title: Novel 9-Alkyl- and 9-Alkylidene-Substituted 1α,25-Dihydroxyvitamin D3 Analogues: Synthesis and Biological Examinations.
abstract: Continuing the structure-activity relationship studies in the vitamin D area, we designed and synthesized novel C-9 substituted calcitriol analogues, possessing different nonpolar groups at this position. 9α-Methyl-1α,25-(OH)2D3, both epimers of 9-methylene-10,19-dihydro-1α,25-(OH)2D3 as well as the parent vitamin with the "reversed" triene system, 9-methylene-19-nor-1α,25-(OH)2D3, were obtained from the previtamin D precursors, constructed by either Suzuki-Miyaura, Sonogashira, or Stille couplings of the corresponding A- and C,D-ring fragments. An alternative synthetic path, leading to the latter vitamin and its homologue with 9-ethylidene group, involved formation of dienynes as precursors of the respective 19-norprevitamin D compounds. 9β-Methyl-19-nor-1α,25-(OH)2D3 was prepared by homogeneous hydrogenation with Wilkinson catalyst, and this analogue was found to be the most active in vitro. Moreover, 9α-methyl-1α,25-(OH)2D3 and 9-methylene-19-nor-1α,25-(OH)2D3 showed some in vitro activity, however, the in vivo assays indicated only weak calcemic potency of these compounds in the intestinal calcium transport.
authors.affiliation: †Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
authors.forename: Urszula
authors.initials: U
authors.lastname: Kulesza
authors.affiliation: ‡Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, Wisconsin 53706, United States.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Plum
authors.affiliation: ‡Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, Wisconsin 53706, United States.
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
authors.affiliation: §Departamento de Química Orgánica, Laboratorio de Investigación Ignacio Ribas, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mouriño
authors.affiliation: †Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Sicinski
mesh_terms: D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D066298:In Vitro Techniques; D066244:Proton Magnetic Resonance Spectroscopy; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C118756:dihydroxy-vitamin D3; D014807:Vitamin D