Bisbenzylisoquinoline alkaloids and P-glycoprotein function: A structure activity relationship study. Issue 12 (15th June 2020)

• Record Type: Journal Article
• Authors: Xu, Wencheng; Chen, Shuhe; Wang, Xiaoqin; Wu, Hongguang; Yamada, Haruki; Hirano, Toshihiko
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 12(2020)
• Publication Date: 2020-06-15
• Subjects: Bisbenzylisoquinoline alkaloids -- Multidrug resistance -- P-glycoprotein -- Tetrandrine -- MOLT-4; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115553
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: 18-membered ring of bisbenzylisoquinolines maintains their P-gp inhibitory activity. 3D structures of bisbenzylisoquinolines determine their P-gp inhibitory activity. 3D structure is more sensitive than 2D to predict the P-gp inhibitory activity. Abstract: 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.