Design and efficient synthesis of 2α-(ω-hydroxyalkoxy)-1α,25-dihydroxyvitamin D3 analogues, including 2-epi-ED-71 and their 20-epimers with HL-60 cell differentiation activity
Design and efficient synthesis of 2α-(ω-hydroxyalkoxy)-1α,25-dihydroxyvitamin D3 analogues, including 2-epi-ED-71 and their 20-epimers with HL-60 cell differentiation activity
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DOI：
10.1021/jo0491051
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发表时间：
2004-10-29
影响因子：
3.6
通讯作者：
Kittaka, A
中科院分区：
文献类型：
--
作者：
Saito, N;Suhara, Y;Kittaka, A
以d -葡萄糖为手性模板，构建了一种简洁高效的2 α -（omega-羟基烷氧基）-1 α，25-二羟基维生素D-3 （4a-c）的合成方法，包括2-epi-ED-71。发现该系列中牛胸腺维生素D受体（VDR）的最佳配体为4b，其与牛胸腺维生素D受体（VDR）的结合亲和力是天然激素1的1.8倍。有趣的是，尽管4a-c对VDR具有很强的结合亲和力，但其诱导HL-60细胞分化的效力几乎与1相同或更弱。接下来，我们对基于4a-c和c20 -外映化的1的“双重修饰”感兴趣，得到2 α -（ω -羟基烷氧基）-20-epi-1 α，25-二羟基维生素D-3 （20-epi-4a-c）。1的3个2 α取代的20-epi类似物（20-epi-4a-c）对VDR均表现出较强的结合亲和力，并通过分子模型分析了它们在VDR配体结合域的构象。双修饰的20-epi-4a-c类似物显示出明显的HL-60细胞分化活性，20-epi-4a的活性比天然激素高58倍。
A concise and efficient synthetic approach to 2alpha-(omega-hydroxyalkoxy)-1alpha,25-dihydroxyvitamin D-3 (4a-c), including 2-epi-ED-71, was developed starting from D-glucose as a chiral template for the construction of the 2alpha-modified A-ring precursors (11a-c). It was found that the best ligand for the bovine thymus vitamin D receptor (VDR) in this series is 4b, which has 1.8 times greater binding affinity for the bovine thymus VDR than that of the natural hormone 1. Interestingly, potency in the induction of HL-60 cell differentiation for 4a-c was almost the same or weaker than that of 1 despite the strong binding affinity for the VDR. Next, we were interested in the "double modification" of 1 based on 4a-c with C20-epimerization, affording 2alpha-(omega-hydroxyalkoxy)-20-epi-1alpha,25-dihydroxyvitamin D-3 (20-epi-4a-c). All three 2alpha-substituted 20-epi analogues of 1 (20-epi-4a-c) exhibited stronger binding affinities for the VDR, and their conformations in the ligand binding domain of VDR were analyzed by molecular modeling. Double-modified analogues of 20-epi-4a-c showed marked HL-60 cell differentiation activity, and 20-epi-4a possesses an activity 58-fold higher than that of the natural hormone 1.