2. Academic Validation
  3. Synthesis and pharmacological evaluation of brominated derivatives of natural product celastrol for treatment of hepatic fibrosis

Synthesis and pharmacological evaluation of brominated derivatives of natural product celastrol for treatment of hepatic fibrosis

  • Eur J Med Chem. 2026 May 5:309:118765. doi: 10.1016/j.ejmech.2026.118765.
Meng-Yu Li 1,  Yang Li 2,  Xiaomin Wang 3,  Fan-Fan Shang 4,  Yuting Long 5,  Yong-Ling Li 6,  Zhengyuan Wang 2,  Ao Zhang 7,  Hao Zhang 8,  Chunyong Ding 9,  Zhenliang Sun 10
Affiliations

Affiliations

  • 1 Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai, 201499, China; Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 2 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 3 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 4 School of Pharmacy and Life Science, Jiujiang University, Jiujiang, 332005, China.
  • 5 School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China.
  • 6 Liuzhou Workers' Hospital, Liuzhou, 545000, China.
  • 7 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; National Key Laboratory of Innovative Immunotherapy, Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai, 201203, China; School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 310013, China. Electronic address: ao6919zhang@sjtu.edu.cn.
  • 8 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: szhanghao@shutcm.edu.cn.
  • 9 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; National Key Laboratory of Innovative Immunotherapy, Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai, 201203, China; Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, 201203, China. Electronic address: chunding@sjtu.edu.cn.
  • 10 Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai, 201499, China. Electronic address: zhenliang6@126.com.
PMID: 41844113 DOI: 10.1016/j.ejmech.2026.118765
Abstract

Effective therapeutic agents against hepatic fibrosis remain scarce. Natural product Celastrol has demonstrated promising anti-hepatic fibrosis activity. However, further clinical development is impaired by its toxicity. We performed a bromination modification at the C-ring, an unexplored moiety of Celastrol, leading to a series of brominated derivatives. Among them, derivative 5 effectively suppressed various stimulus-induced activation of NLRP3 inflammasome to block the activation of HSCs, thus reducing the Collagen deposition. Meanwhile, 5 was identified as a covalent PRDX1 inhibitor with high isoform selectivity, which accelerated ROS accumulation to induce Apoptosis of the activated HSCs. Derivative 5 at a dose of 20 mg/kg exhibited superior safety profile with no significant weight loss or hepatotoxicity. At 1 mg/kg, it significantly ameliorates CCl4-induced hepatic damage and fibrosis in mice. Taken together, our work provided a novel brominated derivative of Celastrol as promising lead compound against hepatic fibrosis.

Keywords

Anti-hepatic fibrosis; Celastrol derivatives; Natural product; PRDX1 covalent inhibitor; Toxicity.

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