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

Yang Zhou; Jiao Zou; Xi Zhong; Jing Xu; Kun Gou; Xia Zhou; Yue Zhou; Xinyu Yang; Xinqi Guan; Yu Zhang; Donglin Chen; Xiaobo Cen; Youfu Luo; Yinglan Zhao

doi:10.1016/j.ejmech.2023.115576

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. Epub 2023 Jun 17.

Authors

Yang Zhou¹, Jiao Zou¹, Xi Zhong², Jing Xu¹, Kun Gou¹, Xia Zhou¹, Yue Zhou¹, Xinyu Yang², Xinqi Guan¹, Yu Zhang³, Donglin Chen², Xiaobo Cen⁴, Youfu Luo⁵, Yinglan Zhao⁶

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: luo_youfu@scu.edu.cn.
⁶ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: zhaoyinglan@scu.edu.cn.

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.

MeSH terms

Amides / pharmacology
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Neoplasms*
Oxidative Phosphorylation
Pyrazoles / pharmacology
Structure-Activity Relationship

Substances

Amides
Antineoplastic Agents
Pyrazoles
IACS-010759