2. Academic Validation
  3. Cantharidin analogue alleviates dextran sulfate sodium-induced colitis in mice by inhibiting the activation of NF-κB signaling

Cantharidin analogue alleviates dextran sulfate sodium-induced colitis in mice by inhibiting the activation of NF-κB signaling

  • Eur J Med Chem. 2023 Nov 15;260:115731. doi: 10.1016/j.ejmech.2023.115731.
Yihang Wu 1,  Zixiu Liu 1,  Zhenxiu He 1,  Jumei Yi 1,  Xingfang Qiao 2,  Chunbin Tan 2,  Yajing Xing 2,  Yaobo Zeng 2,  Dajian Yang 3,  Junlin Yin 1,  Baomin Fan 4,  Guangzhi Zeng 5
Affiliations

Affiliations

  • 1 Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China.
  • 2 Chongqing Key Laboratory of Traditional Chinese Medicine Health, Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China.
  • 3 Chongqing Key Laboratory of Traditional Chinese Medicine Health, Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China. Electronic address: yangdajian@cqacmm.com.
  • 4 Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China. Electronic address: FanBM@ynni.edu.cn.
  • 5 Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission and Ministry of Education, Yunnan Minzu University, Kunming 650504, China. Electronic address: g.zh_zeng@ymu.edu.cn.
PMID: 37643546 DOI: 10.1016/j.ejmech.2023.115731
Abstract

Ulcerative colitis is a chronic inflammatory disease with a remitting-relapsing clinical course, it has evolved into a global burden given its high incidence worldwide. Cantharidin (CTD) derivatives are a class of compounds whose structures characterized with a 7-oxabicyclo [2.2.1]heptane core. Though potent cytotoxicity CTD and its derivatives showed, their clinical usage as anti-cancer drugs was limited by the toxicity in organs. In order to find new CTD analogues with good activity and lower toxicity, 21 CTD analogues with or without alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core were synthesized, some compounds showed better in vitro anti-inflammatory activity compared to CTD and norcantharidin (NCTD). Based on the structure-activity relationship results of in vitro experiment, analogue 3i was chosen for further study. Results from the acute toxicity in mice showed that 3i was hypotoxic with the single-dose MTD (maximum tolerated dose) for oral administration is over 1852 mg/kg, at least 35-fold lower than that of NCTD. Mechanism study indicated that 3i could potently inhibit TNF-α induced activation of NF-κB signaling by down-regulation the expression levels of phosphor- IKK, IκBα, and NF-κB p65, and alleviated dextran sulfate sodium-induced colitis in mice. This study indicated that CTD analogues with alkynyl substitution at C5 position of 7-oxabicyclo [2.2.1]heptane core is a kind of new compounds with good anti-inflammatory activity and lower toxicity in vivo, and might be used as therapeutic agents for inflammatory diseases.

Keywords

Anti-inflammatory activity; Cantharidin analogues; NF-κB signaling; Toxicity; Ulcerative colitis.

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