Studies on the conformation of active form of vitamin D responsible for binding to the receptor and for expression of the activities

为了阐明维生素D与受体（VDR）结合的活性形式的立体化学结构，我们用分子力学方法分析了维生素D的构象，设计并合成了构象受限的维生素D类似物，并测试了它们对VDR的亲和力。1）对1，25（OH）_2D_3（1）及其20-差向异构体（2）的结构分析表明，这些化合物的侧链占据不同的空间区域，并进一步分离为两个区域。2）设计并合成了四个侧链分别占据这四个空间区域的类似物：它们是22-甲基化1，25（OH）_2D_3的C（20）和C（22）的四种非对映体（3，4，5，6）。20 R，22 S-和20 S，22 R-类似物4和5显示出对VDR的显著结合亲和力。结果表明，1，25（OH）_2D_3（1）的A环与VDR的结合主要在这些空间区域进行，而对DBP的结合只有4个空间区域表现出较强的亲和力。5）首次发现了维生素D原分子在C（1）位上的取代基引起的一种新的光化学异构化反应。6）建立了维生素D-SO_2加合物合成19-氟维生素D类似物的方法。

To clarify the stereochemical structure of the active form of vitamin D responsible for binding to the receptor (VDR), we analyzed the conformation of vitamin D by molecular mechanics method, designed and synthesized analogs of vitamin D whose conformations are restricted, and tested their affinity for VDR.1) The analysis of the side chain conformation of 1,25 (OH) _2D_3 (1) and its 20-epi analog (2), showed that the side chains of these compounds occupies different spatial regions that are further separated in two areas.2) Four analogs whose side chain are restricted to occupy each of these four spatial regions were designed and synthesized : They are four diastereomers at C (20) and C (22) of 22-methylated 1,25 (OH) _2D_3 (3,4,5, and 6).3) The affinities of these four analogs for VDR and vitamin D binding protein (DBP) were examined. The 20R,22S-and 20S,22R-analogs 4 and 5 showed significant binding affinity for VDR.It should be noted that especially the potency of 5 was nearly 20 times higher than 1. The results indicate these spatial regions responsible for binding of 1 and 2 to VDR.For DBP only 4 showed significant affinity.4) Analogs of 1,25 (OH) _2D_3 (1) which have a substituent at C (1) were synthesized to investigate the conformation and activity relationship of the A-ring. Introduction of only a methyl group at 1B-position of 1 reduced the affinity to VDR to 1/50 indicating the importance of the 1alpha-hydroxyl group.5) We found for the first time a new photochemical isomerization of provitamin D which is caused by a substituent at C (1).6) The method for synthesizing 19-Fluorovitamin D analogs via vitamin D-SO_2 adduct was developed.