Highly potent 2-methylene analogs of 1¦Á,25-dihydroxyvitamin D₃: Synthesis and biological evaluation

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• 作者：Izabela K. Sibilska^a ; ^b ; Marcin Szybinski^a ; ^b ; Rafal R. Sicinski^a ; ^b ; Lori A. Plum^a ; Hector F. DeLuca^a ; ^{deluca@biochem.wisc.edu}
• 关键词：Vitamin D analogs ; 2MD ; Vitamin D receptor ; Sonogashira coupling
• 刊名：The Journal of Steroid Biochemistry and Molecular Biology
• 出版年：2013
• 出版时间：July, 2013
• 年：2013
• 卷：136
• 期：Complete
• 页码：9-13
• 全文大小：604 K

文摘

As a continuation of our studies on structure-activity relationship of vitamin D compounds we synthesized new calcitriol analogs characterized by the presence of an exomethylene substituent at C-2. The A-ring dienyne synthon was prepared from commercially available quinic acid by two different synthetic routes, and it was then coupled with the triflate enol derived from the corresponding (20R)- and (20S)-Grundmann ketone by palladium catalyzed Sonogashira reaction.

The obtained 1¦Á,25-dihydroxy-2-methylene-vitamin D₃ analogs, epimeric at C-20, were biologically evaluated by in vitro and in vivo studies. Both isomers exhibited unique activity profiles and greater biological potency than 1¦Á,25-(OH)₂D₃. It was established that the biological profiles of the newly obtained vitamin D compounds depend on the configuration at C-20. Thus, introduction of 2-methylene substituent to the calcitriol molecule together with alteration of stereochemistry of its side chain induces remarkable changes in a VDR-mediated signaling response and enhances biological activity.

This article is part of a Special Issue entitled ¡®Vitamin D Workshop¡¯.