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

被引：17

作者：

Xu, Wencheng ^{[2
,3
]}

Chen, Shuhe ^{[2
,3
]}

Wang, Xiaoqin ^{[3
,4
]}

Wu, Hongguang ^{[1
]}

Yamada, Haruki ^{[1
]}

Hirano, Toshihiko ^{[1
]}

机构：

[1] Tokyo Univ Pharm & Life Sci, Sch Pharm, Dept Clin Pharmacol, 1432-1 Horinouchi, Hachioji, Tokyo 1920392, Japan

[2] Hubei Prov Hosp Tradit Chinese Med, Dept Pharm, Wuhan, Peoples R China

[3] Hubei Prov Acad Tradit Chinese Med, Inst Tradit Chinese Med, Wuhan, Peoples R China

[4] Hubei Prov Hosp Tradit Chinese Med, Dept Nephrol, Wuhan, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2020年 / 28卷 / 12期

关键词：

Bisbenzylisoquinoline alkaloids; Multidrug resistance; P-glycoprotein; Tetrandrine; MOLT-4; MULTIDRUG-RESISTANCE; DRUG-RESISTANCE; CANCER; REVERSAL; INHIBITOR; TRANSPORT; TETRANDRINE; MECHANISMS; SUBSTRATE; ABCB1;

D O I：

10.1016/j.bmc.2020.115553

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：6

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