Removal of the 26-Methyl Group from 19-nor-1α,25-Dihydroxyvitamin D3 Markedly Reduces in Vivo Calcemic Activity without Altering in Vitro VDR Binding, HL-60 Cell Differentiation, and T

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• 作者：Pawel Grzywacz ; Grazia Chiellini ; Lori A. Plum ; Margaret Clagett-Dame ; Hector F. DeLuca
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：December 23, 2010
• 年：2010
• 卷：53
• 期：24
• 页码：8642-8649
• 全文大小：941K
• 年卷期：v.53,no.24(December 23, 2010)
• ISSN：1520-4804

文摘

Twelve new analogues of 19-nor-1α,25-dihydroxyvitamin D₃ (5−16) were prepared by convergent syntheses, employing the Wittig−Horner reaction. The necessary Grundmann type ketones (45−48), possessing fixed configurations of the hydroxyl group at C-25, were obtained by a multistep procedure from commercial vitamin D₂ and enantiomers of 1,3-butanediol (23 and 24). We have examined the influence of removal of one of the methyl groups located at C-25 on the biological in vitro and in vivo activity. The in vivo tests showed that the synthesized vitamin D compounds (5−16) exhibit reduced calcemic activity both in bone and in the intestine. However, in vitro potency of 2-methylene and 2α-methyl compounds (5−10, 13, and 14) remained similar or enhanced as compared to that of 1α,25-(OH)₂D₃.