title: Design and synthesis of 2α-(tetrazolylethyl)-1α,25-dihydroxyvitamin D3 as a high affinity ligand for vitamin D receptor.
abstract: X-ray cocrystallographic studies of the human vitamin D receptor (hVDR)-[2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (O1C3)] complex showed that the terminal hydroxy group of the 2α-functional group of O1C3 formed a hydrogen bond with Arg274 in the ligand binding domain (LBD) of hVDR to stabilize the complex; therefore, O1C3 showed 3-times greater binding affinity for VDR than the natural hormone. Here, the effects of a heteroaromatic ring on binding to hVDR instead of the terminal OH group of O1C3 and also on preliminary biological activities were studied. We synthesized 2α-[2-(tetrazol-2-yl)ethyl]-1α,25(OH)2D3 (1a) and its regioisomer 2α-[2-(tetrazol-1-yl)ethyl]-1α,25(OH)2D3 (1b), in which 1a showed much higher hVDR binding affinity and greater osteocalcin promoter transactivation activity in human osteosarcoma (HOS) cells than those of 1b. X-ray cocrystallographic analysis of the hVDR-1a complex showed new hydrogen bond formation between one of the nitrogen atoms of the tetrazole ring and Arg274. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Matsuo
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Asami
authors.initials: A
authors.lastname: Hasegawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takano
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saito
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., 4-3-2 Asahigaoka, 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 Asahigaoka, Hino, Tokyo 191-8512, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Takagi
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., 4-3-2 Asahigaoka, 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 Asahigaoka, Hino, Tokyo 191-8512, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Horie
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Takimoto-Kamimura
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd., 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takenouchi
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: 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: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014815:Vitamins / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: C000592666:2-(2-(tetrazol-2-yl)ethyl)-1,25-dihydroxyvitamin D3; D000970:Antineoplastic Agents; D018167:Receptors, Calcitriol; D014815:Vitamins; D002117:Calcitriol
keywords: 2α-Functionalized vitamin D; Binding affinity; Transactivation; Vitamin D receptor; Vitamin D(3); X-ray cocrystallographic analysis