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  2. Discovery of novel osthole derivatives exerting anti-inflammatory effect on DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice

Discovery of novel osthole derivatives exerting anti-inflammatory effect on DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice

  • Eur J Med Chem. 2024 Feb 22:268:116252. doi: 10.1016/j.ejmech.2024.116252.
Ying Zhou 1 Zhiteng Du 1 Qianqian Wu 1 Mi Guo 1 Zhichao Chen 1 Chenhui Sun 1 Xiaobo Li 1 Yu Zou 1 Zhiwei Zheng 2 Pan Chen 1 Won-Jea Cho 3 Young-Chang Cho 3 Nipon Chattipakorn 4 Yi Wang 5 Guang Liang 6 Qidong Tang 7
Affiliations

Affiliations

  • 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
  • 2 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; College of Pharmacy, Chonnam National University, Gwangju, 61186, South Korea.
  • 3 College of Pharmacy, Chonnam National University, Gwangju, 61186, South Korea.
  • 4 Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
  • 5 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. Electronic address: yi_wang1122@163.com.
  • 6 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325024, Zhejiang, China; School of Pharmacy, Hangzhou Medical College, Hangzhou, 311399, Zhejiang, China. Electronic address: wzmcliangguang@163.com.
  • 7 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325024, Zhejiang, China. Electronic address: tangqidongcn@126.com.
Abstract

The modification based on Natural Products is a practical way to find anti-inflammatory drugs. In this study, 26 osthole derivatives were synthesized, and their anti-inflammatory properties were evaluated. The preliminary activity study revealed that most osthole derivatives could effectively inhibit inflammatory cytokines IL-6 secretion in LPS stimulated mouse macrophages J774A.1. Compound 7m exhibited the most effective anti-inflammatory activity (RAW264.7 IL-6 IC50: 4.57 μM, 32 times more active than osthole) in vitro with no significant influence on cell proliferation. Additionally, the mechanistic analysis demonstrated that compound 7m could block MAPK signal transduction by inhibiting the phosphorylation of JNK and p38, thereby inhibiting the release of inflammatory cytokines. Moreover, in vivo functional investigations revealed that 7m could substantially reduce DSS-induced ulcerative colitis and LPS-induced acute lung injury, with good therapeutic effects. The pharmacokinetics and acute toxicity experiments proved the safety and reliability of 7min vivo. Overall, Compound 7m could further be studied as potential anti-inflammatory candidate.

Keywords

Acute lung injury; Anti-inflammation; IL-6; MAPK pathway; Osthole derivatives; Ulcerative colitis.

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