Synthesis and characterization of 20-hydroxyvitamin D3 with the A-ring modification
Synthesis and characterization of 20-hydroxyvitamin D3 with the A-ring modification
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A环修饰20-羟基维生素D3的合成与表征
DOI：
10.1016/j.jsbmb.2018.10.019
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
b Kentaro Yamaguchi
中科院分区：
文献类型：
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作者：
Toshie Fujishima,a; Tsutomu Suenaga,a Masatoshi Kawahata;b Kentaro Yamaguchi
采用会聚法合成了两个具有a环修饰的新型20-羟基维生素d3类似物（4a,b）。据报道，通过细胞色素P450scc CYP11A1代谢维生素D3的另一途径可提供20-羟基维生素D3(3)，其功能仍有待探索。基于20羟基代谢物的结构，设计了新的类似物（4a,b），包括1α-羟基，25-羟基和2α-甲基。通过Grignard反应引入必需cd环部分（9a,b）的侧链作为关键步骤，合成中间体（8b）的x射线晶体结构分析证实了C20位置的立体化学。利用牛胸腺维生素D受体的初步生物学表征表明，将活性基序引入20-羟基维生素d3支架可提高受体的亲和力。
Two novel 20-hydroxyvitamin D3analogues (4a,b) with the A-ring modification have been synthesized by a convergent manner. An alternative pathway of vitamin D3metabolism by cytochrome P450scc CYP11A1 was reported to afford 20-hydroxyvitamin D3(3), functions of which remain to be explored. Based on the structure of the 20-hydroxy metabolite, novel analogues (4a,b) with the modifications, including the 1α-hydroxy, 25-hydroxy and 2α-methyl groups, have been designed. The side chain of the requisite CD-ring portions (9a,b) was introduced by Grignard reaction as a key step, and the stereochemistry at the C20 position was confirmed by the X-ray crystal structure analysis of the synthetic intermediate (8b). Preliminary biological characterization using the bovine thymus vitamin D receptor suggested that the introduction of the active motifs into the 20-hydroxyvitamin D3scaffold elevated the receptor affinity.