A Methylene Group on C-2 of 24,24-Difluoro-19-nor-1α,25-dihydroxyvitamin D3 Markedly Increases Bone Calcium Mobilization in Vivo

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• 作者：Agnieszka Flores ; Ilaria Massarelli ; James B. Thoden ; Lori A. Plum ; Hector F. DeLuca
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：December 24, 2015
• 年：2015
• 卷：58
• 期：24
• 页码：9731-9741
• 全文大小：702K
• ISSN：1520-4804

文摘

Four side chain fluorinated analogues of 1α,25-dihydroxy-19-norvitamin D have been prepared in convergent syntheses using the Wittig–Horner reaction as a key step. Structures and absolute configurations of analogues <b>3b> and <b>5b> were confirmed by X-ray crystallography. All analogues showed high potency in HL-60 cell differentiation and vitamin D-24-hydroxylase (24-OHase) transcription as compared to 1α,25-dihydroxyvitamin Db>3b> (<b>1b>). Most important is that all of the 20S-configured derivatives (<b>4b> and <b>6b>) had high bone mobilizing activity in vivo. However, in the 20R series, a 2-methylene group was required for high bone mobilizing activity. A change in positioning of the 20R molecule in the vitamin D receptor when the 2-methylene group is present may provide new insight into the molecular basis of bone calcium mobilization induced by vitamin D.