title: Synthesis, biological activity, and conformational analysis of four seco-D-15,19-bisnor-1alpha,25-dihydroxyvitamin D analogues, diastereomeric at C17 and C20.
abstract: The synthesis of four CD-ring-modified 19-nor-1alpha, 25-dihydroxyvitamin D(3) derivatives lacking C15, referred to as 6C analogues, and diastereomeric at C17 and C20 is described. The synthesis involves an Ireland-Claisen rearrangement of a 3-methyl-substituted ester of (1R)-3-methyl-2-cyclohexen-1-ol as the key step, followed by elaboration of the side chain, transformation into a C8 cyclohexanone derivative, and final Wittig-Horner coupling with the 19-nor A-ring phosphine oxide. Despite possessing a more flexible side chain than the parent hormone, biological evaluation showed an unexpected superagonistic antiproliferative and prodifferentiating activity (10-50 times higher as compared to that of 1alpha,25(OH)(2)D(3)) for the diastereomer with the "natural" configuration at C17 and C20. The other diastereomers exhibit a 25-90% decrease in activity. All four analogues show a decreased binding affinity (45% or less), and their calcemic activity is 4-400 times less than that of 1alpha,25(OH)(2)D(3). The conformational behavior of their side chain was studied using molecular mechanics calculations, and the result is presented as volume maps. A relative activity volume was determined by subtraction of the volume map of the least active analogue from the volume map of the most active one. This shows three regions corresponding to preferred orientations in space of the side chain of the active analogue. One of these regions was found to overlap with the region that is preferentially occupied by the most active of the four diastereomeric 22-methyl-substituted 1alpha,25(OH)(2)D(3) analogues.
authors.affiliation: Laboratory for Organic Synthesis, Department of Organic Chemistry, University of Gent, Krijgslaan 281 (S4), B-9000 Gent, Belgium.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.forename: G D
authors.initials: GD
authors.lastname: Zhu
authors.forename: D
authors.initials: D
authors.lastname: Van Haver
authors.forename: M
authors.initials: M
authors.lastname: Vandewalle
authors.forename: P J
authors.initials: PJ
authors.lastname: De Clercq
authors.forename: A
authors.initials: A
authors.lastname: Verstuyf
authors.forename: R
authors.initials: R
authors.lastname: Bouillon
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D018167:Receptors, Calcitriol / Q000378:metabolism; D013237:Stereoisomerism; D013552:Swine; D014407:Tumor Cells, Cultured; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D018167:Receptors, Calcitriol; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D