Synthesis and evaluation of substituted dibenzo[c,e]azepine-5-ones as P-glycoprotein-mediated multidrug resistance reversal agents |
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Authors: | Tang Xiaobo Gu Xiaoke Ren Zhiguang Ma Yuanfang Lai Yisheng Peng Hui Peng Sixun Zhang Yihua |
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Institution: | State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China. |
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Abstract: | A series of substituted dibenzoc,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. |
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