Odrzywolska M, Chodyński M, Halkes S J, van de Velde J P, Fitak H, Kutner A
Pharmaceutical Research Institute, Warszawa, Poland.
Chirality. 1999;11(3):249-55. doi: 10.1002/(SICI)1520-636X(1999)11:3<249::AID-CHIR12>3.0.CO;2-V.
A series of analogs of 1,25-dihydroxycholecalciferol was obtained with an additional chiral center at the terminus of the aliphatic side chain (C-25). The analogs were obtained from (+)-(R)- and (-)-(S)-2-methylglycidols, by opening of the oxirane ring with the carbanions derived from vitamin D C23a,24- or C22-sulfones. The diastereomeric purity of the analogs was determined by high-performance liquid chromatography on a chiral stationary phase. The binding affinity of analogs for the calf thymus intracellular vitamin D receptor (VDR) was two orders of magnitude lower than that of the lead compound of this group, 24a,24b-dihomo-1,25-dihydroxycholecalciferol, and it was comparable to the affinity of analogs of 24-nor-1,25-dihydroxycholecalciferol. However, a twofold difference was observed for analogs diastereomeric at C-25 in their affinity for VDR. The diastereodifferentiation of the binding affinity was found to be specific for vitamin D vicinal 25,26-diols as it disappears for analogs where 26-hydroxyl, neighboring the C-25 chiral center, is replaced with methyl.
获得了一系列1,25 - 二羟基胆钙化醇类似物，其在脂肪族侧链（C - 25）末端有一个额外的手性中心。这些类似物由(+)-(R)-和(-)-(S)-2 - 甲基缩水甘油通过维生素D C23a,24 - 或C22 - 砜衍生的碳负离子开环环氧乙烷环而制得。类似物的非对映体纯度通过在手性固定相上的高效液相色谱法测定。类似物对小牛胸腺细胞内维生素D受体（VDR）的结合亲和力比该组先导化合物24a,24b - 二高 - 1,25 - 二羟基胆钙化醇低两个数量级，并且与24 - 去甲 - 1,25 - 二羟基胆钙化醇类似物的亲和力相当。然而，在C - 25处非对映异构的类似物对VDR的亲和力存在两倍的差异。发现结合亲和力的非对映体区分对维生素D邻位25,26 - 二醇具有特异性，因为对于其中C - 25手性中心相邻的26 - 羟基被甲基取代的类似物，这种区分消失了。
