Phospholipid-flavagine conjugates and methods of using same for targeted cancer therapy - Patents.com

Abstract

Disclosed herein are phospholipid ether (PLE) molecules. Also provided are phospholipid-flavagrine conjugates. The phospholipid-flavagrine conjugates may comprise a PLE linked to the flavagrine via a linker. Also provided herein are methods for treating cancer in a subject and for targeting a drug to tumor or cancer cells in a subject.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 913,571, filed October 10, 2019, the contents of which are incorporated by reference in their entirety herein.

[0002] The present disclosure relates to phospholipid-flavagline conjugates and targeted cancer therapy. [Background technology]

[0003] Introduction The majority of anticancer drugs in clinical use have limited utility due to toxicity to all proliferating cells and / or inability to exert effects on all tumor cells. Although novel agents with unique mechanisms of action designed to enhance targeting continue to be developed, many of these compounds still lack absolute tumor selectivity and off-target effects continue to limit their therapeutic use. Antibody-drug conjugates (ADCs) are designed to bind to specific epitopes on the surface of tumor cells, providing an alternative method to target tumor cells in an attempt to reduce associated toxicity. Although highly selective, antibody-drug conjugates only achieve moderate cellular uptake and limited cell killing activity, so very few antibody-drug conjugates are therapeutically useful. More effective tumor targeting platforms are needed. Summary of the Invention

[0004] In an embodiment, the present disclosure provides a compound of formula (I): [ka] wherein Z is a flavugine analog. Provided is a compound of formula (I) or a pharma- ceutically acceptable salt thereof:

[0005] Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0006] Another aspect of the disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0007] Another aspect of the disclosure provides a method of targeting a drug to a tumor or cancer cell in a subject, the method comprising administering to the subject a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0008] In some embodiments, the compounds described herein localize or translocate to the cytoplasm or organelles of the tumor or cancer cells. In some embodiments, the compounds are selective for the cancer cells of the subject. In some embodiments, the compounds are taken up by the tumor or cancer cells at least about twice as much as healthy cells. In some embodiments, the cancer is melanoma, brain cancer, lung cancer, adrenal cancer, liver cancer, renal or kidney cancer, pancreatic cancer, esophageal cancer, gastric cancer, stomach cancer, colon cancer, colorectal cancer, anal cancer, prostate cancer, ovarian cancer, breast cancer, cervical cancer, lymphoma, leukemia, myeloma, hematopoietic cancer, hepatocellular carcinoma, retinoblastoma, glioma, sarcoma, blastoma, squamous cell carcinoma, adenocarcinoma, or a combination thereof. In some embodiments, the subject is a human.

[0009] The present disclosure provides other aspects and embodiments that will become apparent in view of the following detailed description and accompanying drawings. [Brief description of the drawings]

[0010] [Figure 1A]Figures 1A, 1B, 1C, 1D, and 1E show images of tumor cells containing labeled lipid rafts. Tumor cells had a higher concentration of lipid rafts compared to normal cells. [Figure 1B] Figures 1A, 1B, 1C, 1D, and 1E show images of tumor cells containing labeled lipid rafts. Tumor cells had a higher concentration of lipid rafts compared to normal cells. [Figure 1C] Figures 1A, 1B, 1C, 1D, and 1E show images of tumor cells containing labeled lipid rafts. Tumor cells had a higher concentration of lipid rafts compared to normal cells. [Figure 1D] Figures 1A, 1B, 1C, 1D, and 1E show images of tumor cells containing labeled lipid rafts. Tumor cells had a higher concentration of lipid rafts compared to normal cells. [Figure 1E] Figures 1A, 1B, 1C, 1D, and 1E show images of tumor cells containing labeled lipid rafts. Tumor cells had a higher concentration of lipid rafts compared to normal cells. [Figure 1F] Figure IF shows images of normal fibroblasts and Caki-2 tumor cells containing CLR 1501 (compound (1)). CLR 1501 was highly localized in Caki-2 cells, but was minimally localized in normal fibroblasts. [Figure 1G] Figure 1G shows an image of control A549 cells, and Figure 1H shows an image of A549 cells treated with methyl-b-cyclodextrin to disrupt lipid rafts. When cells in both Figure 1G and Figure 1H were incubated with CLR 1501 (compound (1)), the majority of lipid rafts in A549 cells were disrupted, resulting in a 60% decrease in the uptake of CLR 1501 (compound (1)). [Figure 1H]Figure 1G shows an image of control A549 cells, and Figure 1H shows an image of A549 cells treated with methyl-b-cyclodextrin to disrupt lipid rafts. When cells in both Figure 1G and Figure 1H were incubated with CLR 1501 (compound (1)), the majority of lipid rafts in A549 cells were disrupted, resulting in a 60% decrease in the uptake of CLR 1501 (compound (1)). [Figure 1I] Figures 1I, 1J, and 1K are images of PC3 cells incubated with CLR 1501 (compound (1)) and stained for the endoplasmic reticulum (ER). CLR 1501 (compound (1)) colocalized with the ER in malignant cells but not in normal cells (not shown). [Figure 1J] Figures 1I, 1J, and 1K are images of PC3 cells incubated with CLR 1501 (compound (1)) and stained for the endoplasmic reticulum (ER). CLR 1501 (compound (1)) colocalized with the ER in malignant cells but not in normal cells (not shown). [Figure 1K] Figures 1I, 1J, and 1K are images of PC3 cells incubated with CLR 1501 (compound (1)) and stained for the endoplasmic reticulum (ER). CLR 1501 (compound (1)) colocalized with the ER in malignant cells but not in normal cells (not shown). [Figure 1L] Figures 1L, 1M, and 1N are images of PC3 cells incubated with CLR 1501 (compound (1)) and stained for nuclei and mitochondria. CLR 1501 (compound (1)) colocalized with mitochondria. [Figure 1M] Figures 1L, 1M, and 1N are images of PC3 cells incubated with CLR 1501 (compound (1)) and stained for nuclei and mitochondria. CLR 1501 (compound (1)) colocalized with mitochondria. [Figure 1N]Figures 1L, 1M, and 1N are images of PC3 cells incubated with CLR 1501 (compound (1)) and stained for nuclei and mitochondria. CLR 1501 (compound (1)) colocalized with mitochondria. [Diagram 2] FIG. 2 is an image of a colorectal (HCT-116) tumor-bearing mouse injected with CLR 1502 (compound (2)), showing tumor localization. [Diagram 3] FIG. 3 is a graph of cytotoxicity versus concentration of a cytotoxic compound (FLV1) compared to a cytotoxic compound (CLR 1865, compound (8)) bound to PLE in A549 (human lung adenocarcinoma) cells or normal human dermal fibroblasts (NHDFs). [Figure 4] FIG. 4 is a graph of the fold increase in uptake of CLR 1852 (compound (9)) versus time in A375 (human melanoma) and HEK293 (human embryonic kidney) cells. [Diagram 5] FIG. 5 is an image of a mouse breast cancer model showing the in vivo uptake of CLR 1502 (compound (2)). [Figure 6] FIG. 6 is an image of myeloma cell lines showing the uptake of CLR 1501 (compound (1)). [Figure 7] FIG. 7 shows images of cancer stem cells, normal brain tissue, and normal stem cells showing the specific uptake of CLR 1501 (compound (1)) into cancer cells. [Figure 8] FIG. 8 is a graph of % cytotoxicity versus concentration of CLR 1852 (compound (9)) compared to FLV3 in A549 (human lung adenocarcinoma) cells and normal human dermal fibroblasts (NHDFs). [Figure 9] FIG. 9 is a graph of tumor volume versus time for vehicle compared to CLR 1852 (compound (9)) in the HCT116 tumor model. [Figure 10] FIG. 10 is a graph of body weight versus time for vehicle compared to CLR 1852 (compound (9)) in the HCT116 tumor model. [Figure 11]FIG. 11 is a graph of the concentration of FLV3 (normalized to cytosol volume) detected in the cytosol of A375 (human melanoma) and A549 (human lung adenocarcinoma) cell lines versus time. [Figure 12] FIG. 12 shows representative results of body weight changes in a mouse model following administration of CLR 1899 (0.5 mg / kg, 1 mg / kg, and 2 mg / kg). [Figure 13] FIG. 13 shows representative results of the in vivo efficacy of CLR 1899 in an MCF-7 xenograft model (10 mice per dose group). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Described herein are phospholipid compounds and phospholipid-flavagrine conjugates. Based on a number of animal and human tumors that contain naturally occurring ether lipids at higher concentrations than normal tissues, phospholipid ether (PLE) molecules have been developed. The PLE molecules detailed herein may be used as tumor targeting platforms to selectively deliver drugs to tumor and cancer cells.

[0012] As detailed herein, the tissue distribution of PLE molecules was examined in over 100 different tumor cell types, including fresh human tumor samples. PLE molecules were shown to be taken up more abundantly in tumor tissues compared to normal tissues. PLE molecules can be linked to flavagrine molecules and their analogs via linkers to form phospholipid-flavagrine conjugates.

[0013] 1.Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In case of conflict, this document, including definitions, controls. Although methods and materials similar or equivalent to those described herein can be used to practice or test the present invention, preferred methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0014] As used herein, the terms "comprise(s)", "include(s)", "having", "has", "can", "contain(s)", and variations thereof are intended to be open transitions, terms, or words that do not exclude the possibility of additional acts or structures. The singular forms "a", "and" and "the" include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments that "comprising", "consisting of", or "consisting essentially of" the embodiments or elements presented herein, whether expressly stated or not.

[0015] For the recitation of numerical ranges herein, each intervening number to the same degree of precision is expressly contemplated, for example, for the range 6 to 9, the numbers 7 and 8 are also contemplated in addition to the numbers 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated.

[0016] As used herein, the term "about" applied to one or more values ​​of interest refers to a value similar to the indicated reference value. In certain embodiments, the term "about" refers to a numerical range that is within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% in either direction of the indicated reference value, unless otherwise stated or evidenced otherwise by context (except when such number exceeds 100% of possible values).

[0017] Definitions of certain functional groups and chemical terms are detailed below. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific reactive moieties and reactivities, are described in detail in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 7 th Edition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987, the contents of each of which are incorporated herein by reference in their entirety.

[0018] The term "alkoxy" or "alkoxyl" as used herein refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0019] As used herein, the term "alkyl" refers to a straight or branched, saturated hydrocarbon chain containing 1 to 20 carbon atoms. 1-6 The term "alkyl" means a linear or branched, chain-like saturated hydrocarbon containing 1 to 6 carbon atoms. The term "C1-4 alkyl" means a linear or branched, chain-like saturated hydrocarbon containing 1 to 4 carbon atoms. The term "C1-3 alkyl" means a linear or branched, chain-like saturated hydrocarbon containing 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0020] As used herein, the term "alkenyl" refers to an unsaturated hydrocarbon chain containing 2 to 20 carbon atoms and at least one carbon-carbon double bond.

[0021] As used herein, the term "alkynyl" refers to an unsaturated hydrocarbon chain containing 2 to 20 carbon atoms and at least one carbon-carbon triple bond.

[0022] The term "alkoxyalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0023] The term "arylalkyl," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0024] The term "alkylamino," as used herein, refers to at least one alkyl group, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein.

[0025] As used herein, the term "alkylene" refers to a divalent group derived from a straight or branched, chain-like saturated hydrocarbon of 1 to 10 carbon atoms, e.g., 2 to 5 carbon atoms. Representative examples of alkylene include, but are not limited to, CH2CH2-, -CH2CH2CH2-, -CH2CH2CH-2CH2-, and -CH2CH2CH2CH2CH2-.

[0026] As used herein, the term "amide" means -C(O)NR- or -NRC(O)-, where R can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0027] The term "aminoalkyl," as used herein, means at least one amino group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0028] As used herein, the term "amino" refers to R x and R y may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl; -NR x R y In the case where amino is an aminoalkyl group or any other moiety that simultaneously adds two other moieties, amino is R x may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl; -NR x - may be.

[0029] As used herein, the term "aryl" refers to an aromatic group such as a phenyl group, or a bicyclic fused ring system. A bicyclic fused ring system is exemplified by a phenyl group appended to the parent molecular moiety and fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl group, as defined herein, or a heterocycle, as defined herein. Representative examples of aryl include, but are not limited to, indolyl, naphthyl, phenyl, quinolinyl, and tetrahydroquinolinyl. "Arylalkyl" refers to an alkyl, as defined herein, substituted with an aryl group.

[0030] As used herein, the term "arylene" refers to an aryl, as defined herein, having two monovalent radical centers derived by removing two hydrogen atoms from two different carbon atoms of the parent aryl. Exemplary arylene groups include, but are not limited to, phenylene and naphthylene. "Arylalkylene" refers to an arylalkyl, as defined herein, having two monovalent radical centers derived by removing one hydrogen atom from the aryl group of the group and the other hydrogen removed from the alkyl group of the group.

[0031] As used herein, the term "carboxyl" means a carboxylic acid or -COOH.

[0032] The term "cycloalkyl" means a monovalent saturated hydrocarbon ring or bicyclic group. Cycloalkyl groups do not contain a single heteroatom or a single double bond. Cycloalkyl groups are monocyclic or fused, spiro, or bridged bicyclic ring systems. Monocyclic cycloalkyl groups contain 3 to 10 carbon atoms in the ring, preferably 4 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms. Bicyclic cycloalkyl groups contain 8 to 12 carbon atoms in the ring, preferably 9 to 10 carbon atoms. Cycloalkyl groups can be substituted or unsubstituted. Cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0033] As used herein, the term "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and preferably having from 5 to 10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0034] As used herein, the term "cycloalkynyl" means a monocyclic or polycyclic ring system containing at least one carbon-carbon triple bond and preferably having from 5 to 10 carbon atoms per ring or more than 10 carbon atoms per ring.

[0035] The term "haloalkyl" as used herein means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl, such as 3,3,3-trifluoropropyl.

[0036] As used herein, the term "halogen" or "halo" means Cl, Br, I, or F.

[0037] As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, in which at least one of the carbons of the alkyl group is replaced with a heteroatom, such as oxygen, nitrogen, and sulfur. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides.

[0038] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or bicyclic ring system containing at least one heteroatom independently selected from the group consisting of N, O, and S. An aromatic monocyclic ring is a 5- or 6-membered ring containing at least one heteroatom independently selected from the group consisting of N, O, and S. A 5-membered aromatic monocyclic ring has two double bonds and a 6-membered aromatic monocyclic ring has three double bonds. A bicyclic heteroaryl group is exemplified by a monocyclic heteroaryl ring appended to a parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein. Representative examples of heteroaryl include, but are not limited to, indolyl, pyridinyl (including pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, thienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, and benzyl. Examples of such aryl groups include benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl, quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, 6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl, and thiazolo[5,4-d]pyridin-2-yl.

[0039] As used herein, the term "heterocycle" or "heterocyclic" or "heterocyclyl" refers to a monocyclic heterocycle, a bicyclic heterocycle (heterobicyclic), or a tricyclic heterocycle. A monocyclic heterocycle is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains zero or one double bond and one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The 7- and 8-membered rings contain zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, pipera, These include thienyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl.A bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a bridged monocyclic heterocycle system in which two non-adjacent atoms of the ring are joined by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydroisoquinoline, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), 2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclic heterocycles are exemplified by bicyclic heterocycles fused to a phenyl group, or bicyclic heterocycles fused to a monocyclic cycloalkyl, or bicyclic heterocycles fused to a monocyclic cycloalkenyl, or bicyclic heterocycles fused to a monocyclic heterocycle, or bicyclic heterocycles in which two non-adjacent atoms of the bicyclic ring are joined by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of 2, 3, or 4 carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.1. 3,7 ]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.1 3,7 ]decane. The monocyclic, bicyclic and tricyclic heterocycles can be attached to the parent molecular moiety by any carbon atom or any nitrogen atom contained within the ring, and can be unsubstituted or substituted.

[0040] The term "heteroarylalkyl," as used herein, refers to a heteroaryl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0041] The term "heterocyclylalkyl," as used herein, refers to a heterocycle group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein.

[0042] As used herein, the terms "hydroxyl" or "hydroxy" refer to an --OH group.

[0043] The term "hydroxyalkyl," as used herein, means at least one --OH group appended to the parent molecular moiety by an alkylene group, as defined herein.

[0044] In some instances, the number of carbon atoms in a hydrocarbyl substituent (such as an alkyl or cycloalkyl) is indicated by the prefix "C x - y - " where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms in the substituent. Thus, for example, "C1-3 alkyl" refers to an alkyl substituent containing 1 to 3 carbon atoms.

[0045] The term "substituted" refers to a group that may be further substituted with one or more non-hydrogen substituents. The substituents include, but are not limited to, halogen, =O (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0046] term [ka] is a single bond [ka] or double bond [ka] or triple bond [ka] Represents.

[0047] For the compounds described herein, the groups and substituents may be selected according to the permissible valences of atoms and substituents so that selection and substitution give rise to stable compounds, e.g., the compounds do not undergo spontaneous transformation by rearrangement, cyclization, elimination, and the like.

[0048] As used herein, the term "administration" or "administering" refers to providing, contacting, and / or delivering a compound or conjugate by any suitable route to achieve a desired effect. These compounds or conjugates may be administered to a subject in a number of ways, including but not limited to orally, ophthalmically, nasally, intravenously, topically, as an aerosol, suppository, etc., and may be used in combination.

[0049] As used herein, "cancer" may include cells or tissues derived from a tumor, neoplasm, cancer, precancer, cell line, malignant tumor, or any other source of cells that have the potential to expand and grow indefinitely. Cancer cells may be derived from a source of natural origin or may be artificially created. Cancer cells may also be capable of invading and metastasizing to other tissues. Cancer cells further encompass any malignant cells that have invaded and metastasized to other tissues. In the context of a living organism, one or more cancer cells may also be referred to as cancer, tumor, neoplasm, growth, malignancy, or any other term used in the art to describe cells in a cancerous state. The cancer may include, for example, melanoma, brain cancer, lung cancer, adrenal cancer, liver cancer, renal or kidney cancer, pancreatic cancer, esophageal cancer, gastric cancer, stomach cancer, colon cancer, colorectal cancer, anal cancer, prostate cancer, ovarian cancer, breast cancer, cervical cancer, lymphoma, leukemia, myeloma, hematopoietic cancer, hepatocellular carcinoma, retinoblastoma, glioma, sarcoma, blastoma, squamous cell carcinoma, and adenocarcinoma.

[0050] As used herein, the term "cancer stem cell" refers to a cancer cell that can self-renew and differentiate into the different types of cancer cells found in malignant tumors.

[0051] Generally, reference to a "circulating tumor cell" (CTC) is intended to refer to a single cell, while reference to a "plurality of circulating tumor cells" or a "population of circulating tumor cells" is intended to refer to more than one cancer cell. However, those skilled in the art will understand that reference to a "circulating tumor cell" is intended to include a population of circulating tumor cells, including one or more circulating tumor cells, while reference to a "circulating tumor cell" may include more than one circulating tumor cell. As used herein, the term "circulating tumor cell" or "plurality of circulating tumor cells" refers to any cancer cell or population of cancer cells found in a blood or serum sample of a subject. A plurality of CTCs may also include or consist of a cancer stem cell or population of cancer stem cells found in a blood or serum sample of a subject.

[0052] The terms "control", "reference level" and "reference" are used interchangeably herein. A reference level may be a predetermined value or range that is used as a benchmark for which a measurement result should be evaluated. As used herein, a "control group" refers to a group of control subjects. The predetermined level may be a cut-off value from the control group. The predetermined level may be an average value from the control group. The cut-off value (or the predetermined cut-off value) may be determined by the Adaptive Index Model (AIM) method. The cut-off value (or the predetermined cut-off value) may be determined by Receiver Operating Characteristic (ROC) analysis from biological samples of a patient group. ROC analysis, generally known as a biological technique, determines the ability of a test to distinguish one condition from another. A description of ROC analysis is given by PJ Heagerty et al. (Biometrics 2000, 56, 337-44), the disclosure of which is incorporated herein in its entirety by reference. Alternatively, the cut-off value may be determined by quartile analysis from biological samples of a patient group. For example, the cut-off value may be determined by selecting a value corresponding to any value in the 25th to 75th percentile range, preferably the 25th, 50th, or 75th percentile, more preferably the 75th percentile. Such statistical correction may be performed using any method known in the art and may be performed by any number of commercially available software packages (e.g., from Analyse-it Software Ltd., Leeds, UK; StataCorp LP, College Station, TX; SAS Institute Inc., Cary, NC). A healthy or normal level or range of target or protein activity may be defined according to standard practice. The control may be a subject or a sample thereof with a known disease state. The subject or the sample thereof may be healthy, diseased, diseased before treatment, diseased during treatment, diseased after treatment, or healthy after treatment, or a combination thereof. As used herein, the term "normal subject" refers to a healthy subject, i.e., a subject without clinical signs or symptoms of disease.Normal subjects are clinically evaluated for signs or symptoms of otherwise undetected disease, which may include routine physical and / or laboratory tests. In some embodiments, the control is a healthy control. In some embodiments, the control comprises a cancer.

[0053] As used herein, the term "effective dose" or "therapeutically effective amount" or "therapeutically effective amount" or "effective amount" refers to a dose of a drug that is sufficient to induce a therapeutic effect or is effective for a period of time necessary to achieve a desired therapeutic result. An effective dose may be determined by one skilled in the art and may depend on the individual's medical condition, age, sex, and weight, the method of administration, the stage and severity of the disease, the general health of the subject, the opinion of the prescribing physician, and the ability of the drug to induce a desired response in the individual. A therapeutically effective amount is also one in which the therapeutically effective effects outweigh any toxic or harmful effects of the substance. A "prophylactically effective amount" refers to an amount effective at dosages and periods of time necessary to achieve a desired prophylactic result. Typically, a prophylactic dose is used in subjects prior to or at an early stage of disease, so the prophylactically effective amount will be less than the therapeutically effective amount.

[0054] The term "inhibit" or "inhibiting" means that activity is decreased or prevented in the presence of an inhibitor as opposed to in the absence of the inhibitor. The term "inhibition" refers to a decrease or downregulation of a process or lack of stimulation of a process, resulting in the absence or minimization of expression or activity of a biomarker or polypeptide. Inhibition may be direct or indirect. Inhibition may be specific, i.e., an inhibitor inhibits a biomarker or polypeptide and not others.

[0055] As used herein, the term "sample" or "test sample" can mean any sample for detecting or determining the presence and / or level of a compound or target in the sample. The sample may include a liquid, solution, emulsion, mixture, or suspension. The sample may include a medical sample. The sample may include any biological fluid or tissue such as blood, whole blood, blood fractions such as plasma and serum, peripheral blood mononuclear cells (PBMCs), muscle, interstitial fluid, sweat, saliva, urine, tears, synovial fluid, bone marrow, cerebrospinal fluid, nasal secretions, sputum, amniotic fluid, bronchoalveolar lavage fluid, gastric lavage, vomit, fecal matter, lung tissue, peripheral blood mononuclear cells, total white blood cells, lymph node cells, spleen cells, tonsil cells, cancer cells, tumor cells, bile, digestive fluid, skin, or combinations thereof. In some embodiments, the sample includes an aliquot. In other embodiments, the sample includes a biological fluid. The sample can be obtained by any means known in the art. The sample can be obtained directly from a patient and used, or can be pretreated by filtration, distillation, extraction, concentration, centrifugation, inactivation of interfering components, addition of reagents, and the like, such as adjusting the characteristics of the sample by some methods discussed herein or otherwise known in the art. The sample can be obtained before diagnosis, before treatment, during treatment, after treatment, or after diagnosis, or combinations thereof.

[0056] As used herein, the term "specificity" refers to the number of true negatives divided by the number of true negatives + the number of false positives, and the specificity ("spec") can be in the range of 0 < spec < 1. Thus, a method having both a sensitivity and a specificity equal to 1 or 100% is preferred.

[0057] Generally, by "specifically binds", it means that a compound or conjugate binds to its target more readily than it binds to random and unrelated targets.

[0058] As used herein, "subject" can refer to a mammalian animal that desires or requires the compounds or methods described herein. The subject can be a human or a non-human animal. The subject can be a mammalian animal. The mammalian animal can be a primate or a non-primate. The mammalian animal can be a primate, such as a human, a non-primate, such as a dog, a cat, a horse, a cow, a pig, a mouse, a rat, a camel, a llama, a goat, a rabbit, a sheep, a hamster, and a guinea pig, or a non-human primate, such as a monkey, a chimpanzee, a gorilla, an orangutan, and a gibbon. The subject can be of any age or developmental stage, such as an adult, an adolescent, or an infant. The subject can be male or female. In some embodiments, the subject has a specific genetic marker.

[0059] As used herein, the term "toxic" refers to a quantity of a chemical entity, drug, or substance that is harmful to a subject and causes any side effects. The term "non-toxic" refers to a substance that is relatively low in ability to harm a subject. "Cytotoxic" refers to a chemical entity, drug, or substance that is toxic to cells. Toxicity refers to effects on whole organisms such as animals, bacteria, plants, or other subjects as defined herein, as well as effects on substructures of an organism such as cells (cytotoxicity) or organs such as the liver (hepatotoxicity). A central concept in toxicology is that effects are dose-dependent; even water can cause water intoxication if ingested in large enough quantities, while even highly toxic substances such as snake venom have a dose below which they have no detectable toxic effects. A relatively non-toxic composition or compound may allow a wide range of subjects to safely handle the composition or compound without serious safety concerns or risks.

[0060] As used herein, the terms "treat", "treated" or "treating" refer to a therapeutic method that slows (mitigates) an undesired physiological condition, disorder, or disease in a subject or obtains a beneficial effect or desired clinical outcome. For purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in the extent of a condition, disorder, or disease, stabilization (i.e., does not worsen) of the condition, disorder, or disease state, delay in onset or slower deterioration of a condition, disorder, or disease, remission of a condition, disorder, or disease state, and remission (whether partial or total), or enhancement or amelioration of a condition, disorder, or disease, whether detectable or undetectable. Treatment also includes extending survival time compared to expected survival time in the absence of treatment. "Treatment" or "treating", when referring to protecting a subject from a disease, means inhibiting, preventing, ameliorating, or completely eliminating the disease. Preventing a disease includes administering a composition of the present invention to a subject before the onset of the disease. Suppressing a disease includes administering a composition of the invention to a subject after induction of the disease but before clinical appearance of the disease. Preventing or ameliorating a disease includes administering a composition of the invention to a subject after clinical appearance of the disease. The disease may include cancer.

[0061] 2. Phospholipid Ethers Provided herein is a phospholipid ether (PLE) molecule having the formula (I'): [ka] X is hydrogen, methyl, or phenyl substituted with carboxyl; It may be according to formula (I') or a salt thereof.

[0062] In some embodiments, the PLE comprises the following: [ka] and [ka] is selected from.

[0063] The PLE may be conjugated to a detectable moiety (also called a reporter or label), such as, for example, a fluorescent molecule, a chemiluminescent molecule, a radiolabel, a magnetic label, an infrared molecule, or a combination thereof. A magnetic label is a label moiety that, when sufficiently associated with a magnetic proximity sensor, can be detected by the magnetic proximity sensor, causing the magnetic proximity sensor to output a signal. A magnetic label may include one or more substances selected from paramagnetic substances, superparamagnetic substances, ferromagnetic substances, ferromagnetic substances, antiferromagnetic substances, combinations thereof, and the like. A fluorescent label is a label moiety that can be detected by a fluorescence detector. Suitable fluorescent molecules (fluorophores) include, but are not limited to, fluorescein, fluorescein isothiocyanate, succinimidyl ester of carboxyfluorescein, succinimidyl ester of fluorescein, 5-isomer of fluorescein dichlorotriazine, caged carboxyfluorescein-alanine-carboxamide, Oregon Green 488, Oregon Green 514, Lucifer Yellow, acridine orange, rhodamine, tetramethylrhodamine, Texas Red, propidium iodide, JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazoylcarbocyanine iodide), tetrabromorhodamine 123, rhodamine 6G, TMRM (tetramethylrhodamine methyl ester), TMRE (tetramethylrhodamine methyl ester), tetramethylrhodamine methyl ester, ... rhodamine ethyl ester), tetramethylrosamine, rhodamine B and 4-dimethylaminotetramethylrosamine, green fluorescent protein, blue-shifted green fluorescent protein, cyan-shifted green fluorescent protein, red-shifted green fluorescent protein, yellow-shifted green fluorescent protein, 4-acetamido-4'-isothiocyanato-stilbene-2,2'-disulfonic acid, acridine, acridine isothiocyanate and other acridine and derivatives, 5-(2'-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS), 4-amino-N-[3-vinylsulfonyl)phenyl]naphthalimide (naphth-alimide)-3,5 disulfonic acid, N-(4-anilino-1-naphthyl)maleimide; anthranilamide; 4,4-difluoro-5-(2-thienyl)-4-bora-3a,4a diaza-5-indacene-3-propionic acid BODIPY; Cascade Blue; Brilliant Yellow; Coumarins and derivatives such as Coumarin, 7-amino-4-methylcoumarin (AMC, Coumarin 120), 7-amino-4-trifluoromethylcoumarin (Coumarin 151); Cyanine dyes, Cyanosine, 4',6-diaminidino-2-phenylindole (DAPI), 5',5"-dibromopyrogallol-sulfonaphthalein (Bromopyrogallol Red), 7-diethylamino-3-(4'-isothiocyanatophenyl)-4-methylcoumarin, diethylenetriamine pentaacetate, 4,4'-diisothiocyanatophenyl Natodihydro-stilbene-2-,2'-disulfonic acid, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, 5-(dimethylamino)naphthalene-1-sulfonyl chloride (DNS, dansyl chloride), 4-dimethylaminophenylazophenyl-4'-isothiocyanate (DABITC), eosin and derivatives such as eosin, eosin isothiocyanate, erythrosine and derivatives such as erythrosine B, erythrosine isothiocyanate, ethidium, fluorescein and derivatives such as 5-carboxyfluorescein (FAM), 5-(4,6-dichlorotriazin-2-yl)amino-1-fluorescein (DTAF), 2',7'dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), fluorescein, fluorescein isothiocyanate, QFITC, (XRITC), fluorescamine, IR144, IR1446, malachite green isothiocyanate, 4-methylumberyl-ferroneorthocresolphthalein, nitrotyrosine, pararosaniline, phenol red, B-phycoerythrin, o-phthaldialdehyde, pyrene and derivatives such as pyrene, pyrene butyrate, succinimidyl 1-pyrene, butyrate quantum dots, reactive red 4 (Cibacron™ Brilliant Red 3B-A) rhodamine and derivatives such as 6-carboxy-X-rhodamine (R OX), 6-carboxyrhodamine (R6G), Lissamine rhodamine B sulfonyl chloride rhodamine (Rhod), rhodamine B, rhodamine 123, rhodamine X isothiocyanate, sulforhodamine B, sulforhodamine 101, sulfonyl chloride derivative of sulforhodamine 101 (Texas Red), N,N,N',N'-tetramethyl-6-carboxyrhodamine (TAMRA), tetramethylrhodamine, tetramethylrhodamine (hodamine) isothiocyanate (TRITC), riboflavin, 5-(2'-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS), 4-(4'-dimethylaminophenylazo)benzoic acid (DABCYL), rosolic acid, CAL Fluor Orange 560, terbium chelate derivatives, Cy3; Cy5; Cy5.5; Cy7; IRD700; IRD800; La Jolla Blue, phthalocyanines, and naphthalocyanines, coumarin and related dyes, xanthene dyes such as rhodol, resorufins, bimanes, acridines, isoindoles, dansyl dyes, aminophthalhydrazides such as luminol and isoluminol derivatives, aminophthalimides, aminonaphthalimides, aminobenzofurans, aminoquinolines, dicyanohydroquinones, and fluorescent europium and terbium complexes, combinations thereof, and the like.

[0064] The detectable moiety may be covalently or cleavably attached to the PLE. For example, the labeled PLE may be attached to the following: [ka] and [ka] You may choose from.

[0065] Compound (1) above is PLE(3) with a fluorescent moiety, BODIPY, stably linked to the PLE, and can also be referred to as CLR 1501. Compound (2) above is PLE(3) with a near-infrared molecule, IR-775, stably linked to the PLE, and can also be referred to as CLR 1502. Compounds (1) and (2) can also be referred to as phospholipid drug conjugates (PDCs).

[0066] The PLE, or conjugate thereof, may be specific to tumor or cancer cells. Upon administration to a subject, the PLE, or conjugate thereof, may localize to tumor or cancer cells. The PLE, or conjugate thereof, may be taken up in greater amounts by tumor or cancer cells than by healthy cells. The PLE, or conjugate thereof, may be taken up in greater amounts by tumor or cancer cells than by healthy cells at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold more by tumor or cancer cells than by healthy cells.

[0067] 3. Phospholipid-flavagrine conjugate compounds PLE can be linked to a flavagrine compound via a linker to form a phospholipid-flavagrine conjugate (also called a PLE-flavagrine conjugate).

[0068] In one aspect, the present application relates to a compound of formula (I): [ka] wherein Z is a flavugine analogue. Provided is a compound of formula (I), or a pharma- ceutically acceptable salt thereof:

[0069] Flavaglines are a family of natural products found in plants of the Aglaia genus (Meliaceae family). Flavaglines are characterized by a cyclopenta[b]benzofuran skeleton. Flavaglines may have potent insecticidal, antifungal, anti-inflammatory, neuroprotective, cardioprotective, and anticancer activities. Flavaglines may enhance chemotherapy efficacy and / or reduce cardiac side effects of chemotherapy. Suitable flavaglines analogs include, for example, compounds disclosed in U.S. Patent Application Publication No. 2018 / 0086729, the contents of which are incorporated herein by reference in their entirety. Flavaglines may include, for example, FLV1, FLV3, derivatives or structural analogs thereof, or combinations thereof. As used herein, the term "flavagline analog" or "flavagline anticancer agent" includes all natural and synthetic flavagline compounds, derivatives thereof, and structural analogs thereof.

[0070] In some embodiments, the flavugine analog comprises FLV1, or a salt thereof. [ka]

[0071] In some embodiments, the flavugine analog comprises FLV3, or a salt thereof. [ka]

[0072] Suitable compounds disclosed herein include: [ka] and [ka] or a pharma- ceutically acceptable salt thereof.

[0073] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0074] A conjugate compound of formula (II) [ka] X is [ka] or [ka] Also provided is a conjugate compound of formula (II), or a salt thereof, wherein Y is a disulfide-containing linker and Z is a flavogline anticancer drug. The conjugate compound of formula (II) may also be referred to as a phospholipid drug conjugate (PDC).

[0075] In formula (II), the linker may be a cleavable linker, such as a disulfide, specifically designed to deliver the flavagonine to tumor or cancer cells. In some embodiments, the linker comprises a disulfide. In some embodiments, the linker is one of the following: [ka] Includes.

[0076] In some embodiments, the phospholipid-flavagrine conjugate compound of formula (II) is [ka] and [ka] or a pharma- ceutically acceptable salt thereof.

[0077] The compounds described herein may exist as stereoisomers in which asymmetric or chiral centers exist. Stereoisomers are "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. As used herein, the terms "R" or "S" are the configurations defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45, 13-30. Various stereoisomers and mixtures thereof are contemplated by this disclosure and are specifically included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers and diastereomers. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparation of racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attachment of the mixture of enantiomers to an asymmetric auxiliary, separation of the resulting diastereomeric mixture by recrystallization or chromatography, and liberation of the optically pure product from any auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on a chiral chromatographic column, or (3) fractional recrystallization. It should be understood that the compounds described herein may include tautomeric forms as well as geometric isomers, and that these isomers also constitute embodiments of the present disclosure. The compounds described herein may also exist as racemic mixtures.

[0078] The present disclosure also includes isotopically labeled compounds, such as isotopically labeled PLE, isotopically labeled flavoglin, isotopically labeled linker, or isotopically labeled phospholipid-flavaglin conjugate. Isotopically labeled compounds are identical to those detailed herein except for the fact that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, each of the following: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 The elements are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. Deuterium, i.e. 2 Substitution with heavier isotopes such as H can provide certain therapeutic advantages resulting from improved metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. The compounds may incorporate positron-emitting isotopes for medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron-emitting isotopes that can be incorporated into the compounds include: 11 C. 13 N, 15 O, and 18 F. Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using a suitable isotopically labeled reagent in place of the non-isotopically labeled reagent.

[0079] The disclosed PLE or phospholipid-flavaglin conjugates can exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts or zwitterions of compounds that are soluble or dispersible in water or oil, suitable for treating disorders without undue toxicity, irritation, and allergic reactions, commensurate with a reasonable benefit / risk ratio, and effective for the intended use. The salts may be prepared during the final isolation and purification of the compounds, or isolated by reacting the amino group of the compounds with a suitable acid. For example, the compounds may be dissolved in a suitable solvent, such as, but not limited to, methanol and water, and treated with at least one equivalent of acid, such as hydrochloric acid. The resulting salts may be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to obtain the salts. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfate, phosphate, and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides, iodides, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.

[0080] During the final isolation or purification of the disclosed compounds, base addition salts may be prepared by reacting the carbonyl group with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a metal cation, such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or a primary, secondary, or tertiary organic amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0081] The phospholipid-flavagrine conjugate compounds described herein may be specific to tumor or cancer cells. Upon administration to a subject, the compounds may localize to tumor or cancer cells. The compounds may localize or translocate to the cytoplasm or organelles of tumor or cancer cells. The compounds may be taken up more by tumor or cancer cells than healthy cells. The compounds may be taken up at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold more by tumor or cancer cells than healthy cells.

[0082] The flavagrine or flavagrine analog may be cleaved from the compound, such as cleaved in vivo upon administration to a subject. The flavagrine or flavagrine analog may be localized or translocated to the cytoplasm or organelles of tumor or cancer cells. The flavagrine or flavagrine analog may be taken up more by tumor or cancer cells than healthy cells. The flavagrine or flavagrine analog may be taken up at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold more by tumor or cancer cells than healthy cells.

[0083] The compounds described herein may be synthesized by the method described in Example 1 or other methods known in the art. The synthesis process may include steps of preparing the PLE portion, the flavoglyne analog portion, and the complete compound shown in Example 1. Suitable flavoglynes include commercially available products, such as those from Haoyuan Chemexpress Co. (Shanghai, China).

[0084] 4. Pharmaceutical Compositions The compounds described herein, or their pharmaceutically acceptable salts, may be formulated into pharmaceutical compositions according to standard techniques well known to those skilled in the art of pharmaceutical technology.In one embodiment, the present disclosure provides a pharmaceutical composition comprising the compounds described herein, or their pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.As used herein, the term "pharmaceutically acceptable carrier" refers to a non-toxic, inert solid, semi-solid or liquid excipient, diluent, encapsulating material, or any type of formulation auxiliary.

[0085] The route of administration of the compound and the form of the composition will dictate the type of carrier to be used. Pharmaceutical compositions can be in a variety of forms suitable for, for example, systemic administration (e.g., oral, rectal, sublingual, buccal, implants, intranasal, intravaginal, transdermal, intravenous, intraarterial, intratumoral, intraperitoneal, or parenteral) or local administration (e.g., transdermal, pulmonary, nasal, aural, ocular, liposomal delivery system, or iontophoresis). In some embodiments, the pharmaceutical composition is for administration to the central nervous system of a subject. Methods and formulations can generally be found in "Remington's Pharmaceutical Sciences," (Meade Publishing Co., Easton, Pa.). Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage. All carriers are optional in the composition.

[0086] Pharmaceutically acceptable carriers include, for example, diluents, lubricants, binders, disintegrants, colorants, flavorings, sweeteners, antioxidants, preservatives, flow agents, solvents, suspending agents, wetting agents, surfactants, emollients, propellants, humectants, dispersing agents, pH adjusters, and combinations thereof.

[0087] Some examples of materials that can serve as pharma- ceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, or potassium sorbate, saturated vegetable fatty acids, water, partial glyceride mixtures of salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, etc.), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyoxyethylene polyoxypropylene block polymers, wool fat, sugars (such as cellulose, cellulose acetate, cellulose acetate), and the like. Ingredients that may be included in the composition include, but are not limited to, lactose, glucose, and sucrose, starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, additives (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar-agar, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, releasing agents, coating agents, emulsifiers, sweeteners, flavorants, fragrances, preservatives, antioxidants, and may be present in the composition at the discretion of the formulator.

[0088] The amount of components in the composition may vary depending on the type of composition prepared, but generally, a systemic composition may contain 0.01% to 50% of a compound (such as a PLE or a phospholipid-flavagrine conjugate) and 50% to 99.99% of one or more carriers. A composition for parenteral administration may typically contain 0.1% to 10% of a compound and 90% to 99.9% of one or more carriers. Oral dosage forms may contain, for example, at least about 5%, or about 25% to about 50% of a compound. Orally administered compounds may contain about 50% to about 95% of a carrier, or about 50% to about 75% of a carrier. The amount of carrier utilized in combination with the disclosed compounds is sufficient to provide a practical amount of the composition for administration of the compound per unit dose. Techniques and compositions for making dosage forms useful in the methods of the invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0089] In some embodiments, the pharmaceutical composition consists essentially of a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0090] Liquid dosage forms include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Solid dosage forms include, but are not limited to, capsules, tablets, pills, powders, cements, putties, and granules. Dosage forms for topical or transdermal administration of the compounds include, but are not limited to, ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches.

[0091] The liquid carrier or vehicle can be a solvent or liquid dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof.

[0092] The pharmaceutical composition may be in a suitable dosage form for injection or infusion, such as a sterile aqueous solution or dispersion containing the active ingredient suitable for extemporaneous preparation, such as a sterile injectable or infusible solution or dispersion. The final dosage form should be sterile, liquid, flowable and stable under the conditions of manufacture and storage. Sterile injectable solutions may be prepared by mixing the required amount of at least one compound disclosed herein, or its pharma- ceutically acceptable salt, in a suitable solvent with various other ingredients as required, and then optionally sterilizing by filtration. In the case of sterile powders for preparation of sterile injectable solutions, the preparation method may include vacuum drying and freeze-drying techniques, which result in a powder of the active ingredient present in a sterile solution plus any additional desired ingredients.

[0093] In some embodiments, the composition is a solution, such as a solution suitable for administration by infusion or injection. The solution may be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions may also be prepared in glycerol, liquid polyethylene glycol, triacetin, and mixtures thereof, as well as in oils. These preparations may contain a preservative to prevent the growth of microorganisms. Prevention of microbial activity can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0094] Injectable forms may be prepared by forming microencapsule matrices of the compounds disclosed herein, or pharma-ceutically acceptable salts thereof, in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0095] In some embodiments, the composition may comprise at least one compound described herein and at least one additional anti-cancer drug. Anti-cancer drugs useful in the present disclosure include, but are not limited to, paclitaxel, irinotecan, topotecan, gemcitabine, cisplatin, geldanamycin, mertansine, abiraterone, afatinib, aminolevulinic acid, aprepitant, axitinib, azacitidine, belinostat, bendamustine, bexarotene, bleomycin, bortezomib, bosutinib, busulfan, cabazitaxel, cabozantinib, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, cetuximab, clopidogrel, cyclosporine ... Lambucil, clofarabine, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin, decitabine, denosumab, dexrazoxane, docetaxel, dolastatins (e.g. monomethylauristatin E), doxorubicin, enzalutamide, epirubicin, eribulin mesylate, erlotinib, etoposide, everolimus, floxuridine, fludarabine phosphate, fluorouracil, ganetespib, gefitinib, gemtuzumab b, ozogamicin, hexamethylmelamine, hydroxyurea, ibritumomab, tiuxetan, ibrutinib, idelalisib, ifosfamide, imatinib, ipilimumab, ixabepilone, lapatinib, leucovorin calcium, lomustine, maytansinoids, mechlorethamine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin C, mitotane, mitoxantrone, nelarabine, nelfinavir, nilotinib, obinutuzumab, ofatumumab, omacetaxine mepesuccinate, Oxaliplatin, panitumumab, pazopanib, pegaspargase, pembrolizumab, pemetrexed, pentostatin, pertuzumab, plicamycin, pomalidomide, ponatinib hydrochloride, pralatrexate, procarbazine, radium-223 chloride, ramucirumab, regorafenib, letaspimycin, ruxolitinib, semustine, siltuximab, sorafenib, streptozocin, sunitinib malate, tanespimycin, temozolomide, temsirolimus, teniposide, thalidomide, thioguanine,These include thiotepa, toremifene, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vincristine, vinorelbine, vismodegib, vorinostat, and ziv-aflibercept. Any compound currently known to be an anti-cancer agent or capable of acting as an anti-cancer agent is also useful in the present disclosure.

[0096] 5. Administration The compounds described herein, or pharma- ceutically acceptable salts thereof, or the pharmaceutical compositions described herein, may be administered to a subject. The compounds and compositions may be administered in a variety of doses and by techniques known to those skilled in the art of medical treatment, taking into consideration factors such as the age, sex, weight, and condition of the particular subject, as well as the route of administration.

[0097] The compounds and compositions of the present invention may be administered prophylactically or therapeutically. In prophylactic administration, the compounds and compositions may be administered in an effective amount to induce a prophylactic response. In therapeutic applications, the compounds and compositions may be administered to a subject in need thereof in an amount effective to induce a therapeutic effect.

[0098] For example, a therapeutically effective amount of a compound may be from about 1 mg / kg to about 1000 mg / kg, from about 5 mg / kg to about 950 mg / kg, from about 10 mg / kg to about 900 mg / kg, from about 15 mg / kg to about 850 mg / kg, from about 20 mg / kg to about 800 mg / kg, from about 25 mg / kg to about 750 mg / kg, from about 30 mg / kg to about 700 mg / kg, from about 35 mg / kg to about 650 mg / kg, from about 40 mg / kg to about 600 mg / kg, from about 45 mg / kg to about 750 mg / kg, from about 50 mg / kg to about 750 mg / kg, from about 60 mg / kg to about 800 mg / kg, from about 75 mg / kg to about 800 mg / kg, from about 80 mg / kg to about 900 mg / kg, from about 90 mg / kg to about 1000 mg / kg, from about 110 mg / kg to about 1200 mg / kg, from about 130 mg / kg to about 1400 mg / kg, from about 150 mg / kg to about 1600 mg / kg, from about 160 mg / kg to about 1800 mg / kg, from about 180 mg / kg to about 2000 mg / kg, from about 25 mg / kg to about 2600 mg / kg, from about 270 mg / kg to about 2800 mg / kg, from about 290 mg / kg to about 3000 mg / kg, from about 310 mg / kg to about 3200 mg / kg, from about 330 mg / kg to about 340 mg / kg to about 350 mg / kg, from about 350 mg / kg to about 3600 mg / kg, from The dose may be from about 1 mg / kg to about 550 mg / kg, from about 50 mg / kg to about 500 mg / kg, from about 55 mg / kg to about 450 mg / kg, from about 60 mg / kg to about 400 mg / kg, from about 65 mg / kg to about 350 mg / kg, from about 70 mg / kg to about 300 mg / kg, from about 75 mg / kg to about 250 mg / kg, from about 80 mg / kg to about 200 mg / kg, from about 85 mg / kg to about 150 mg / kg, and from about 90 mg / kg to about 100 mg / kg.

[0099] The compounds can be administered by methods well known in the art, such as those described in Donnelly et al. (Ann. Rev. Immunol. 1997, 15, 617-648); Felgner et al. (U.S. Patent No. 5,580,859, issued December 3, 1996); Felgner (U.S. Patent No. 5,703,055, issued December 30, 1997); and Carson et al. (U.S. Patent No. 5,679,647, issued October 21, 1997), all of which are incorporated herein by reference in their entirety. The compounds can be compounded into particles or beads that can be administered to an individual, for example, using a vaccine gun. One of skill in the art will appreciate that the choice of a pharma- ceutically acceptable carrier, including a physiologically acceptable compound, will depend, for example, on the route of administration.

[0100] The compound can be delivered by a variety of routes. Typical delivery routes include parenteral administration, such as intradermal, intramuscular or subcutaneous delivery. Other routes include oral administration, intranasal, intravaginal, transdermal, intravenous, intraarterial, intratumoral, intraperitoneal, and epidermal routes. In some embodiments, the compound is administered to the subject intravenously, intraarterially, or intraperitoneally. In some embodiments, the compound is administered to the subject intravenously. In some embodiments, the compound is administered to the subject orally.

[0101] In some embodiments, the compound is administered in a controlled release formulation.The compound can be, for example, released into circulation.In some embodiments, the compound can be released for at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 1 week, at least about 1.5 weeks, at least about 2 weeks, at least about 2.5 weeks, at least about 3.5 weeks, at least about 4 weeks, or at least about 1 month.

[0102] The compound can be administered in a single dose or episodic or repeated doses. For example, the compound can be administered once every hour, every 2 hours, every 4 hours, every 8 hours, every 12 hours, every 25 hours, every 36 hours, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every week, every 2 weeks, every 3 weeks, or every 4 weeks.

[0103] 6. Method The basis for selective tumor targeting of the compounds described herein lies in the differences in the cell membrane of cancer cells compared to that of most normal cells. Phospholipid ether (PLE) molecules exploit the metabolic transformations that tumor cells undergo to generate the energy required for rapid cell division. Tumors enhance the utilization of the beta-oxidation pathway to convert long-chain fatty acids (LCFAs) into energy. To increase the uptake of LCFAs, tumor cells alter specialized microdomains formed by the cell membrane known as "lipid rafts". Lipid rafts form due to metabolic transformations and the demand for phospholipids. Inside tumor cells, these regions become redundant and stabilized, making them promising tumor-specific targets. Specifically, the cell membrane of cancer cells is highly enriched in lipid rafts. In normal cells, the presence of lipid rafts is limited and transient (~2 nanoseconds). In tumors, the presence of lipid rafts is increased and stabilized (up to 10 days). Cancer cells have 5-10 times more lipid rafts than healthy cells. In addition, lipid rafts are highly abundant in almost all types of tumors, and have been demonstrated in 100% of cancer cells in individuals tested. Lipid rafts are highly organized and specialized regions of the membrane phospholipid bilayer that contain high concentrations of various signaling molecules, sphingolipids, glycosphingolipids, and cholesterol, and serve to organize cell surface and intracellular signaling molecules (e.g., growth factor and cytokine receptors, phosphatidylinositol 3 kinase (PI3K) / Akt survival pathway). Data indicate that lipid rafts serve as portals for the influx of phospholipid ethers. The remarkable selectivity of these compounds for cancer cells versus non-cancer cells is due to the high affinity of PLEs for cholesterol and the abundance of cholesterol-rich lipid rafts in cancer cells. The central role played by lipid rafts is highlighted by the fact that disruption of lipid raft structure inhibits the uptake of PLEs into cancer cells. Blocking the formation of lipid rafts has been shown to reduce PLE uptake by up to 60%. This feature, combined with the rapid internalization of phospholipid-drug conjugates by lipid rafts, makes them ideal targets.

[0104] The compounds disclosed herein, such as PLE analogs, may be LCFA mimetics. The molecules disclosed herein have undergone extensive structure-activity relationship (SAR) analysis related to targeting lipid rafts on tumor cells and have been found to bind specifically to these regions. The molecules disclosed herein provide direct entry into the cytoplasm and translocation along the Golgi apparatus network inside the cytoplasm of cells to the endoplasmic reticulum and mitochondria. In some embodiments, the compounds disclosed herein comprise a uniquely designed phospholipid ether conjugated to a flavagrine (FLV) analog. FLV is a potent cytotoxin that inhibits translation, cell cycle progression, and induces apoptosis.

[0105] The compounds described herein, or their pharmaceutically acceptable salts, or compositions comprising the compounds described herein, may be used to treat cancer.In one embodiment, the present disclosure provides a method for treating cancer in a subject in need of such treatment, comprising administering to the subject an effective amount of the compounds described herein, or their pharmaceutically acceptable salts, or compositions comprising the compounds described herein.

[0106] In another aspect, the disclosure provides a compound, or a pharma- ceutically acceptable salt thereof, as described herein, for use in treating cancer in a subject in need thereof.

[0107] In another aspect, the disclosure provides the use of a compound, or a pharma- ceutically acceptable salt thereof, as described herein, for the manufacture of a medicament for treating cancer in a subject in need thereof.

[0108] In one embodiment, the disclosure provides a method of targeting a drug to tumor or cancer cells in a subject, the method comprising administering to the subject a compound described herein, or a pharma- ceutically acceptable salt thereof, or a composition comprising a compound described herein. Targeting can result in targeted delivery of the compound of the invention to cancer cells and / or targeted treatment of cancer.

[0109] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, localizes or translocates to the cytoplasm or organelles of the tumor or cancer cell.

[0110] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, is selective for cancer cells in the subject.

[0111] In some embodiments, the compound, or a pharma- ceutically acceptable salt thereof, is taken up at least about 2-fold more by tumor or cancer cells than by healthy cells. The compound, or a pharma- ceutically acceptable salt thereof, is taken up at least about 2-fold more by tumor or cancer cells than by healthy cells, at least about 3-fold more by tumor or cancer cells, at least about 4-fold more by tumor or cancer cells, at least about 5-fold more by tumor or cancer cells, at least about 6-fold more by tumor or cancer cells, at least about 8-fold more by tumor or cancer cells, at least about 9-fold more by tumor or cancer cells, at least about 10-fold more by tumor or cancer cells, at least about 15-fold more by tumor or cancer cells, at least about 20-fold more by tumor or cancer cells, at least about 25-fold more by tumor or cancer cells, at least about 30-fold more by tumor or cancer cells than by healthy cells.

[0112] Cancers that may be treated with a compound described herein, or a pharma- ceutically acceptable salt thereof, or a composition comprising a compound described herein, include, but are not limited to, breast cancer, including male breast cancer, anal cancer, appendix cancer, extrahepatic bile duct cancer, gastrointestinal carcinoid tumors, colon cancer, esophageal cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumors ("gist"), pancreatic islet tumors, adult primary liver cancer, pediatric liver cancer, pancreatic cancer, rectal cancer, small intestine cancer, and stomach (gastric) cancer. Digestive / gastrointestinal cancer, including pancreatic adenocarcinoma, adrenal cortical carcinoma, pancreatic endocrine tumors, Merkel cell carcinoma, non-small cell lung neuroendocrine tumors, small cell lung neuroendocrine tumors, parathyroid cancer, pheochromocytoma, pituitary tumors and thyroid tumors; endocrine and neuroendocrine cancers, including intraocular melanoma and retinoblastoma; bladder cancer, kidney (renal cell) cancer, penile cancer, prostate cancer, transitional cell renal pelvis cancer and ureter cancer, testicular cancer, urethral cancer and Genitourinary cancers, including pediatric central nervous system cancer, pediatric extracranial germ cell tumors, extragonadal germ cell tumors, germ cell tumors, including ovarian germ cell tumors and testicular cancer, cervical cancer, endometrial cancer, gestational trophoblastic tumors, ovarian epithelial cancer, ovarian germ cell tumors, uterine sarcoma, gynecological cancers, including vaginal and vulvar cancer, hypopharyngeal cancer, laryngeal cancer, lip and oral cavity cancer, metastatic squamous neck cancer with potential primaryPrimary) oral cavity cancer, nasopharyngeal cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, pharyngeal cancer, head and neck cancer including salivary gland cancer and pharyngeal cancer, adult acute lymphoblastic leukemia, childhood acute lymphoblastic leukemia, adult acute myeloid leukemia, childhood acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and leukemia including hairy cell leukemia, AIDS-related lymphoma, cutaneous T-cell lymphoma, adult Hodgkin lymphoma, childhood Hodgkin lymphoma, Hodgkin lymphoma during pregnancy, mycosis fungoides, adult non-Hodgkin lymphoma, childhood non-Hodgkin lymphoma, non-Hodgkin lymphoma during pregnancy, primary central nervous system lymphoma, cerebrovascular disease, These include lymphomas, including Leigh syndrome and Waldenstrom's macroglobulinemia, Ewing's sarcoma, osteosarcoma and malignant fibrous histiocytoma of bone, musculoskeletal cancers, including childhood rhabdomyosarcoma and soft tissue sarcoma, neurological cancers, including adult brain tumors, pediatric brain tumors, astrocytoma, brain stem glioma, central nervous system atypical teratoma / rhabdoid tumor, central nervous system embryonal tumor, craniopharyngioma, ependymoma, neuroblastoma, primary central nervous system (CNS) lymphoma, respiratory / thoracic cancers, including non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, thymoma and thymic carcinoma, and skin cancers, including Kaposi's sarcoma, melanoma and squamous cell carcinoma. In certain embodiments, the cancer may be melanoma, lung cancer, colorectal cancer, breast cancer, or a combination thereof.

[0113] In some embodiments, the cancer is melanoma, brain cancer, lung cancer, adrenal cancer, liver cancer, renal or kidney cancer, pancreatic cancer, esophageal cancer, gastric cancer, stomach cancer, colon cancer, colorectal cancer, anal cancer, prostate cancer, ovarian cancer, breast cancer, cervical cancer, lymphoma, leukemia, myeloma, hematopoietic cancer, hepatocellular carcinoma, retinoblastoma, glioma, sarcoma, blastoma, squamous cell carcinoma, adenocarcinoma, or a combination thereof. In some embodiments, the cancer is melanoma, lung cancer, colorectal cancer, breast cancer, or a combination thereof.

[0114] In some embodiments, the cancer may comprise one or more circulating tumor cells. For example, the one or more circulating tumor cells may be selected from the group consisting of breast cancer, lung cancer, thyroid cancer, cervical cancer, melanoma, squamous cell carcinoma, prostate cancer, pancreatic cancer, colorectal cancer, and cancer stem cells, and malignant plasma cells.

[0115] In some embodiments, the cancer may be metastatic. For example, the metastatic cancer may be selected from the group consisting of breast cancer, lung cancer, melanoma, and colorectal cancer.

[0116] In some embodiments, the cancer may comprise cancer stem cells. For example, the cancer stem cells may be selected from the group consisting of breast cancer, lung cancer, melanoma, and colorectal cancer.

[0117] In some embodiments, the lung cancer may include small cell lung cancer, non-small cell lung cancer, or a combination thereof.

[0118] In some embodiments, melanoma may include superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentigo melanoma, amelanotic melanoma, nevoid melanoma, spitzoid melanoma, desmoplastic melanoma, or combinations thereof.

[0119] In some embodiments, colorectal cancer may include adenocarcinoma.

[0120] In some embodiments, the breast cancer may include invasive ductal carcinoma, metastatic breast cancer, inflammatory breast cancer, triple-negative breast cancer, intraductal carcinoma in situ, or combinations thereof. In some embodiments, the cancer is breast cancer and the subject may be estrogen receptor positive, both estrogen receptor negative and progesterone receptor negative, expressing HER2 (HER2+), not expressing HER2 (HER2-), or combinations thereof.

[0121] In some embodiments, the subject is a human, such as an adult or an infant, hi some embodiments, the subject is an animal, such as a mammal.

[0122] The method may include administering a compound of the invention, or a pharma- ceutically acceptable salt thereof, in an amount as described herein. In some embodiments, the method includes administering about 0.0001 to about 1000 mg / kg of a compound described herein, or a pharma- ceutically acceptable salt thereof. A beneficial dosage of a compound can be determined by comparing the in vitro activity of the compound with the in vivo activity of the compound in an animal model. Methods for extrapolating effective dosages of rodents, pigs, and other animals to humans are known in the art, see, for example, U.S. Patent No. 4,938,949.

[0123] In some embodiments, the compounds, or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein may be administered orally or intravenously. In general, however, suitable doses will often be in the range of about 0.0001 mg / kg to about 1000 mg / kg, such as about 0.001 mg / kg to about 10.0 mg / kg. For example, suitable doses may be in the range of about 0.001 mg / kg to about 5.0 mg / kg of body weight per day, such as about 0.01 mg / kg to about 1.0 mg / kg of the recipient's body weight per day, about 0.01 mg / kg to about 3.0 mg / kg of the recipient's body weight per day, about 0.1 mg / kg to about 5.0 mg / kg of the recipient's body weight per day, or about 0.2 mg / kg to 4.0 mg / kg of the recipient's body weight per day. The compound may be administered in unit dosage form, for example, containing 1-100 mg, 10-100 mg, or 5-50 mg of active ingredient per unit dosage form.

[0124] The desired dose may conveniently be presented as a single dose or as divided doses administered at appropriate intervals, such as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete spaced administrations.

[0125] The appropriate in vivo dosage and the specific method of administration to be administered may vary depending on the age, weight, severity of the affliction, and species of mammal being treated, the specific compound being utilized, and the specific application for which these compounds are utilized. The determination of effective dosage levels to achieve the desired results may be accomplished by known methods, such as, for example, human clinical trials, in vivo studies, and in vitro studies. For example, the effective dosage of the compounds disclosed herein, or pharma- ceutically acceptable salts thereof, may be determined by comparing the in vitro activity and the in vivo activity of animal models. Such comparisons may be made by comparison to established drugs.

[0126] Dosage and dosage may be adjusted individually to provide plasma levels of the active moiety sufficient to maintain a modulating effect or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC will depend on individual characteristics and the route of administration. However, FIPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the MEC value. Compositions should be administered using a dosing regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably 30-90% and most preferably 50-90%. In the case of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0127] The compositions described herein may be administered with additional compositions to prolong the stability, delivery, and / or activity of the compositions, or may be combined with additional therapeutic agents, or may be provided before or after administration of the additional therapeutic agents.Combination therapy includes administration of a single pharmaceutical dosage formulation that includes one or more of the compounds described herein and one or more additional pharmaceutical agents, as well as administration of the compound and each additional therapeutic agent in its own separate pharmaceutical dosage formulation.For example, the compounds described herein may be administered to a subject together with additional anti-cancer agents described herein. EXAMPLES

[0128] 7. Working Example Example 1 chemical synthesis PLE.PLE may be synthetically made according to Schematic 1 below. [ka]

[0129] Flavaglines. Flavaglines were commercially available. FLV1 and FLV3 were purchased from Haoyuan Chemexpress Co. (Shanghai, China). FLV1 and FLV3 were alternatively synthetically prepared according to Scheme 2 below. [ka]

[0130] PLE-flavagrine constructs. CLR 1852 (compound (9)) and CLR 1865 (compound (8)) were synthetically prepared according to Scheme 3 below. [ka]

[0131] Synthesis of CLR 1899. CLR 1899 was synthesized according to Scheme 4. The structure was verified by NMR and MS data. [ka]

[0132] Example 2 Presence of lipid rafts on tumor cells Over 100 cell lines were stained with cholera toxin subunit B, fixed with 4% formaldehyde, and stained with filipin III for 30 min. As shown in Figure 1A-D, almost all tumor types tested demonstrated high concentrations of lipid rafts in the cell membrane (over 100 cell lines, fresh patient samples, etc.). As shown in Figure 1E, A549 cells were co-cultured with normal fibroblasts for 48 h, then stained with cholera toxin subunit B, fixed with 4% formaldehyde, and stained with filipin III for 30 min. These results demonstrated that tumor cells have higher concentrations of lipid rafts than normal cells.

[0133] Example 3 Selective uptake of PDC into tumor cells Normal fibroblasts and Caki-2 tumor cells (human clear cell renal cell carcinoma) were plated and co-cultured overnight (Figure 1F). Cells were then incubated with 5 μM CLR 1501 (compound (1)) in complete medium for 24 hours at 37°C. The next day, cells were washed and co-stained with a nuclear stain (Hoescht 33342). CLR 1501 was excited and detected with an Alexa-Fluor 488 filter. CLR 1501 was highly localized in Caki-2 cells but minimally localized in normal fibroblasts.

[0134] Example 4 Disruption of lipid rafts reduced PDC uptake A549 cells were plated overnight in separate wells. The following day, cells were left untreated (Figure 1G) or treated with methyl-b-cyclodextrin (Figure 1H), which was found to selectively disrupt lipid rafts. All cells were incubated with 5 μM CLR 1501 (compound (1)) for 24 hours. Disruption of most lipid rafts in A549 cells was accompanied by a 60% decrease in CLR 1501 uptake (Figure 1H) compared to untreated cells (Figure 1G).

[0135] Example 5 Tracking PDC to the endoplasmic reticulum Human prostate cancer cells (PC3) were plated overnight on microplates VI (Ibidi, Verona, WI) and then incubated for 37 h in complete medium. o Cells were incubated with 5 μM CLR 1501 (compound (1)) for 24 h at 37°C. After washing, the cells were co-stained with ER-tracker® according to the protocol and imaged using a Nikon A1R confocal light microscope. CLR 1501 and ER were detected using an exciton, standard fluorescence filter, Alexa-Fluor 488. CLR 1501 co-localized with ER in malignant cells (Figure 1I-K), but not in normal cells (not shown).

[0136] Example 6 Tracking PDC to the endoplasmic reticulum PC3 (grade IV, human prostate cancer) cell line was cultured overnight on microslide VI (Ibidi, Verona, WI). The next day, the cells were incubated in complete medium for 37 h. o The cells were incubated with 5 μM CLR 1501 (compound (1)) for 24 h at 37 °C. The next day, after washing with PBS, the cells were co-stained with a nuclear stain (Hoechst33342) and a mitochondrial marker (Mitotracker®) (Invitrogen, Carlsbad, CA). The cells were observed using a Nikon A1R confocal microscope. CLR 1501 was excited and detected using an Alexa-Fluor 488 filter, while the nuclear and mitochondrial stains were detected using exciton, DAPI and Texas-Red filters, respectively. CLR 1501 was co-localized with mitochondria (Figure 1L-1N).

[0137] Example 7 PDC provides targeted delivery in vivo Nude mice bearing colorectal (HCT-116) tumors were injected with 1 mg of CLR 1502 (compound (2)) and were imaged with a Pearl infrared imaging system. Different colors indicate the intensity of CLR 1502 over time. Approximately 5.5 hours after injection, the tumors still showed a red color (indicating the highest distribution of CLR 1502) (Figure 2). Maximal distribution of CLR 1502 was obtained within 24 hours. Early targeting was observed within 30 minutes (not shown).

[0138] Example 8 Cytotoxic PDC provides targeting and potentially improved therapeutic index A549 (human lung adenocarcinoma) cells and normal human dermal fibroblasts (NHDF) were plated overnight in 96-well dishes. All cells were treated with increasing concentrations of either the parent cytotoxic compound alone (FLV1 or FLV3) or PDC (parent cytotoxic compound linked to a PLE moiety by a cleavable linker, CLR 1865) (compound (8)) or CLR 1852 (compound (9))). The parent cytotoxic compounds showed almost the same potency against A549 cells as they did against NHDF cells. However, the PDC molecule showed selectivity for A549 cells (Figure 3). The PDC molecule showed little effect up to the highest concentration against NHDF cells, but showed almost similar potency to the parent molecule in A549 cells. The difference in cytotoxicity of the PDC molecule against tumor cells and against normal cells may represent a possibility to improve the therapeutic index of the parent molecule.

[0139] Example 9 Cytotoxic PDC provides targeting We assessed the uptake of CLR 1852 (compound (9)) in A375 (human melanoma) and HEK293 (human embryonic kidney) cells. The cells were incubated with CLR 1852 (compound (9)) for 24 hours. Within 24 hours of treatment, tumor cells were found to have anywhere from a 6- to 28-fold increase in PDC compared to normal cells (Figure 4).

[0140] The results of Examples 2-9 showed that phospholipid ether molecules target tumor cells via lipid rafts. PDC showed significant uptake into tumor cells even in co-culture with normal cells. Upon invading tumor cells, PDC tracked to mitochondria and the endoplasmic reticulum. In vivo, PDC both targeted tumors and rapidly accumulated inside tumors. Cytotoxic PDC offered the potential for improved targeting and improved safety.

[0141] Example 10 Cellular uptake of PLE Various cancer cell lines were exposed to fluorescently labeled PLE (CLR 1501, compound (1)) in vitro and in vivo. Tumor cell uptake was measured continuously for 24 hours. The results are shown in Table 1 and Figures 5, 6, and 7. The PLE compound was specific to tumors and cancer cells.

[0142] Fluorescently labeled PLE (CLR 1501, compound (1)) was administered to benign tissue, but no uptake was observed (Table 2). [Table 1] [Table 2]

[0143] Example 11 Activity of PLE-flavagrine conjugates in cancer cells The PLE-flavagrine conjugates CLR 1852 (compound (9)) and CLR 1865 (compound (8)) were administered to the cell lines A375 (human malignant melanoma), A549 (human lung adenocarcinoma), HCT116 (human colon carcinoma), and NHDF (normal human dermal fibroblasts). IC 50 The results are shown in Table 3. [Table 3]

[0144] The cytotoxicity of CLR 1852 was determined across a range of concentrations, and as shown in Figure 8, CLR 1852 showed a modest decrease in potency compared to FLV3 alone, likely due to incomplete release.

[0145] The stability of CLR 1865 (compound (8)), CLR 1852 (compound (9)), and FLV3 in plasma was tested with propantheline as a control (Table 4). Small amounts of the molecules were exposed to plasma, which was then analyzed by HPLC or MS to determine if the molecules were degraded. CLR 1865 and CLR 1852 showed excellent human plasma stability. In mouse plasma, CLR 1852 was superior to CLR 1865. CLR 1865 was stable in mouse plasma for only 3.3 hours. CLR 1852 was stable in plasma for at least 7 hours. [Table 4]

[0146] The therapeutic index (TI) of CLR 1865 and CLR 1852 was tested in mice (Table 5). Listed in Table 5 are the doses administered to mice and the number of mice alive after treatment ("3 / 3" means that 3 out of 3 mice were alive). Both CLR 1852 and CLR 1865 showed a superior improvement in tolerability compared to FLV3 alone. CLR 1852 did not achieve a maximum tolerated dose (MTD), likely because solubility limited higher dosing. The MTD for CLR 1865 was 5-10 mg / kg. The in vivo therapeutic index was at least 25 for CLR 1852 and at least 12.5 for CLR 1865. [Table 5]

[0147] The efficacy of CLR 1852 in HCT 116 cells (human colon cancer) was tested. CLR 1852 was administered to HCT 116 cells three times at a dose of 1 mg / mg each. Compared to vehicle, CLR 1852 began to reduce tumor volume at about 27 days (Figure 9). Compared to vehicle, CLR 1582 caused a moderate weight loss, likely due to toxicity (Figure 10). CLR 1582 was at least six-fold more tolerable than FLV3 alone (data not shown).

[0148] CLR 1852 and FLV3 alone were administered to A375 and A549 cells. The levels of FLV3 in cell lysates and growth medium were measured using LC / MS. As shown in Figure 11, high levels of FLV3 were present in cell lysates after 24 hours. Intermediate levels of FLV3 were present in growth medium after 24 hours. Intracellular FLV3 levels appeared to reach a plateau at 24 hours, while extracellular FLV3 levels continued to increase.

[0149] Example 12 Activity of CLR 1899 in cancer cells CLR 1899 was administered to cell lines A375 (human malignant melanoma), A549 (human lung adenocarcinoma), HCT116 (human colon carcinoma), and NHDF (normal human dermal fibroblasts). In vitro cytotoxicity results are shown in Table 6. [Table 6]

[0150] To determine whether CLR 1899 was tolerated in vivo, the compound was administered intravenously to healthy C57BL / 6 mice at dose levels of 0.5 mg / kg, 1.0 mg / kg, or 2.0 mg / kg and body weight changes were monitored (Figure 12). CLR 1899 showed no toxicity or adverse events upon repeated dosing as measured by body weight changes. The in vivo efficacy of CLR 1899 was tested in an MCF-7 xenograft model (Figure 13, 10 mice per dose group). Reductions in tumor volume were recorded. In these studies, CLR 1899 demonstrated activity equivalent to docetaxel in stopping or slowing tumor growth.

[0151] The foregoing description of the specific embodiments so fully reveals the general nature of the present invention that others, by applying knowledge within the art, can easily modify and / or adjust various applications of such specific embodiments without undue experimentation. Such adjustments and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance provided herein. It is understood that the phraseology or terminology herein is for the purpose of description and not for the purpose of limitation, as the terminology or terminology herein would be interpreted by one of ordinary skill in the art in light of the teaching and guidance.

[0152] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments, but should be defined in accordance with the following claims and their equivalents.

[0153] All publications, patents, patent applications, and / or other documents cited in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, and / or other document was individually indicated to be incorporated by reference for all purposes.

[0154] For reasons of completeness, various aspects of the disclosure are described in the following numbered clauses.

[0155] Clause 1. A compound of formula (I), [ka] wherein Z is a flavugine analogue. A compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0156] Clause 2. Below: [ka] and [ka] 2. The compound of claim 1, selected from the group consisting of:

[0157] Clause 3. A pharmaceutical composition comprising a compound according to any one of clauses 1-2, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0158] Clause 4. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of clauses 1-2, or a pharma- ceutically acceptable salt thereof.

[0159] Clause 5. A method of targeting a drug to a tumor or cancer cell in a subject, the method comprising administering to the subject a compound described in any one of clauses 1-2, or a pharma- ceutically acceptable salt thereof.

[0160] Clause 6. The method according to any one of clauses 4 to 5, wherein the compound, or a pharma- ceutically acceptable salt thereof, is localized or translocated to the cytoplasm or organelles of the tumor or cancer cell.

[0161] Clause 7. The method of any one of clauses 4 to 6, wherein the compound, or a pharma- ceutically acceptable salt thereof, is selective for cancer cells of the subject.

[0162] Clause 8. The method according to any one of clauses 4 to 7, wherein the compound, or a pharma- ceutically acceptable salt thereof, is taken up by tumor or cancer cells in at least about two-fold greater amount than by healthy cells.

[0163] Clause 9. The method of any one of clauses 4 to 8, wherein the cancer is melanoma, brain cancer, lung cancer, adrenal cancer, liver cancer, renal or kidney cancer, pancreatic cancer, esophageal cancer, gastric cancer, stomach cancer, colon cancer, colorectal cancer, anal cancer, prostate cancer, ovarian cancer, breast cancer, cervical cancer, lymphoma, leukemia, myeloma, hematopoietic cancer, hepatocellular carcinoma, retinoblastoma, glioma, sarcoma, blastoma, squamous cell carcinoma, adenocarcinoma, or a combination thereof.

[0164] Clause 10. The method of any one of clauses 4 to 9, wherein the cancer is melanoma, lung cancer, colorectal cancer, breast cancer, or a combination thereof.

[0165] Clause 11. The lung cancer includes small cell lung cancer, non-small cell lung cancer, or a combination thereof; The melanoma includes superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentigo melanoma, amelanotic melanoma, nevoid melanoma, spitzoid melanoma, desmoplastic melanoma, or a combination thereof; The colorectal cancer comprises an adenocarcinoma; or The breast cancer includes invasive ductal carcinoma, metastatic breast cancer, inflammatory breast cancer, triple-negative breast cancer, ductal carcinoma in situ, or a combination thereof. 11. The method according to any one of clauses 4 to 10.

[0166] Clause 12. The method of any one of clauses 4 to 11, wherein the cancer comprises cancer stem cells.

[0167] Clause 13. The method of any one of clauses 4 to 12, wherein the cancer comprises metastatic cancer cells.

[0168] Clause 14. The method of any one of clauses 4 to 13, wherein the cancer comprises circulating tumor cells.

[0169] Clause 15. The method of any one of clauses 4 to 14, wherein the subject is a human.

Claims

1. A compound of formula (I) 【Chemistry 1】 wherein Z is flavugin. A compound of formula (I) or a pharma- ceutically acceptable salt thereof.

2. below: 【Chemistry 2】 and 【Chemistry 3】 2. The compound of claim 1, selected from the group consisting of:

3. A pharmaceutical composition comprising a compound according to any one of claims 1 to 2, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

4. A composition for treating cancer in a subject in need thereof, comprising a compound according to any one of claims 1 to 2, or a pharma- ceutically acceptable salt thereof.

5. A composition for targeting a drug to a tumor or cancer cell in a subject, comprising a compound according to any one of claims 1 to 2, or a pharma- ceutically acceptable salt thereof.

6. The composition of any one of claims 4 to 5, wherein the compound, or the pharma- ceutically acceptable salt thereof, is localized or translocated to the cytoplasm or organelles of the tumor or cancer cell.

7. The composition of any one of claims 4 to 6, wherein the compound, or the pharma- ceutically acceptable salt thereof, is selective for cancer cells of the subject.

8. The composition of any one of claims 4 to 7, wherein the compound, or the pharma- ceutically acceptable salt thereof, is taken up by tumor or cancer cells in at least about two times greater amount than by healthy cells.

9. The composition according to any one of claims 4 to 8, wherein the cancer is melanoma, brain cancer, lung cancer, adrenal cancer, liver cancer, renal or kidney cancer, pancreatic cancer, esophageal cancer, gastric cancer, stomach cancer, colon cancer, colorectal cancer, anal cancer, prostate cancer, ovarian cancer, breast cancer, cervical cancer, lymphoma, leukemia, myeloma, hematopoietic cancer, hepatocellular carcinoma, retinoblastoma, glioma, sarcoma, blastoma, squamous cell carcinoma, adenocarcinoma, or a combination thereof.

10. The composition of any one of claims 4 to 9, wherein the cancer is melanoma, lung cancer, colorectal cancer, breast cancer, or a combination thereof.

11. the lung cancer comprises small cell lung cancer, non-small cell lung cancer, or a combination thereof; the melanoma comprises superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentigo melanoma, amelanotic melanoma, nevoid melanoma, spitzoid melanoma, desmoplastic melanoma, or a combination thereof; the colorectal cancer comprises adenocarcinoma; or The breast cancer includes invasive ductal carcinoma, metastatic breast cancer, inflammatory breast cancer, triple-negative breast cancer, ductal carcinoma in situ, or a combination thereof; The composition according to any one of claims 4 to 10.

12. The composition of any one of claims 4 to 11, wherein the cancer comprises cancer stem cells.

13. The composition of any one of claims 4 to 12, wherein the cancer comprises metastatic cancer cells.

14. The composition of any one of claims 4 to 13, wherein the cancer comprises circulating tumor cells.

15. The composition according to any one of claims 4 to 14, wherein the subject is a human.

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