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Synthesis of deuterium-labelled analogues of NLRP3 inflammasome inhibitor MCC950
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2017-12-26 , DOI: 10.1016/j.bmcl.2017.12.054
Manohar Salla 1 , Mark S Butler 1 , Nicholas L Massey 1 , Janet C Reid 1 , Matthew A Cooper 2 , Avril A B Robertson 1
Affiliation  

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 (IC50 = 8 nM). These deuterated analogues are useful as internal standards in LC-MS analyses of biological samples from in vivo studies.



中文翻译:

NLRP3炎性体抑制剂MCC950的氘标记类似物的合成

本研究描述了 NOD 样受体含有蛋白 3 (NLRP3) 炎症小体抑制剂 MCC950 的二、四和六氘化类似物的合成。在二和四氘代类似物中,氘被掺入到 1,2,3,5,6,7-六氢-s - indacene 部分,而在六氘代 MCC950 中,氘被掺入到 2-(furan-3-yl )丙-2-醇部分。二氘化的 MCC950 类似物是由 4-amino-3,5,6,7-tetrahydro- s -indacen-1(2 H )-one 5合成的。从 5-bromo-2,3-dihydro-1 H -inden-1-one 9开始,通过 10 个化学步骤合成了四氘代类似物,而六氘代类似物是在四个化学步骤中合成的,从 3-糠酸乙酯24 开始。所有化合物都表现出与 MCC950 相似的活性 (IC 50  = 8 nM)。这些氘代类似物可用作来自体内研究的生物样品的 LC-MS 分析中的内标。

更新日期:2017-12-26
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