1. Synthesis and biological evaluation of parthenolide derivatives with reduced toxicity as potential inhibitors of the NLRP3 inflammasome
- Author
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Hao Chen, Zhongjin Yang, Ping Sun, Yitao Ou, Dan Wu, Wenhui Hu, and Nannan Wu
- Subjects
Lipopolysaccharides ,Drug ,Cell Survival ,Inflammasomes ,media_common.quotation_subject ,Interleukin-1beta ,Clinical Biochemistry ,Cell ,Anti-Inflammatory Agents ,Pharmaceutical Science ,Inflammation ,Pharmacology ,01 natural sciences ,Biochemistry ,Mice ,chemistry.chemical_compound ,Therapeutic index ,NLR Family, Pyrin Domain-Containing 3 Protein ,Drug Discovery ,medicine ,Animals ,Humans ,Parthenolide ,Cytotoxicity ,Molecular Biology ,IC50 ,Cells, Cultured ,media_common ,010405 organic chemistry ,Organic Chemistry ,Inflammasome ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,chemistry ,Drug Design ,Molecular Medicine ,medicine.symptom ,Neuroglia ,Sesquiterpenes ,Signal Transduction ,medicine.drug - 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.
- Published
- 2020
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