Discovery of new tricyclic spiroindole derivatives as potent P-glycoprotein inhibitors for reversing multidrug resistance enabled by a synthetic methodology-based library

作者全名：Yu, Tao; Zeng, Rong; Guan, Yu; Pan, Bin; Li, Hong-Wei; Gu, Jing; Zheng, Peng-Fei; Qian, Yan; Ouyang, Qin

作者地址：[Yu, Tao; Qian, Yan] Chongqing Med Univ, Affiliated Hosp 2, Dept Pharm, Chongqing 400010, Peoples R China; [Yu, Tao; Zeng, Rong; Pan, Bin; Li, Hong-Wei; Gu, Jing; Zheng, Peng-Fei; Ouyang, Qin] Third Mil Med Univ, Dept Med Chem, Chongqing 400038, Peoples R China; [Zeng, Rong] Army Med Univ, Third Military Med Univ, Xinqiao Hosp, Affiliated Hosp 2,Dept Gastroenterol, Chongqing 400037, Peoples R China; [Guan, Yu] Sichuan Univ Sci & Engn, Coll Chem & Environm Engn, Zigong 643000, Peoples R China

通信作者：Qian, Y (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Pharm, Chongqing 400010, Peoples R China.; Zheng, PF; Ouyang, Q (通讯作者)，Third Mil Med Univ, Dept Med Chem, Chongqing 400038, Peoples R China.

来源：RSC MEDICINAL CHEMISTRY

ESI学科分类：　

WOS号：WOS:001204787600001

JCR分区：Q2

影响因子：4.1

年份：2024

卷号：15

期号：5

开始页：1675

结束页：1685

文献类型：Article

关键词：　

摘要：The discovery of novel and highly effective P-gp inhibitors is considered to be an effective strategy for overcoming tumor drug resistance. In this paper, a phenotypic screening via a self-constructed synthetic methodology-based library identified a new class of tricyclic spiroindole derivatives with excellent tumor multidrug resistance reversal activity. A stereospecific compound OY-103-B with the best reversal activity was obtained based on a detailed structure-activity relationship study, metabolic stability optimization and chiral resolution. For the VCR-resistant Eca109 cell line (Eca109/VCR), co-administration of 5.0 mu M OY-103-B resulted in a reversal fold of up to 727.2, superior to the typical third-generation P-gp inhibitor tariquidar. Moreover, the compound inhibited the proliferation of Eca109/VCR cells in a concentration-dependent manner in plate cloning and flow cytometry. Furthermore, fluorescence substrate accumulation assay and chemotherapeutic drug reversal activity tests demonstrated that OY-103-B reversed tumor drug resistance via P-gp inhibition. In conclusion, this study provides a novel skeleton that inspires the design of new P-gp inhibitors, laying the foundation for the treatment of drug-resistant tumors. Based on synthetic methodology-based library, a new class of tricyclic spiroindole derivatives as potent P-glycoprotein inhibitors with excellent tumor multidrug resistance reversal activity was discovered.

基金机构：National Natural Science Foundation of China [CSTB2022NSCQ-BHX0031]; Chongqing Natural Science Foundation Postdoctoral Project [22207123, 82273775]; Natural Science Foundation of China [2021XQN05]; Third Military Medical University

基金资助正文：We sincerely thank our collaborators Prof. Ying-Chun Chen and Prof. Wei Du at West China School of Pharmacy, Sichuan University for contributing to establish the compound library. We are grateful for financial support from Chongqing Natural Science Foundation Postdoctoral Project (CSTB2022NSCQ-BHX0031), Natural Science Foundation of China (22207123 and 82273775), and the Third Military Medical University (2021XQN05).