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

• Published in: European journal of medicinal chemistry 2023-11, Vol.260, p.115731, Article 115731
• Main Authors: Wu, Yihang, Liu, Zixiu, He, Zhenxiu, Yi, Jumei, Qiao, Xingfang, Tan, Chunbin, Xing, Yajing, Zeng, Yaobo, Yang, Dajian, Yin, Junlin, Fan, Baomin, Zeng, Guangzhi
• Format: Article
• Language: English
• Subjects: Animals; Anti-inflammatory activity; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cantharidin - pharmacology; Cantharidin - therapeutic use; Cantharidin analogues; Colitis - chemically induced; Colitis - drug therapy; Dextran Sulfate; Heptanes; Mice; NF-kappa B; NF-κB signaling; Toxicity; Ulcerative colitis
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115731

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. [Display omitted] •Fourteen cantharidin analogues were synthesized by iridium-catalyzed asymmetric hydroalkynylation reactions.•Cantharidin analogues with alkynyl substitution showed good in vitro anti-inflammatory activities.•Cantharidin analogue 3i inhibited TNF-α induced activation of NF-κB pathway.•Cantharidin analogue 3i showed weak in vivo toxicity and attenuated DSS-induced colitis in mice.