Salla Manohar, Butler Mark S, Massey Nicholas L, Reid Janet C, Cooper Matthew A, Robertson Avril A B
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia; Inflazome Ltd., The Tower, Trinity TEC, Pearse Street, Dublin, Ireland.
Bioorg Med Chem Lett. 2018 Feb 15;28(4):793-795. doi: 10.1016/j.bmcl.2017.12.054. Epub 2017 Dec 26.
This study describes the syntheses of di, tetra and hexa deuterated analogues of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome inhibitor MCC950. In di and tetra deuterated analogues, deuteriums were incorporated into the 1,2,3,5,6,7-hexahydro-s-indacene moiety, whereas in the hexa deuterated MCC950 deuteriums were incorporated into the 2-(furan-3-yl)propan-2-ol moiety. The di deuterated MCC950 analogue was synthesised from 4-amino-3,5,6,7-tetrahydro-s-indacen-1(2H)-one 5. Tetra deuterated analogues were synthesised in 10 chemical steps starting with 5-bromo-2,3-dihydro-1H-inden-1-one 9, whereas the hexa deuterated analogue was synthesised in four chemical steps starting with ethyl-3-furoate 24. All of the compounds exhibited similar activity to MCC950 (IC = 8 nM). These deuterated analogues are useful as internal standards in LC-MS analyses of biological samples from in vivo studies.
本研究描述了含NOD样受体吡啉结构域蛋白3（NLRP3）炎性小体抑制剂MCC950的二氘代、四氘代和六氘代类似物的合成。在二氘代和四氘代类似物中，氘原子引入到1,2,3,5,6,7-六氢-s-茚满部分，而在六氘代MCC950中，氘原子引入到2-(呋喃-3-基)丙-2-醇部分。二氘代MCC950类似物由4-氨基-3,5,6,7-四氢-s-茚满-1(2H)-酮5合成。四氘代类似物以5-溴-2,3-二氢-1H-茚-1-酮9为起始原料，经10步化学反应合成，而六氘代类似物以3-呋喃甲酸乙酯24为起始原料，经4步化学反应合成。所有化合物均表现出与MCC950相似的活性（IC = 8 nM）。这些氘代类似物可用作体内研究生物样品LC-MS分析中的内标。
