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

(1)活性维生素D_3侧链类似物的合成及生物活性：设计合成22位烷基化的活性维生素D_3类似物，研究活性维生素D_3与受体（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（22E）和(22Z)-22-en-24-one的共轭加成，合成了（22R）和(22S)-甲基化类似物。只有22s -甲基类似物模拟了活性维生素D_3的活性。结果表明，活性维生素D_3最适合VDR和DBP的侧链构象为相同的17-20-22-23抗形式。采用相同的合成策略，合成了另外8个22取代的活性维生素D类似物，它们是C（20）和C（22）的非对映体。这些类似物的构象分析和生物活性提供了对负责活性的维生素D侧链的空间排列的洞察。(2) 1-取代的活性维生素D_3类似物的合成及其生物活性：为了研究活性维生素D_3活性的a环构象，通过两种途径合成了多种1-取代的1- α， 25-二羟基维生素D_3衍生物。在方法1中，从容易获得的C(22)-类固醇开始合成。方法2以1-氧原维生素D为起始原料，经RLi处理后，主要产生（64%）1- β - r -1 α -羟基原维生素D。有趣的是，在1-位置引入甲基几乎完全掩盖了1-羟基的作用。

(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.