Novel chlorpromazine derivatives as anti-endometrial carcinoma agents with reduced extrapyramidal side effects

Lijuan Li; Xiaohu Liu; Yunxia Cui; Yang Chen; Huiwen Wu; Jing Wang; Xiaodi Gong; Xiaoyan Gao; Linlin Yang; Jian Li; Xiao Sun; Fei Mao; Yudong Wang

doi:10.1016/j.bioorg.2022.106008

Novel chlorpromazine derivatives as anti-endometrial carcinoma agents with reduced extrapyramidal side effects

Bioorg Chem. 2022 Oct:127:106008. doi: 10.1016/j.bioorg.2022.106008. Epub 2022 Jul 15.

Authors

Lijuan Li¹, Xiaohu Liu², Yunxia Cui¹, Yang Chen², Huiwen Wu², Jing Wang¹, Xiaodi Gong¹, Xiaoyan Gao¹, Linlin Yang¹, Jian Li³, Xiao Sun⁴, Fei Mao⁵, Yudong Wang⁶

Affiliations

¹ Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
³ State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Yunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from West Yunnan, College of Pharmacy, Dali University, Dali 671000, China; Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, China; Key Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou 570228, Hainan, China.
⁴ Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: sunxiao@shsmu.edu.cn.
⁵ State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: maofei@ecust.edu.cn.
⁶ Department of Gynecologic Oncology, the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Municipal Key Clinical Specialty, Female Tumor Reproductive Specialty, Shanghai, China. Electronic address: wangyudong@shsmu.edu.cn.

PMID: 35868106
DOI: 10.1016/j.bioorg.2022.106008

Abstract

As the traditional conservative remedy for endometrial carcinoma (EC), progesterone has great limitations due to its poor performance, and a new strategy is urgently needed. Our previous work revealed that the antipsychotic drug chlorpromazine (CPZ) has stronger antitumor activity on EC than progesterone does, which may provide a promising conservative alternative for EC patients. Unfortunately, the severe extrapyramidal symptoms (EPSs) at concentrations (>5 mg/kg) that are required for anticarcinoma activity limited its repurposing. Therefore, a series of novel CPZ derivatives were designed and synthesized to avoid EPS and retain its antitumor activity. Among them, 11·2HCl and 18 displayed greater inhibitory activity by modulating SOS1. Notably, even at a dose of 100 mg/kg, 11·2HCl/18 had little effect on the extrapyramidal system. In conclusion, 11·2HCl and 18 greatly repressed the malignant features of endometrial carcinoma and decreased extrapyramidal side effects compared with the original drug CPZ.

Keywords: Anti-endometrial carcinoma; Chlorpromazine derivatives; Conservative alternative; SOS1 signal; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antipsychotic Agents* / pharmacology
Antipsychotic Agents* / therapeutic use
Carcinoma* / drug therapy
Chlorpromazine / adverse effects
Humans
Progesterone

Substances

Antipsychotic Agents
Progesterone
Chlorpromazine