New vitamin D3 derivatives with unexpected antiproliferative activity: 1-(hydroxymethyl)-25-hydroxyvitamin D3 homologs.
New vitamin D3 derivatives with unexpected antiproliferative activity: 1-(hydroxymethyl)-25-hydroxyvitamin D3 homologs.
复制标题
具有意想不到的抗增殖活性的新型维生素 D3 衍生物：1-(羟甲基)-25-羟基维生素 D3 同系物。
DOI：
10.1021/jm00095a026
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发表时间：
1992
影响因子：
7.3
通讯作者：
Kensler,TW
中科院分区：
文献类型：
--
作者：
Posner,GH;Nelson,TD;Guyton,KZ;Kensler,TW
令人惊讶的是，合成的1-（羟甲基）-25-羟基维生素D3非对映异构体（-）-2和（+）-3都保留了天然骨化三醇在鼠角质形成细胞中的抗增殖活性。然而，初步研究表明，这两种合成的非对映异构体对于结合1，25-（OH）2-D3受体的有效性小于骨化三醇的0.1%，并且它们对于器官培养的鸡胚十二指肠中的钙结合蛋白-D ^ K诱导的有效性小于骨化三醇的0.1%。通过将对映体纯的C，D-环酮12与高度对映体富集的A-环氧化膦（-）-IIa和（+）-IIb组合，以会聚方式合成1-（羟甲基）-25-羟基维生素D3同系物（-）-2和（+）-3。这些A环手性化合物是由3-溴-2-吡喃酮和丙烯醛经热[2+ 4]环加成反应合成的，其代谢产物1a，25-二羟基维生素D3（calcitriol，1）除了调节磷代谢、肠钙吸收（伊卡）和骨钙动员（BMT）外，还具有促进细胞分化和抑制细胞增殖的作用。1钙柠檬三醇也影响人体免疫系统。[2]骨化三醇和一些合成维生素D_3衍生物最近已用于临床化疗，治疗骨质疏松症、癌症、免疫缺陷综合征、皮肤病皮炎和银屑病等多种疾病。[3]在埃塞俄比亚[4]和制药工业[5]的研究人员中，一个主要的国际目标仍然是制备维生素D3类似物作为新药，其中促钙活性与细胞生长调节有效分离。为了实现这一目标，已经合成并评价了200多种骨化三醇类似物。其中，所有领先的候选药物在环A中具有共同的骨化三醇的羟基取代基特征;它们主要在连接到甾体框架的环D的侧链中不同。事实上，现在普遍认为，Ia-羟基是所需生物活性所必需的。6已经制备了各种缺乏-羟基的骨化三醇类似物，并且已经发现其生物活性比骨化三醇低得多;实例包括1/3-羟基、7-氟、8和1-未官能化的（即，25-羟基维生素D3）。9最近对文献的计算机搜索显示没有已知的骨化三醇的l-（羟烷基）衍生物。
Surprisingly, both of the synthetic l-(hydroxymethyl)-25-hydroxyvitamin D3 diastereomers (—)-2 and (+)-3 retained the antiproliferativeactivity of natural calcitriol in murine keratinocytes. Preliminary studies indicated, however, that both of these synthetic diastereomers were less than 0.1% as effective as calcitriol for binding to the l, 25-(OH) 2-D3 receptor and that they were less them 0.1% as potent as calcitriol for calbindin-D^ K induction in organ-cultured embryonic chick duodenum. l-(Hydroxymethyl)-25-hydroxyvitamin D3 homologs (—)-2 and (+)-3 were synthesized in a convergent manner by combining enantiomerically pure C, D-ring ketone 12 with highly enantiomericallyenriched A-ring phosphineoxides (-)-lla and (+)-llb. These A-ring chirons were prepared starting from thermal [2+ 4] cycloaddition of 3-bromo-2-pyrone and acrolein.In addition to regulatingphosphorus metabolism and intestinal calcium absorption (ICA) as well as bone calcium mobilization (BCM), the hormonally active metabolite la, 25-dihydroxyvitamin D3 (calcitriol, 1) potently promotes cell differentiation and inhibits cell proliferation. 1 Cal-citriol also affects the human immune system. 2 Calcitriol and some synthetic vitamin D3 derivatives have been used recently in practical, clinical chemotherapy of such diverse human illnesses as osteoporosis, cancer, immunodeficiency syndromes, and the skin disorders dermatitis and psoria-sis. 3 A major international objective among researchers in academia4 and in the pharmaceutical industry5 still is to prepare vitamin D3 analogs as new drugs in which calcitropic activity is effectively separated from cell growth regulation. Toward this goal, well over 200 analogs of calcitriol have been synthesized and evaluated. Among these, all of the leading drug candidates have in common in ring-A the-hydroxyl substituent characteristic of calcitriol; they differ mostly in the side chain attached to ring-D of the steriod framework. Indeed, it is now com-monly accepted that the la-hydroxyl group is required for desirable biological activity. 6 Various calcitriol analogs lacking the-hydroxyl group have been prepared and have been found to be much less biologically active than calcitriol; examples include 1/3-hydroxyl, 7-fluoro, 8 and 1-unfunctionalized (ie, 25-hydroxyvitamin D3). 9 A recent computer search of the literature showed no known l-(hydroxyalkyl) derivative of calcitriol.