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

Shuai-Jiang Liu; Qian Zhao; Cheng Peng; Qing Mao; Fengbo Wu; Feng-Hua Zhang; Quan-Sheng Feng; Gu He; Bo Han

doi:10.1016/j.ejmech.2021.113359

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. Epub 2021 Mar 9.

Authors

Shuai-Jiang Liu¹, Qian Zhao¹, Cheng Peng², Qing Mao¹, Fengbo Wu³, Feng-Hua Zhang¹, Quan-Sheng Feng¹, Gu He⁴, Bo Han⁵

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Female
Humans
Isoxazoles / chemical synthesis
Isoxazoles / chemistry
Isoxazoles / pharmacology*
MCF-7 Cells
Mammary Neoplasms, Experimental / drug therapy
Mammary Neoplasms, Experimental / metabolism
Mammary Neoplasms, Experimental / pathology
Mice
Molecular Structure
Nitro Compounds / chemical synthesis
Nitro Compounds / chemistry
Nitro Compounds / pharmacology*
Oxindoles / chemistry
Oxindoles / pharmacology
Phospholipid Hydroperoxide Glutathione Peroxidase / antagonists & inhibitors*
Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-mdm2 / metabolism
Pyrrolidines / chemistry
Pyrrolidines / pharmacology
Spiro Compounds / chemistry
Spiro Compounds / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Isoxazoles
Nitro Compounds
Oxindoles
Pyrrolidines
Spiro Compounds
Phospholipid Hydroperoxide Glutathione Peroxidase
Mdm2 protein, mouse
Proto-Oncogene Proteins c-mdm2