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  3. Design, synthesis, and bioactivity evaluation of novel indole-selenide derivatives as P-glycoprotein inhibitors against multi-drug resistance in MCF-7/ADR cell

Design, synthesis, and bioactivity evaluation of novel indole-selenide derivatives as P-glycoprotein inhibitors against multi-drug resistance in MCF-7/ADR cell

  • Eur J Med Chem. 2024 Feb 10:268:116207. doi: 10.1016/j.ejmech.2024.116207.
Zhikun Yang 1,  Disheng Luo 2,  Chen Shao 3,  Haoqiang Hu 2,  Xue Yang 4,  Yue Cai 3,  Xiaozhou Mou 4,  Qihao Wu 5,  Hongtao Xu 6,  Xuanrong Sun 3,  Hong Wang 7,  Wei Hou 8
Affiliations

Affiliations

  • 1 College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou, 310014, China; Bingjiang Cyberspace Security, Institute of Zhejiang University of Technology, Hangzhou, 310051, China.
  • 2 College of Pharmaceutical Science and Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou, 310014, China.
  • 3 College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou, 310014, China.
  • 4 General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
  • 5 Departments of Chemistry, Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, 06516, United States.
  • 6 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.
  • 7 College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: [email protected].
  • 8 College of Pharmaceutical Science and Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address: [email protected].
PMID: 38364715 DOI: 10.1016/j.ejmech.2024.116207
Abstract

The inhibition of P-glycoprotein (P-gp) has emerged as an intriguing strategy for circumventing multidrug resistance (MDR) in Anticancer chemotherapy. In this study, we have designed and synthesized 30 indole-selenides as a new class of P-gp inhibitors based on the scaffold hopping strategy. Among them, the preferred compound H27 showed slightly stronger reversal activity (reversal fold: 271.7 vs 261.6) but weaker cytotoxicity (inhibition ratio: 33.7% vs 45.1%) than the third-generation P-gp inhibitor tariquidar on the tested MCF-7/ADR cells. Rh123 accumulation experiments and Western blot analysis demonstrated that H27 displayed excellent MDR reversal activity by dose-dependently inhibiting the efflux function of P-gp rather than its expression. Besides, UIC-2 reactivity shift assay revealed that H27 could bind to P-gp directly and induced a conformation change of P-gp. Moreover, docking study revealed that H27 matched well in the active pockets of P-gp by forming some key H-bonding interactions, arene-H interactions and hydrophobic contacts. These results suggested that H27 is worth to be a starting point for the development of novel Se-containing P-gp inhibitors for clinic use.

Keywords

Indole-selenide derivatives; MCF-7/ADR; P-glycoprotein inhibitor; Scaffold hopping; Structure-activity relationship.

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