Chemical synthesis of 20S-hydroxyvitamin D3, which shows antiproliferative activity
Chemical synthesis of 20S-hydroxyvitamin D3, which shows antiproliferative activity
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DOI：
10.1016/j.steroids.2010.05.021
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发表时间：
2010-12-01
期刊：
影响因子：
2.7
通讯作者：
Slominski, Andrzej
中科院分区：
文献类型：
--
作者：
Li, Wei;Chen, Jianjun;Slominski, Andrzej
20 S-羟基维生素D3（20 S-（OH）D3）是细胞色素P450 SCC代谢维生素D3的体外产物，最近被分离、鉴定并显示具有抗增殖活性，但不会诱导高钙血症。20 S-（OH）D3的酶法生产是繁琐的，昂贵的，并且不能满足广泛的化学和生物学研究的要求。在这里，我们首次报道了20 S-（OH）D3的化学合成，它表现出P450 SCC生成的化合物的生物学特性。具体而言，它被P450 SCC羟基化为20，23-二羟基维生素D3和17，20-二羟基维生素D3，并被CYP 27 B1转化为1 α，20-二羟基维生素03。它抑制人表皮角质形成细胞增殖的效力低于正常人表皮角质形成细胞中的1 α，25-二羟基维生素D3（1，25（OH）2D 3），但在永生化HaCaT角质形成细胞中具有相同的效力。它还以与1，25（OH）2D 3相似的效力刺激VDR基因表达，并刺激外皮蛋白（分化标志物）和CYP 24基因表达，显示后者基因的效力低于1，25（OH）2D 3。用仓鼠黑色素瘤细胞进行的测试证明了与1，25（OH）203相似或更显著的细胞增殖和集落形成能力的剂量依赖性抑制。因此，我们开发了一种化学方法来合成20 S-（OH）D3，这将允许制备一系列20 S-（OH）D3类似物来研究结构-活性关系，以进一步优化这类化合物的治疗用途。(C)2010年爱思唯尔公司All rights reserved.
20S-hydroxyvitamin D3 (20S-(OH)D3), an in vitro product of vitamin D3 metabolism by the cytochrome P450scc, was recently isolated, identified and shown to possess antiproliferative activity without inducing hypercalcemia. The enzymatic production of 20S-(OH)D3 is tedious, expensive, and cannot meet the requirements for extensive chemical and biological studies. Here we report for the first time the chemical synthesis of 20S-(OH)D3 which exhibited biological properties characteristic of the P450scc-generated compound. Specifically, it was hydroxylated to 20,23-dihydroxyvitamin D3 and 17,20-dihydroxyvitamin D3 by P450scc and was converted to 1 alpha,20-dihydroxyvitamin 03 by CYP27B1. It inhibited proliferation of human epidermal keratinocytes with lower potency than 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) in normal epidermal human keratinocytes, but with equal potency in immortalized HaCaT keratinocytes. It also stimulated VDR gene expression with similar potency to 1,25(OH)2D3, and stimulated involucrin (a marker of differentiation) and CYP24 gene expression, showing a lower potency for the latter gene than 1,25(OH)2D3. Testing performed with hamster melanoma cells demonstrated a dose-dependent inhibition of cell proliferation and colony forming capabilities similar or more pronounced than those of 1,25(OH)203. Thus, we have developed a chemical method for the synthesis of 20S-(OH)D3, which will allow the preparation of a series of 20S-(OH)D3 analogs to study structure-activity relationships to further optimize this class of compound for therapeutic use. (C) 2010 Elsevier Inc. All rights reserved.