Highly potent 2-methylene analogs of 1 alpha,25-dihydroxyvitamin D-3: Synthesis and biological evaluation

作者：Sibilska Izabela K; Szybinski Marcin; Sicinski Rafal R; Plum Lori A; DeLuca Hector F^*

来源：Journal of Steroid Biochemistry and Molecular Biology, 2013, 136: 9-13.

DOI：10.1016/j.jsbmb.2013.02.001

• Vitamin D analogs
• 2MD
• Vitamin D receptor
• Sonogashira coupling

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. %26lt;br%26gt;The obtained 1 alpha,25-dihydroxy-2-methylene-vitamin D-3 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 alpha,25-(OH)(2)D-3. 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. %26lt;br%26gt;This article is part of a Special Issue entitled %26apos;Vitamin D Workshop%26apos;.

• 出版日期2013-7