2. Academic Validation
  3. Design, synthesis, and biological evaluation of nitroisoxazole-containing spiro[pyrrolidin-oxindole] derivatives as novel glutathione peroxidase 4/mouse double minute 2 dual inhibitors that inhibit breast adenocarcinoma cell proliferation

Design, synthesis, and biological evaluation of nitroisoxazole-containing spiro[pyrrolidin-oxindole] derivatives as novel glutathione peroxidase 4/mouse double minute 2 dual inhibitors that inhibit breast adenocarcinoma cell proliferation

  • Eur J Med Chem. 2021 May 5:217:113359. doi: 10.1016/j.ejmech.2021.113359.
Shuai-Jiang Liu 1,  Qian Zhao 1,  Cheng Peng 2,  Qing Mao 1,  Fengbo Wu 3,  Feng-Hua Zhang 1,  Quan-Sheng Feng 1,  Gu He 4,  Bo Han 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Basic Medical Sciences, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China.
  • 2 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Basic Medical Sciences, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China. Electronic address: pengcheng@cdutcm.edu.cn.
  • 3 State Key Laboratory of Biotherapy and Department of Pharmacy, West China Hospital, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
  • 4 State Key Laboratory of Biotherapy and Department of Pharmacy, West China Hospital, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: hegu@scu.edu.cn.
  • 5 State Key Laboratory of Southwestern Chinese Medicine Resources, School of Basic Medical Sciences, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China. Electronic address: hanbo@cdutcm.edu.cn.
PMID: 33725632 DOI: 10.1016/j.ejmech.2021.113359
Abstract

A series of highly active CF3-containing 3'-(nitroisoxazole)spiro[pyrrolidin-3,2'-oxindoles] were synthesized and found to be novel Glutathione Peroxidase 4 (GPX4)/mouse double minute 2 (MDM2) dual inhibitors. Bioactive spirooxindole and isoxazole skeletons were combined, and the resulting compounds exhibited strong activities against both targets. In particular, compound 3d displayed excellent activity in the suppression of MDM2-mediated degradation of p53, as well as levels of GPX4, in MCF-7 breast Cancer cells. Moreover, 3d also exhibited inhibitory effects on MDM2 and GPX4 in MCF-7 xenograft model to trigger ferroptotic and apoptotic cell death in in vivo experiments, which was consistent with the results of in vitro experiments.

Keywords

1,3-Dipolar cycloaddition; Breast adenocarcinoma; Ferroptosis; Isoxazole; Novel GPX4/MDM2 dual inhibitors; Spirooxindole.

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