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

Miki Matsuo, Asami Hasegawa, Masashi Takano, Hiroshi Saito, Shinji Kakuda, Kenichiro Takagi, Eiji Ochiai, Kyohei Horie, Midori Takimoto-Kamimura, Kazuya Takenouchi, Daisuke Sawada, Atsushi Kittaka

Research output: Contribution to journalReview articlepeer-review

10 Citations (Scopus)


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)2D 3 (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'.

Original languageEnglish
Pages (from-to)201-203
Number of pages3
JournalJournal of Steroid Biochemistry and Molecular Biology
Issue numberPART A
Publication statusPublished - Oct 2014
Externally publishedYes


  • 2α-Functionalized vitamin D
  • Binding affinity
  • Transactivation
  • Vitamin D receptor
  • X-ray cocrystallographic analysis

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology


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