Synthesis and biological activity of cyclopropyl Δ7-dafachronic acids as DAF-12 receptor ligands
Synthesis and biological activity of cyclopropyl Δ7-dafachronic acids as DAF-12 receptor ligands
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DOI：
10.1039/d1ob00912e
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发表时间：
2021-05-26
影响因子：
3.2
通讯作者：
Gioiello, Antimo
中科院分区：
文献类型：
--
作者：
Mancino, Valentina;Ceccarelli, Giada;Gioiello, Antimo
从胆汁酸猪去氧胆酸中制备了Delta 7-dafachronic酸的四种环丙基立体异构体，并将其用作化学工具，以利用羧基尾部和C25-甲基的取向和空间布置对于结合在β-12受体上的重要性。合成路线基于（a）瓦尔登转化和立体选择性PtO 2-氢化，以将L形5 β-胆甾类支架转化为平面5 α-甾醇中间体;（B）通过Wittig和环丙烷化反应进行侧链的两碳同系化;以及（c）形成3-酮基和Δ 7双键。分离合成的异构体，并通过AlphaScreen测定法测试其作为α-12配体的活性。结果显示，与母体内源性配体相比，所有四种立体异构体的效力和功效显著损失。计算分析已经证明了羧酸和C25-甲基基团的dafachronic酸的构型和构象排列作为α-12结合和活化的关键结构决定因素。
The four cyclopropyl stereoisomers of Delta 7-dafachronic acids were prepared from the bile acid hyodeoxycholic acid and employed as chemical tools to exploit the importance of the orientation and spatial disposition of the carboxyl tail and the C25-methyl group for the binding at the DAF-12 receptor. The synthesis route was based on (a) Walden inversion and stereoselective PtO2-hydrogenation to convert the L-shaped 5 beta-cholanoid scaffold into the planar 5 alpha-sterol intermediate; (b) two-carbon homologation of the side chain by Wittig and cyclopropanation reaction; and (c) formation of the 3-keto group and Delta 7 double bond. The synthesized isomers were isolated and tested for their activity as DAF-12 ligands by AlphaScreen assays. Results showed a significant loss of potency and efficacy for all the four stereoisomers when compared to the parent endogenous ligand. Computational analysis has evidenced the configurational and conformational arrangement of both the carboxylic and the C25-methyl group of dafachronic acids as key structural determinants for DAF-12 binding and activation.