Design and synthesis of 2α-(tetrazolylethyl)-1α,25-dihydroxyvitamin D3 as a high affinity ligand for vitamin D receptor

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 144; pp. 201 - 203
• Main Authors: Matsuo, Miki, Hasegawa, Asami, Takano, Masashi, Saito, Hiroshi, Kakuda, Shinji, Takagi, Kenichiro, Ochiai, Eiji, Horie, Kyohei, Takimoto-Kamimura, Midori, Takenouchi, Kazuya, Sawada, Daisuke, Kittaka, Atsushi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2014
• Subjects: 2α-Functionalized vitamin D; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Binding affinity; Bone Neoplasms - drug therapy; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Calcitriol - analogs & derivatives; Calcitriol - chemical synthesis; Calcitriol - pharmacology; Drug Design; Humans; Osteosarcoma - drug therapy; Osteosarcoma - metabolism; Osteosarcoma - pathology; Receptors, Calcitriol - metabolism; Structure-Activity Relationship; Transactivation; Vitamin D receptor; Vitamin D3; Vitamins - chemical synthesis; Vitamins - pharmacology; X-ray cocrystallographic analysis; Vitamin D3; Binding affinity; 2α-Functionalized vitamin D; X-ray cocrystallographic analysis; Transactivation; Vitamin D receptor; Vitamin D
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2013.09.001

•We synthesized 2α-heteroarylethyl active vitamin D3 for SAR study.•The 2α-[2-(tetrazol-2-yl)ethyl] group enhanced transactivation activity.•X-ray cocrystallographic analyses of two hVDR-(new ligand) complexes were performed. 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’.