shown in Figures 11A and 11B, respectively.

[0273]

[0274] Percent inhibition of COX-1, COX-2, IL-6, NO, and TNF-a using compounds J1-J17 and reference compounds Ibuprofen and Indomethin at a concentration of 10 pM is shown in Figure 3 and Tables 2-5.

[0275] Table 2. % Inhibition of COX-1 and COX-2 by compounds J1-J7 and reference drugs Ibuprofen and Indomethacin.

[0276] Table 3. % Inhibition of Tumor Necrosis Factor Alpha (TNFa) by compounds J1-J7 and reference drugs Ibuprofen and Indomethacin. Table 3 cont’d

[0277] Table 4. % Inhibition of NO (nitrite / nitrate) production by compounds J1-J7 and reference drugs Ibuprofen and Indomethacin. Table 5. % Inhibition of IL-6 production by compounds J1-J7 and reference drugs Ibuprofen and Indomethacin.

[0278] Percent inhibition of human mouse double minute 2 (MDM2-p53) binding protein homolog using compounds J1-J17 at a concentrations of 10 pM is sohwn in Figure 4 and Table 6.

[0279] Table 6. % inhibition of human mouse double minute 2 (MDM2-p53) binding protein homolog using compounds J1-J17. Percent viability of cell lines 5637 (Figure 5) and MDA-MB231LUC (Figure 7) were tested using Ibuprofen, 1ST- 5ST, and compounds J1-J5 respectively at different concentrations (5pM and 10 pM).

[0280] Percent viability of cell lines 5637 WT (Figure 6), MB231LUC (Figure 8), MCF-7 (Figure 9), and MCF-12 (Figure 10) were tested using Ibuprofen, 1ST- 5ST, and compounds J1-J5 respectively at different concentrations (5pM, I pM, 0.5pM, and 0. IpM). Table 7. Anticancer properties of the curcumin hybrid conjugates.

Claims

CLAIMSWe claim:

1. A compound having a structure of:wherein:(i) each occurrence of R is independently hydrogen, a halide (e.g., F, Cl, Br, etc.), an unsubstituted Ci-Ce alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.), an alkoxyl (e.g., methoxy, ethoxy, etc.), -(C=O)H, -(C=O)Ri, -(C-O)OH, -(C=O)OR1, -(C=O)Xi, - NH2, -NHRI, -NR1R2, -CF3, -CN, -(S=O)OH, -NO2, -SH, -OH, -(C=O)NHRb-(C=O)NRIR2;(ii) Ri and R2are independent hydrogen or an unsubstituted Ci-Ce alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.);(iii) each occurrence of R’ is independently hydrogen or a side chain of an amino acid (e.g., a naturally occurring amino acid);(iv) n is an integer from 1 to 6, from 1 to 5, from 1 to 4, or from 1 to 3; and(v)is an anti-inflammatory drug moiety.

2. The compound of claim 1 , having a structure of:

3. The compound of claim 1, wherein each occurrence of R is independently hydrogen, a halide (e.g., F, Cl, Br, etc.), an unsubstituted C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, etc.), an alkoxyl (e.g., methoxy, ethoxy, etc.).

4. The compound of any one of claims 1-3, wherein each occurrence of R is independently hydrogen, F, Cl, CH3, or OCH3.

5. The compound of claim 1, wherein each occurrence of R’ is independently hydrogen or a side of a naturally occurring amino acid (e.g., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine).

6. The compound of claim 1, wherein each occurrence of R’ is independently hydrogen or an unsubstituted C1-C4 alkyl, optionally wherein each occurrence of R’ is independently hydrogen or CH3.

7. The compound of claim 1 , wherein A' is a non-steroidal anti-inflammatory drug (NSAID) moiety, such as an ibuprofen moiety, a naproxen moiety, a diclofenac moiety, a mefenamic acid moiety, an indomethacin moiety, or an aspirin moiety.

8. The compound of claim 1, wherein the anti-inflammatory drug moiety is an ibuprofen moiety having the structure9. The compound of claim 1 , wherein the anti-inflammatory drug moiety is a dichloroacetic acid moiety having the structure10. The compound of claim 1, wherein the compound is any one of the following:

11. A pharmaceutical composition comprising the compound of any one of claims 1-10, and optionally one or more pharmaceutically acceptable excipients.

12. The pharmaceutical composition of claim 11, further comprising a second active agent, optionally wherein the second active agent is an anticancer agent or anti-inflammatory agent, or a combination thereof.

13. The pharmaceutical composition of claim 11, wherein the compound in the pharmaceutical composition is in an amount ranging from about 0.1 pM to about 1 mM, from about 0.1 pM to about 500 pM, from about 0.1 pM to about 200 pM, from about 0.1 pM to about 100 pM, from about 0.1 pM to about 50 pM, or from about 0.1 pM to about 20 pM.

14. A method for treating cancer using the pharmaceutical composition of claim 11 comprising:(i) administering the pharmaceutical composition to a subject in need thereof, wherein step (i) occurs one or more times.

15. The method of claim 14, wherein the pharmaceutical composition is administered by oral administration, intramuscular administration, intravenous administration, intraperitoneal administration, subcutaneous administration, or topical administration, or a combination thereof.

16. The method of claim 14, wherein in step (i), the dosage of the compound administered is from about 0.1 pg to about 1000 pg, from about 0.1 pg to about 500 pg, from about 0.1 pg to about 100 pg, from about 0.5 pg to about 50 pg, from about 1 pg to about 1000 pg, from about 1 pg to about 500 pg, from about 1 pg to about 100 pg, from about 1 pg to about 50 pg, from about 1 pg to about 25 pg, from about 1 pg to about 10 pg, from about 0.1 pg to about 50 pg, from about 5 pg to about 50 pg, or from about 0. 1 pg to about 20 pg per g of the subject.

17. The method of claim 14, wherein the cancer is a solid cancer.

18. The method of claim 14, wherein the cancer is a breast cancer or colon cancer, or a combination thereof.

19. The method of claim 14, wherein more than one administration step is performed, and wherein each administration is performed regularly every 5 mins, every 10 mins, every 20 mins, every 30 mins, every hour, every 2 hours, every day, every two days, every 3 days, every week, every two weeks, or every month, etc.; or irregularly with a time interval of 5 mins, 10 mins, 20 mins, 30 mins, 1 hour, 2 hours, 1 day, 2 days, 3 days, 5 days, 1 week, or 2 weeks.

20. The method of claim 14, further comprising administering an active agent prior to, during, and / or subsequent to step (i), optionally wherein the active agent is an anticancer agent or anti-inflammatory agent, or a combination hereof.

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