Bisbenzylisoquinoline alkaloids and P-glycoprotein function: A structure activity relationship study.

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.

• Authors: Wencheng Xu, Shuhe Chen, Xiaoqin Wang, Hongguang Wu, Haruki Yamada, Toshihiko Hirano
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 28 Issue 12 Pg. 115553 (06 15 2020) ISSN: 1464-3391 [Electronic] England
• PMID: 32503690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• Alkaloids
• Benzylisoquinolines
• cepharanthine
• fangchinoline
• berbamine

Topics

• ATP Binding Cassette Transporter, Subfamily B (chemistry, metabolism)
• Alkaloids (chemistry, metabolism, pharmacology)
• Benzylisoquinolines (chemistry, metabolism, pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Molecular Conformation
• Structure-Activity Relationship