Sicinski R R, DeLuca H F
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, 53706, USA.
Bioorg Med Chem. 1999 Dec;7(12):2877-89. doi: 10.1016/s0968-0896(99)00249-7.
Construction of 25-hydroxy-steroidal side chain substituted with iodine at C-22 was elaborated on a model PTAD-protected steroidal 5,7-diene and applied to a synthesis of (22R)- and (22S)-22-iodo-1alpha,25-dihydroxyvitamin D3. Configuration at C-22 in the iodinated vitamins, obtained by nucleophilic substitution of the corresponding 22S-tosylates with sodium iodide, was determined by comparison of their iodine-displacement processes and cyclizations leading to isomeric five-membered (22,25)-epoxy-1alpha-hydroxyvitamin D3 compounds. Also, 20(22)-dehydrosteroids have been obtained and their structures established by 1H NMR spectroscopy. When compared to the natural hormone, (E)-20(22)-dehydro-1alpha,25-dihydroxyvitamin D3 was found 4 times less potent in binding to the porcine intestinal vitamin D receptor (VDR) and 2 times less effective in differentiation of HL-60 cells. 22-Iodinated vitamin D analogues showed somewhat lower in vitro activity, whereas (22,25)-epoxy analogues were inactive. Interestingly, it was established that (22S)-22-iodo-1alpha,25-dihydroxyvitamin D3 was 3 times more potent than its (22R)-isomer in binding to VDR and four times more effective in HL-60 cell differentiation assay. The restricted mobility of the side chain of both 22-iodinated vitamin D compounds was analyzed by a systematic conformational search indicating different spatial regions occupied by their 25-oxygen atoms. Preliminary data on the in vivo calcemic activity of the synthesized vitamin D analogues indicate that (E)-20(22)-dehydro-1alpha,25-dihydroxyvitamin D3 and 22-iodo-1alpha,25-dihydroxyvitamin D3 isomers were ca. ten times less potent than the natural hormone 1alpha,25-(OH)2D3 both in intestinal calcium transport and bone calcium mobilization.
在一个经PTAD保护的甾体5,7 - 二烯模型上阐述了在C - 22位被碘取代的25 - 羟基甾体侧链的构建，并将其应用于(22R)-和(22S)-22 - 碘-1α,25 - 二羟基维生素D3的合成。通过用碘化钠对相应的22S - 甲苯磺酸盐进行亲核取代得到的碘化维生素中C - 22位的构型，是通过比较它们的碘取代过程和环化反应来确定的，这些反应会生成异构的五元(22,25)-环氧-1α - 羟基维生素D3化合物。此外，还获得了20(22)-脱氢甾体，并通过1H NMR光谱确定了它们的结构。与天然激素相比，发现(E)-20(22)-脱氢-1α,25 - 二羟基维生素D3与猪肠道维生素D受体(VDR)结合的能力低4倍，在HL - 60细胞分化中的效果低2倍。22 - 碘化维生素D类似物在体外活性略低，而(22,25)-环氧类似物无活性。有趣的是，已确定(22S)-22 - 碘-1α,25 - 二羟基维生素D3在与VDR结合时比其(22R)-异构体强3倍，在HL - 60细胞分化试验中效果强4倍。通过系统的构象搜索分析了两种22 - 碘化维生素D化合物侧链的受限流动性，表明它们的25 - 氧原子占据不同的空间区域。合成的维生素D类似物体内血钙活性的初步数据表明，(E)-20(22)-脱氢-1α,25 - 二羟基维生素D3和22 - 碘-1α,25 - 二羟基维生素D3异构体在肠道钙转运和骨钙动员方面的效力均比天然激素1α,25-(OH)2D3低约10倍。
