Anti-AIDS agents 89. Identification of DCX derivatives as anti-HIV and chemosensitizing dual function agents to overcome P-gp-mediated drug resistance for AIDS therapy

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• 作者：Ting Zhou^a ; Emika Ohkoshi^a ; Qian Shi^a ; ^{qshi1@email.unc.edu} ; Kenneth F. Bastow^b ; ^{khlee@unc.edu} ; Kuo-Hsiung Lee^a ; ^c ; ^{ken_bastow@unc.edu}
• 关键词：Pyranochromone derivatives ; Chemoresistance ; P-glycoprotein (P-gp) inhibitors ; Anti-HIV agents ; Dual function inhibitors
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 May, 2012
• 卷：22
• 期：9
• 页码：3219-3222
• 文件大小：371 K

摘要

In this study, 19 dicamphanoyl-dihydropyranochromone (DCP) and dicamphanoyl-dihydropyranoxanthone (DCX) derivatives, previously discovered as novel anti-HIV agents, were evaluated for their potential to reverse multi-drug resistance (MDR) in a cancer cell line over-expressing P-glycoprotein (P-gp). Seven compounds fully reversed resistance to vincristine (VCR) at 4 渭M, a 20-fold enhancement compared to the first generation chemosensitizer, verapamil (4 渭M). The mechanism of action of DCPs and DCXs was also resolved, since the most active compounds (3, 4, and 7) significantly increased intracellular drug accumulation due, in part, to inhibiting the P-gp mediated drug efflux from cells. We conclude that DCPs (3 and 4) and DCXs (7, 11, and 17) can exhibit polypharmacologic behavior by acting as dual inhibitors of HIV replication and chemoresistance mediated by P-gp. As such, they may be useful in combination therapy to overcome P-gp-associated drug resistance for AIDS treatment.