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Studies on the synthesis, conformational analysis, and biological activity of active vitamin D analogs in the purpose of developing therapeutic agent with selective activity

研究活性维生素D类似物的合成、构象分析和生物活性，以开发具有选择性活性的治疗剂

基本信息

批准号：
04671289
负责人：
YMADA Sachiko
金额：
$ 0.9万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

项目摘要

(1) Syntheses and biological activity of active vitamin D_3 side chain analogs :Active vitamin D_3 analogs alkylated at the 22-position were designed and synthesized to study the stereochemical structures required to bind to the receptor (VDR) for the active vitamin D_3 and to serum vitamin D binding protein (DBP). (22R)-and(22S)-Methylated analogs were synthesized via kinetically controlled conjugate addition of Me_2CuLi to (22E)-and (22Z)-22-en-24-one as the key step. Only the 22S-methyl analog mimicked the activities of the active vitamin D_3. The results suggest that the side chain conformation of the active viramin D_3 best fitted to VDR and DBP is the same 17-20-22-23 anti form. Additional eight 22-substituted active vitamin D analogs who are diastereomers at C(20) and C(22) were synthesized by using the same synthetic strategy. Conformational analysis and biological activity of these analogs provided an insight into the spatial arrangement of vitamin D side chain esponsible for the activities.(2) Syntheses and biological activity of 1-substituted active vitamin D_3 analogs :To study the A-ring conformation responsible for the activity of the active vitamin D_3, various 1beta-substituted 1alpha, 25-dihydroxyvitamin D_3 derivatives were synthesized via two routes. In the method 1, synthesis was started with readily available C(22)-steroid. The method 2 used 1-oxoprevitamin D as the starting material which gave predominantly (64%) 1beta-R-1alpha-hydroxy previtamin D on treatment with RLi. Interestignly the introduction of a methyl group at the 1beta-position masked almost completely the action of 1-alpha hydroxyl group.

(1)活性维生素D_3侧链类似物的合成及生物活性：设计并合成了22位烷基化的活性维生素D_3类似物，以研究其与活性维生素D_3受体（VDR）和血清维生素D结合蛋白（DBP）结合所需的立体化学结构。通过动力学控制Me_2CuLi与（22 E）-和（22 Z）-22-烯-24-酮的共轭加成反应合成了（22 R）-和（22 S）-甲基化类似物。只有22 S-甲基类似物模拟活性维生素D_3的活性。结果表明，活性病毒蛋白D_3的侧链构象与VDR和DBP的最佳拟合形式相同，为17-20-22-23反式。通过使用相同的合成策略合成了另外八种在C（20）和C（22）处为非对映体的22-取代的活性维生素D类似物。构象分析和生物活性的这些类似物提供了一个洞察的维生素D侧链的空间排列的活动。(2)1-取代维生素D_3类似物的合成及生物活性研究：为了研究维生素D_3活性的A环构象，通过两条路线合成了不同的1 β-取代1 α，25-二羟基维生素D_3衍生物。在方法1中，合成从容易获得的C（22）-类固醇开始。方法2使用1-氧代前维生素D作为起始原料，用RLi处理后主要产生（64%）1 β-R-1 α-羟基前维生素D。有趣的是，在1 β-位引入甲基几乎完全掩盖了1 α-羟基的作用。