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1. Bioorg Med Chem Lett. 2012 Apr 15;22(8):2675-80. Epub 2012 Mar 8.

Synthesis and evaluation of substituted dibenzo[c,e]azepine-5-ones as
P-glycoprotein-mediated multidrug resistance reversal agents.

Tang X, Gu X, Ren Z, Ma Y, Lai Y, Peng H, Peng S, Zhang Y.

State Key Laboratory of Natural Medicines, China Pharmaceutical University,
Nanjing 210009, PR China; Center of Drug Discovery, China Pharmaceutical
University, Nanjing 210009, PR China.

A series of substituted dibenzo[c,e]azepine-5-ones (7a-h) were synthesized and
evaluated as P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) reversal
agents. The most potent compound 7h could significantly and selectively enhance
the chemo-sensitivity of drug-resistant K562/A02 cells to the cytotoxic effect of
adriamycin (ADR) in a dose-dependent manner. Further studies indicated that 7h
could markedly increase intracellular accumulation of both rhodamine 123 and ADR
in K562/A02 cells and inhibit their efflux from the cells. And 7h had little
effect on the levels of P-gp mRNA and protein in K562/A02 cells. These results
suggest that the anti-MDR effect of 7h might be attributed to the inhibition of
drug efflux function of P-gp, leading to the increased drug accumulation in
K562/A02 cells, and thus the compound could be served as a lead for developing
P-gp-mediated MDR reversal agents.

Copyright © 2012 Elsevier Ltd. All rights reserved.

PMID: 22450134 [PubMed - in process]