title: 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.
abstract: 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 μM, a 20-fold enhancement compared to the first generation chemosensitizer, verapamil (4 μM). 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.
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.forename: Emika
authors.initials: E
authors.lastname: Ohkoshi
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D019380:Anti-HIV Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002867:Chromones; D018432:Drug Resistance, Multiple; D024882:Drug Resistance, Viral / Q000187:drug effects*; D006801:Humans; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D044004:Xanthones
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D019380:Anti-HIV Agents; D002867:Chromones; D044004:Xanthones; D014750:Vincristine; C009689:xanthone; D014700:Verapamil