Lipid raft, caveolin protein, and caveolar function modulation compounds and associated synthetic and therapeutic methods
First Claim
1. A method for synthesizing a target trichloronitroplatinum(IV) compound, the method comprising:
- dissolving a predetermined molar amount of solid K2Pt(II)Cl4 in a solvent to form a solution;
stirring an equimolar amount of solid silver(I) nitrite into the solution;
removing an AgCl precipitate from the solution, leaving in the solution a trichloronitroplatinum(IV) compound having two open Pt substitution positions; and
adding to the solution an equimolar amount of a metal-coordinating ligand for each of the two open Pt substitution positions of the trichloronitroplatinum(IV) compound to synthesize a target trichloronitroplatinum(IV) compound.
0 Assignments
0 Petitions
Accused Products
Abstract
The present invention is directed to the modulation of lipid rafts, caveolin proteins, or caveolar functions and processes by platinum(IV) compounds. Caveolae and/or lipid rafts are associated with cell transcription regulation, membrane and cellular transport, cell membrane receptor function, cellular trafficking, antigen presentation, cell differentiation and activation, cytokine modulation, membrane structure and function, and protein modulation. Caveolae, caveolin proteins and lipid rafts are known therapeutic targets for numerous biological functions. Diseases and disorders currently known to be therapeutically targeted through caveolae and/or lipid rafts include diabetes, cancer, cardiovascular diseases, atherosclerosis, pulmonary fibrosis, multiple sclerosis, viral and prion diseases, neuronal disorders, degenerative muscular dystrophies, and autoimmune disorders.
-
Citations
22 Claims
-
1. A method for synthesizing a target trichloronitroplatinum(IV) compound, the method comprising:
-
dissolving a predetermined molar amount of solid K2Pt(II)Cl4 in a solvent to form a solution; stirring an equimolar amount of solid silver(I) nitrite into the solution; removing an AgCl precipitate from the solution, leaving in the solution a trichloronitroplatinum(IV) compound having two open Pt substitution positions; and adding to the solution an equimolar amount of a metal-coordinating ligand for each of the two open Pt substitution positions of the trichloronitroplatinum(IV) compound to synthesize a target trichloronitroplatinum(IV) compound. - View Dependent Claims (2, 3, 4, 9)
-
-
5. A platinum(IV) compound having the structure shown in at least one of formula (I), (II), (III), and (IV):
-
wherein X and Y are, independently, any halogen, —
CN, —
SCN, —
NCS, —
NO2, —
ONO, —
OHSO3, —
OH2PO3, —
OHSO2, —
SO3H, —
OH, —
OR2, —
OS(CH3)2, —
OCOR2, —
OCOOR2, —
OSO2CH3, —
SH, —
SR2, —
S2CN(R2)2, —
OSiO3, OBO2H, —
OHSeO2, —
NHCOH, —
NH2CHO, —
NH2CH2OH, —
NH2C(OH)3, or —
NH2CH(OH)2, or —
NHCOR2, or X and Y together form a ring structure selected from the group consisting of cyclobutane dicarboxylate (CBDCA) (OCOC4H6OCO)2−
;
oxalate (C2O4)2−
, malanato (OOCCH2COO)2−
, dithiocarbamate ((R2)2NCS2)−
, acetylacetonate (CH3COCHCOCH3)−
, carboxylate (CO2R2)−
, sulfate (SO4)2, phosphate (HPO4)2−
, selenate (SeO4)2−
, silicate (SiO4)2−
, diborate (B2O5)4−
, (acetylacetonate (OCCH3CH2CH3O)−
, ethylene diamine (H2C2H4NH2), bis(diphenylphosphino)ethane (dppe) ((C6H5)2PC2H4P(C6H5)2), bis(dimethylphosphino)ethane (dmpe) ((CH3)2PC2H4P(CH3)2), 2,2′
-bipyridine ((NC5H4)2) and glyme (CH3OCH2CH2OCH3);R1 is —
NO2, —
ONO, —
CN, —
SCN, —
NCS, —
COOH, COOR2, —
CHO, —
COR or —
SO3H;R2 is any halogen, —
COOH, —
OH, —
NH2, —
HSO3, —
OHSO3, —
OH2PO3, —
OBO2, —
OHSiO3, —
OHSeO2, an alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heteroalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycloalkoxy, or heterocycloalkoxycarbonyl, any of which can be optionally substituted with any halogen, —
COOH, —
OH, —
NO2, —
NH2, —
HSO3, —
OHSO3, —
OH2PO3, —
OBO2, —
OHSiO3, —
OHSeO2, N-alkyl, alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, alkycarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, heteroalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycloalkoxy, or heterocycloalkoxycarbonyl;R3 is —
NH3, —
NH2R2, —
NH(R2)2, —
N(R2)3, —
NH2COR2, —
NH2COH, —
NH2CHO, —
NH2CH2OH, —
NH2C(OH)3, —
NH2CH(OH)2, —
OCH3 or —
OR2,or R3, R3, X, and Y together comprise porphyrin or phthalocyanine; or R3, R2, X, and Y together comprise porphyrin or phthalocyanine; or a pharmaceutically acceptable salt thereof. - View Dependent Claims (6, 7)
-
-
8. A platinum(IV) compound having the structure shown in formula I, II, III, or IV:
-
wherein X and Y are, independently, any halogen, —
CN, —
SCN, —
NCS, —
NO2, —
ONO, —
OHSO3, —
OH2PO3, —
OHSO2, —
SO3H, —
OH, —
OR2, —
OS(CH3)2, —
OCOR2, —
OCOOR2, —
OSO2CH3, —
SH, —
SR2, —
S2CN(R2)2, —
OSiO3, —
OBO2H, —
OHSeO2, —
NHCOH, —
NH2CHO, —
NH2CH2OH, —
NH2C(OH)3 or —
NH2CH(OH)2 or —
NHCOR2, or X and Y together form a ring structure selected from the group consisting of cyclobutane dicarboxylate (CBDCA) (OCOC4H6OCO)2−
;
oxalate (C2O4)2−
, malanato (OOCCH2COO)2−
, dithiocarbamate ((R2)2NCS2)−
, acetylacetonate (CH3COCHCOCH3)−
, carboxylate (CO2R2)−
, sulfate (SO4)2, phosphate (HPO4)2−
, selenate (SeO4)2−
, silicate (SiO4)2−
, diborate (B2O5)4−
, (acetylacetonate (OCCH3CH2CH3O)−
, ethylene diamine (H2C2H4NH2), bis(diphenylphosphino)ethane (dppe) ((C6H5)2PC2H4P(C6H5)2), bis(dimethylphosphino)ethane (dmpe) ((CH3)2PC2H4P(CH3)2), 2,2′
-bipyridine ((NC5H4)2) and glyme (CH3OCH2CH2OCH3);R1 is —
NO2, —
ONO, —
CN, —
SCN, —
NCS, —
COOH, COOR2, —
CHO, —
COR or —
SO3H;R2 is chloride, bromide, fluoride or iodide;
—
COOH, —
OH, —
NH2, —
HSO3, —
OHSH3, —
OH2PO3, —
OBO2, —
OHSiO3, —
OHSeO2, folate, N-acetylcysteine, taurine, ethanolamine, safranin, riboflavin, 7-ethoxycoumarin, methylene blue, thiamine, caffeine, N-acetyl galactosamine, naringin, N-acetyl neuraminic acid, methyl alpha-D-mannopyranoside, xanthine, hydantoin, 6-aminonicotinamide, theophylline, N-acetyl glucosamine, alpha-aminoisobutyric acid, cytarabine, pantothenic acid, nicotinamide, fluorescein, rhodamine, biotin, inosine, theobromine, histidine, niacine, eosin, luminol, pyrimidine, thiosalicylic acid, 7-amino-4-methylcoumarin, tris, nicotine, 2,6-dichloro-4-nitropyridine, 2,6-dimethyl-4-nitropyridine, quinoline, pyridoxine, nicotinic acid, carbazole, morpholine, pyrimidinecarboxylic acid, imidazole, thiazole, oxazole, succinimidyl ester, pyridine, benzimidazole, benzoxazole, 2-(2-aminophenyl)-benzothiazole, 2-(4-aminophenyl)-benzothiazole, benzothiazole, hydroorotic acid, palmitate, purine, adenine, guanine, hypoxanthine, uric acid, isoguanine, serine, cytosine, thymidine, uracil, myristic acid, oleic acid, succinimide, triethanolamine, diethanolamine, thiazolidinedione, flavin, anthranilic acid, methionine, cysteine, tyrosine, threonine, N-acetyl mannose;R3 is —
NH3, —
NH2R2, —
NH(R2)2, —
N(R2)3, —
NH2COR2, —
NH2COH, —
NH2CHO, —
NH2CH2OH, —
NH2C(OH)3, —
NH2CH(OH)2, —
OCH3 or —
OR2,or R3, R3, X, and Y together comprise porphyrin or phthalocyanine; or R3, R2, X, and Y together comprise porphyrin or phthalocyanine; or a pharmaceutically acceptable salt thereof.
-
-
10. A method for increasing the effectiveness of a drug subject to multidrug resistance or upregulated p53 in a patient in need thereof, the method comprising administering to the patient an effective amount of a platinum (IV) compound with the drug.
-
11. A method for inhibiting the development of TH17 thymus lymphocytes or the production of associated inflammatory cytokines IL-17, IL-6, or IL-22, the method comprising administering in vivo or ex vivo an effective amount of a platinum(IV) compound to a patient in need thereof.
-
12. A method for modulating stem cell activities, the method comprising contacting the lipid rafts, caveolae, or caveolin proteins of a stem cell with an effective amount of a platinum(IV) compound in vivo, ex vivo, or in vitro.
-
13. A method for reducing infiltration into the central nervous system associated with leakage of cells across the blood brain barrier, the method comprising administering an effective amount of a platinum(IV) compound to a patient in need thereof.
-
14. A method for regenerating liver tissue or of supporting a liver transplant in a patient in need thereof, the method comprising administering an effective amount of a platinum(IV) compound to a patient in need thereof.
-
15. A method for modulating or characterizing lipid raft or caveolar structure, function, or activity in a cell, the method comprising contacting said cell with an effective amount of a platinum(IV) compound, wherein the cell is in vitro, in vivo, or ex vivo, and the cell is bacterial, viral, or derived from any living animal.
-
16. An adjuvant for enhancing antigen presentation in the adaptive immune response system of a subject, the adjuvant comprising an effective amount of a platinum(IV) compound.
-
17. A method for treating or preventing an oncological disorder in a patient in need thereof, the disorder selected from the group consisting of a cancer, a tumor, a tumor immune evasion response, metastasis, viral cell transformation, and tumor-associated angiogenesis, the method comprising administering an effective amount of a platinum(IV) compound to the patient.
-
18. A method for treating or preventing an autoimmune or inflammatory disease in a patient in need thereof, the autoimmune disease selected from the group consisting of a TH17-associated disease, multiple sclerosis, rheumatoid arthritis, myelosuppression, diabetes, asthma, Alzheimers disease, or diabetic retinopathy, the method comprising administering an effective amount of a platinum(IV) compound to the patient.
-
19. A method for preventing or treating infection of a pathogen in a patient in need thereof, the pathogen selected from a group consisting of a virus, a prion, a viral protein, toxin, and a bacteria, the method comprising administering an effective amount of a platinum (IV) compound to the patient.
-
20. A method for reducing matrix metalloproteinases (MMP) in a patient in need thereof, including MT-MMP-1 (transmembrane MMP-1 or MMP14), MMP-2, and MMP-9, the method comprising administering an effective amount of a platinum(IV) compound to the patient.
-
21. A method for preventing or treating HIV-associated dementia (HAD) or HIV-Encephalitis in a patient in need thereof, the method comprising administering an effective amount of a platinum (IV) compound to said patient.
-
22. A method for modulating caveolin-associated proteins, transport of ions or molecules across or within cell membranes, cellular excretions or cell receptors that associate with lipid rafts or caveolae in a cell, the method comprising contacting the cell with an effective amount of a platinum(IV) compound, wherein the cell is in vitro, in vivo, or ex vivo, wherein the cell is bacterial, viral, or derived from any living animal.
Specification