化学
流出
P-糖蛋白
阿霉素
对接(动物)
多重耐药
细胞毒性
药理学
结构-活动关系
立体化学
分子模型
体外
生物化学
化疗
抗生素
生物
医学
护理部
遗传学
作者
Zhikun Yang,Yue Cai,Xue Yang,Ya-Sheng Li,Qihao Wu,Yanlei Yu,Zhen Chen,Bin Wei,Jin‐Miao Tian,Xiaoze Bao,Xinyi Ye,Jianwei Chen,Huawei Zhang,Xiaozhou Mou,Xuanrong Sun,Hong Wang
标识
DOI:10.1021/acs.jmedchem.2c01999
摘要
A proposed strategy to overcome multidrug resistance (MDR) of anticancer drugs in chemotherapy is to disable the efflux function of P-glycoprotein (P-gp). In this study, based on ring-merging and fragment-growing strategies, 105 novel benzo five-membered heterocycle derivatives were designed, synthesized, and screened. Exploration of the structure-activity relationship (SAR) led to the identification of d7 with low cytotoxicity and promising reversal activity to doxorubicin in MCF-7/ADR cells. Furthermore, the mechanism studies revealed that the reversal activity of d7 stemmed from the inhibition of P-gp efflux. Molecular docking further clarified the observed trends in SAR with d7 displaying potent affinity to P-gp. Additionally, coadministration of d7 with doxorubicin achieved stronger antitumor activity in a xenograft model than doxorubicin alone. These results suggest that d7 is a potential MDR reveal agent acting as a P-gp inhibitor and provides guidelines for the future development of new P-gp inhibitors.
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