Synthesis and biological evaluation of novel pyrazole amides as potent mitochondrial complex I inhibitors

  • Eur J Med Chem. 2023 Oct 5;258:115576. doi: 10.1016/j.ejmech.2023.115576.
Yang Zhou  1 ,  Jiao Zou  1 ,  Xi Zhong  2 ,  Jing Xu  1 ,  Kun Gou  1 ,  Xia Zhou  1 ,  Yue Zhou  1 ,  Xinyu Yang  2 ,  Xinqi Guan  1 ,  Yu Zhang  3 ,  Donglin Chen  2 ,  Xiaobo Cen  4 ,  Youfu Luo  5 ,  Yinglan Zhao  6
Affiliations
  • 1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2. West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
  • 3. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; School of Medicine, Tibet University, Lhasa, 850000, China.
  • 4. National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 5. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 6. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 37392582 DOI: 10.1016/j.ejmech.2023.115576
Abstract

Targeting mitochondrial complex I (CI) is emerging as an attractive Anticancer strategy, and CI inhibitor IACS-010759 has achieved breakthrough success. However, the narrow therapeutic index of IACS-010759 seriously hinders its further application. In this study, a series of novel pyrazole amides were designed and optimized based on IACS-010759, and their potential CI inhibitory effects were biologically evaluated. Among them, the maximum tolerated dose (MTD) values of SCAL-255 (compound 5q) and SCAL-266 (compound 6f) were 68 mg/kg, which was nearly 10 times that of IACS-010759 (6 mg/kg), showing good safety. In addition, SCAL-255 and SCAL-266 significantly inhibited the proliferation of HCT116 and KG-1 cells in vitro and exerted satisfactory inhibitory activity against KG-1 cells in vivo. These results suggested that the optimized compounds might serve as promising CI inhibitors against Oxidative Phosphorylation (OXPHOS)-dependent Cancer, which merits further study.

Keywords
Antitumor; Mitochondrial complex I; Pyrazole amides.
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