Xu Wencheng, Chen Shuhe, Wang Xiaoqin, Wu Hongguang, Yamada Haruki, Hirano Toshihiko
Department of Pharmacy, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, PR China; Institute of Traditional Chinese Medicine, Hubei Province Academy of Traditional Chinese Medicine, Wuhan, PR China.
Institute of Traditional Chinese Medicine, Hubei Province Academy of Traditional Chinese Medicine, Wuhan, PR China; Department of Nephrology, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, PR China.
Bioorg Med Chem. 2020 Jun 15;28(12):115553. doi: 10.1016/j.bmc.2020.115553. Epub 2020 May 11.
Conflicts with the notion that specific substrate interactions were required in the control of reaction path in active transport systems, P-glycoprotein showed extraordinarily low specificity. Therefore, overexpression P-glycoprotein excluded a large number of anticancer agents from cancer cells, and multidrug resistance happened. Several kinds of bisbenzylisoqunoline alkaloids were reported to modulate P-glycoprotein function and reverse drug resistance. In order to provide more information for their structure activity relationship on P-glycoprotein function, the effects of tetrandrine, isotetrandrine, fangchinoline, berbamine, dauricine, cepharanthine and armepavine on the P-glycoprotein function were compared by using daunorubicin-resistant leukemia MOLT-4 cells in the present study. Among them, tetrandrine exhibited the strongest P-glycoprotein inhibitory effect, followed with fangchinoline and cepharanthine, and subsequently with berbamine or isotetrandrine. However, dauricine and armepavine showed little influence on the P-glycoprotein function. These data revealed that the 18-membered ring of the bisbenzylisoquinoline alkaloids maintained the P-glycoprotein inhibitory activity, suggesting that double isoquinoline units connected by two oxygen bridges were indispensable. Moreover, stereo-configuration of bisbenzylisoquinoline 3D structures determined their inhibitory activities, which provided a new viewpoint to recognize the specificity of binding pocket in P-glycoprotein. Our data also indicated that 3D chemical structure was more sensitive than 2D to predict the P-glycoprotein inhibitory-potencies of bisbenzylisoqunoline alkaloids.
与主动转运系统中控制反应路径需要特定底物相互作用这一概念相矛盾的是，P-糖蛋白表现出极低的特异性。因此，P-糖蛋白的过表达使大量抗癌药物无法进入癌细胞，从而产生多药耐药性。据报道，几种双苄基异喹啉生物碱可调节P-糖蛋白功能并逆转耐药性。为了提供更多关于它们对P-糖蛋白功能的构效关系的信息，本研究使用耐柔红霉素的白血病MOLT-4细胞比较了粉防己碱、异粉防己碱、防己诺林碱、小檗胺、蝙蝠葛碱、千金藤素和阿朴吗啡碱对P-糖蛋白功能的影响。其中，粉防己碱对P-糖蛋白的抑制作用最强，其次是防己诺林碱和千金藤素，随后是小檗胺或异粉防己碱。然而，蝙蝠葛碱和阿朴吗啡碱对P-糖蛋白功能影响很小。这些数据表明，双苄基异喹啉生物碱的18元环维持了对P-糖蛋白的抑制活性，表明由两个氧桥连接的双异喹啉单元是必不可少的。此外，双苄基异喹啉3D结构的立体构型决定了它们的抑制活性，这为认识P-糖蛋白中结合口袋的特异性提供了新的视角。我们的数据还表明，3D化学结构比2D化学结构更能灵敏地预测双苄基异喹啉生物碱对P-糖蛋白的抑制效力。
