Curcumin analogues as zinc chelators and their uses

摘要

This invention provides a compound having the structure;
wherein α, β, X, Y, and R1-R11 are defined herein. This invention also provides a pharmaceutical composition comprising the above compounds, a method of inhibiting the activity and/or levels of a matrix metalloproteinase (MMP), a method of inhibiting the production of a cytokine in a population of cells, a method of inhibiting the production of a growth factor in a population of cells, and a method of inhibiting NFκ-B activation in a population of cells.

主权项

1. A method of treating a subject afflicted with periodontal disease, rheumatoid arthritis (RA), osteoarthritis (OA), emphysema, acute respiratory distress syndrome, multiple sclerosis, atherosclerosis, myocardial infarction, neuroinflammation, inflammatory bowel disease, diabetes, stroke, peripheral neuropathy, brain trauma, pancreatitis, or osteoporosis comprising administering to the subject a compound having the structure: wherein bond α and β are each, independently, present or absent; X is CR5 or N; Y is CR10 or N; R1 is H, CF3, halogen, —NO2, —OCF3, —OR12, —NHCOR12, —SR12, —SO2R13, —COR14, —CSR14, —C(═NR12)R14, —C(═NH)R14, —SOR12, —POR12, —P(═O)(OR12)(OR13), or —P(OR12)(OR13),
wherein R12 and R13 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;R14 is C2-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, heteroaryl, heterocyclyl, methoxy, —OR15, —NR16R17, or wherein R15 is H, C3-10 alkyl, C2-10 alkenyl, C2-10 alkynyl;R16 and R17 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;R18, R19, R21, and R22 are each independently H, halogen, —NO2, —CN, —NR23R24, —SR23, —SO2R23, —CO2R23, —OR25, CF3, —SOR23, —POR23, —C(═S)R23, —C(═NH)R23, —C(═NR24)R23, —C(═N)R23, —P(═O)(OR23)(OR24), —P(OR23)(OR24), —C(═S)R23, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R23, R24, and R25 are each, independently, H, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;R20 is halogen, —NO2, —CN, —NR26R27, CF3, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R26 and R27 are each, independently, H, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, or heterocyclyl; R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are each independently, H, halogen, —NO2, —CN, —NR28R29, —NHR28R29+, —SR28, —SO2R28, —OR28, —CO2R28, CF3, C1-10 alkyl, C1-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R28 and R29 are each, H, CF3, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or —C(═O) heterocyclyl; and wherein when R1 is H, R3, R4, R5, R8, R9, or R10, is halogen, —NO2, —CN, —NR28R29, —NHR28R29+, —SR28, —SO2R28, —CO2R28, CF3, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, heteroaryl, or heterocyclyl;
wherein R28 and R29 are each, H, CF3, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, or —C(═O)-heterocyclyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; or a salt thereof, so as to thereby treat the subject afflicted with periodontal disease, rheumatoid arthritis (RA), osteoarthritis (OA), emphysema, acute respiratory distress syndrome, multiple sclerosis, atherosclerosis, myocardial infarction, neuroinflammation, inflammatory bowel disease, diabetes, stroke, peripheral neuropathy, brain trauma, pancreatitis, breast cancer, skin cancer, prostate cancer or osteoporosis.