Synthesis and conformational analysis of 17alpha,21-cyclo-22-unsaturated analogues of calcitriol.
Six new calcitriol analogues, conformationally restricted at their side chain by the introduction of both a cyclopropane ring at C17-C20 and a double or triple bond at C22, were synthesized using the Wittig-Horner approach to construct the triene system. The six CD-ring and side-chain bearing fragments were prepared from ketone 14 by a divergent route to generate both series of epimers at C20, followed by stereoselective cyclopropanation. The (E)-alkenyl side chain was synthesized by means of a Wittig reaction. The alkynyl side chain was prepared by Corey-Fuchs homologation, followed by alkylation. The (Z)-alkenyl side chain was prepared from the previous alkyne by partial hydrogenation. The 20-epi analogues bind more strongly to VDR than the corresponding analogues with the C20 natural stereochemistry. These results can be reasoned by conformational analysis and hydrophobic interactions with the VDR ligand-binding domain.
Riveiros
Ricardo
R
Departamento de Química Fundamental, Universidad de A Coruña, E-15071 A Coruña, Spain, and Departamento de Química OrgAnica y Unidad Asociada al C.S.I.C., Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain.
Rumbo
Antonio
A
Sarandeses
Luis A
LA
Mouriño
Antonio
A
D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D002417:Cattle; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D018167:Receptors, Calcitriol / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization
D018167:Receptors, Calcitriol; D002117:Calcitriol