title: Synthesis of 2α- and 2β-(3-hydroxypropyl)- 7,8-cis-14-epi-1α,25-dihydroxy-19-norvitamin D3and their biological activity.
abstract: According to the binding mode of 14-epi-1α,25-dihydroxy-19-nortachysterol in the ligand binding domain of human vitamin D receptor (hVDR), i.e., 5,6- and 7,8-s-trans configuration that was shown by X-ray co-crystallographic analysis, 7,8-cis-locked 1α,25(OH)2D3analogs were synthesized. In this paper, the synthesis and biological activity of 2α- and 2β-(3-hydroxypropyl)-7,8-cis-14-epi-1α,25-dihydroxy-19-norvitamin D3are reported. The A-ring and CD-ring precursors for the Julia-Kociensky coupling reaction to create a diene system of the target molecules were prepared using our original methods. hVDR binding affinity and osteocalcin promoter transactivation activity of the new 7,8-cis-14-epi-vitamin D3analogs were evaluated. Interestingly, the 2β-substituted 7,8-cis-analog was a better binder for hVDR than the 2α-isomeric counterpart.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sawada
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., 4-3-2 Hino, Tokyo 191-8512, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Ochiai
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., 4-3-2 Hino, Tokyo 191-8512, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Takeuchi
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., 4-3-2 Hino, Tokyo 191-8512, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kakuda
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., 4-3-2 Hino, Tokyo 191-8512, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Kamimura-Takimoto
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Kawagoe
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan. Electronic address: akittaka@pharm.teikyo-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
mesh_terms: D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic / Q000379:methods; D006801:Humans; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014815:Vitamins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018167:Receptors, Calcitriol; C579457:VDR protein, human; D014815:Vitamins; C083610:1,25-dihydroxy-19-norvitamin D3; D002117:Calcitriol
keywords: 7,8-cis-19-norvitamin D(3) analog; Synthesis; Transactivation; VDR binding affinity; Vitamin D receptor