Synthesis and biological evaluation of parthenolide derivatives with reduced toxicity as potential inhibitors of the NLRP3 inflammasome

[Display omitted] 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.