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1. Bioorg Med Chem Lett. 2012 Mar 13. [Epub ahead of print]

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.

Zhou T, Ohkoshi E, Shi Q, Bastow KF, Lee KH.

Natural Products Research Laboratories, UNC Eshelman School of Pharmacy,
University of North Carolina, Chapel Hill, NC 27599-7568, USA.

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 4μM, a 20-fold
enhancement compared to the first generation chemosensitizer, verapamil (4μM).
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.

Copyright © 2012 Elsevier Ltd. All rights reserved.

PMID: 22465634 [PubMed - as supplied by publisher]