Design, synthesis and evaluation of an NLRP3 inhibitor diazirine photoaffinity probe. Issue 19 (7th May 2020)

• Record Type: Journal Article
• Authors: Hill, James R.; Coll, Rebecca C.; Schroder, Kate; Robertson, Avril A.B.
• Is Part Of: Tetrahedron letters. Volume 61:Issue 19(2020)
• Publication Date: 2020-05-07
• Subjects: NLRP3 inflammasome -- Diazirine -- Photoaffinity -- Sandmeyer; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2020.151849
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: Highlights: Synthesis of TPD-950-Br, a trifluoromethyl phenyl diazirine-analogue of MCC950. TPD-950-Br is a potent NLRP3 inhibitor, IC50 = 164 nM. TPD-950-Br cross-links with methanol when UV irradiated. TPD-950-Br is synthesised via a Sandmeyer-style sulfochlorination. Abstract: The NLRP3 inhibitor MCC950/CRID3 ameliorates a remarkable number of inflammatory disorders in animal models. Herein we describe a trifluoromethyl phenyl diazirine (TPD) photoaffinity probe, called TPD-950-Br, to probe the molecular interactions of MCC950. We show that TPD-950-Br covalently captures proximal species upon photo-activation and inhibits IL-1β production in an NLRP3 inhibitor assay.