title: Highly potent 2-methylene analogs of 1α,25-dihydroxyvitamin D3: synthesis and biological evaluation.
abstract: 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 1α,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 1α,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'.
authors: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
authors: Izabela K
authors: IK
authors: Sibilska
authors: Marcin
authors: M
authors: Szybinski
authors: Rafal R
authors: RR
authors: Sicinski
authors: Lori A
authors: LA
authors: Plum
authors: Hector F
authors: HF
authors: Deluca
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014808:Vitamin D Deficiency / Q000188:drug therapy / Q000378:metabolism
chemical_list: D018167:Receptors, Calcitriol; D002117:Calcitriol