Design, synthesis and biological evaluation studies of novel anti-fibrosis agents bearing sulfoxide moiety

Shixuan Jiao; Wanqiu Huang; Zhijun Cao; Ya Chen; Siliang Chen; Zhongcheng Yang; Wenxin Wang; Huixin Yao; Xuekun Wang; Zheng Li; Luyong Zhang

doi:10.1016/j.bmc.2022.117096

Design, synthesis and biological evaluation studies of novel anti-fibrosis agents bearing sulfoxide moiety

Bioorg Med Chem. 2022 Dec 1:75:117096. doi: 10.1016/j.bmc.2022.117096. Epub 2022 Nov 12.

Authors

Shixuan Jiao¹, Wanqiu Huang², Zhijun Cao¹, Ya Chen³, Siliang Chen³, Zhongcheng Yang³, Wenxin Wang³, Huixin Yao³, Xuekun Wang⁴, Zheng Li⁵, Luyong Zhang⁶

Affiliations

¹ Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, China.
² Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China.
³ Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China.
⁴ College of Pharmacy, Liaocheng University, Liaocheng 252059, China.
⁵ Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, China. Electronic address: li.zheng.sky@163.com.
⁶ Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of New Drug Discovery and Evaluation of the Guangdong Provincial Education Department, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China. Electronic address: lyzhang@cpu.edu.cn.

PMID: 36395681
DOI: 10.1016/j.bmc.2022.117096

Abstract

Fibrosis, a chronic disease with high morbidity and mortality, is mainly characterized by excessive accumulation of extracellular matrix (ECM). At present, pathogenesis of fibrosis is incompletely understood, and there is an urgent need to develop safe and effective drugs. In this study, we designed and synthesized a series of novel small-molecule compounds through structural modification and fragment hybridization. Among them, a potential anti-fibrosis drug compd.1 was founded to be able to dose-dependently down-regulate ACTA2 and CTGF mRNA levels in human hepatic stellate cells (LX-2) treated with TGF-β. In addition, compd.1 significantly improved the bridging fibrosis and collagen content in the CCl₄-induced liver fibrosis mice model. Moreover, compd.1 reduced lung inflammation and fibrotic area in bleomycin-induced pulmonary fibrosis mice model. These findings suggested that compd.1 is a promising candidate for further anti-fibrosis researches, and extended chemical space might help us to explore better anti-fibrosis drug.

Keywords: Bleomycin; Fibrosis; Inflammation; Structural modification.

Publication types

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

MeSH terms

Animals
Antifibrotic Agents*
Bleomycin / pharmacology
Fibrosis
Hepatic Stellate Cells
Humans
Liver Cirrhosis / chemically induced
Liver Cirrhosis / drug therapy
Mice
Pulmonary Fibrosis* / chemically induced

Substances

Antifibrotic Agents
Bleomycin