Synthesis and biological evaluation of parthenolide derivatives with reduced toxicity as potential inhibitors of the NLRP3 inflammasome. Issue 17 (1st September 2020)

• Record Type: Journal Article
• Authors: Ou, Yitao; Sun, Ping; Wu, Nannan; Chen, Hao; Wu, Dan; Hu, Wenhui; Yang, Zhongjin
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 17(2020)
• Publication Date: 2020-09-01
• Subjects: Parthenolide -- NLRP3 inflammasome inhibitor -- NO donor -- Low cytotoxicity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127399
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Parthenolide (PTL) can target NLRP3 inflammasome to treat inflammation and its related disease, but its cytotoxicity limits further development as an anti-inflammatory drug. A series of PTL analogs and their Michael-type adducts were designed and synthesized, and most of them showed high activities against the NLRP3 inflammasome pathway. The most potent compound 8b inhibited the release of IL-1β with IC50 values of 0.3 μM in J774A.1 cell and 1.0 μM in primary glial cells, respectively. Moreover, 8b showed low toxicity against J774A.1 cell (IC50 = 24.1 μM) and HEK-293T (IC50 = 69.8 μM) with a ~8 folds increase of therapeutic index compared to its parent PTL. The preliminary mechanism study revealed that 8b mediated anti-inflammation is associated with the NLRP3 inflammasome signal pathway. Based on these investigations, we propose that 8b might be a potential drug candidate for ultimate development of the anti-inflammation drug.