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 journalArticle

9 Citations (Scopus)

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)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
Volume144
Issue numberPART A
DOIs
Publication statusPublished - 2014
Externally publishedYes

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Calcitriol Receptors
Calcitriol
Ligands
Hydrogen
Hydrogen bonds
X-Rays
Ergocalciferols
Osteocalcin
X ray analysis
Osteosarcoma
Bioactivity
Human Activities
Vitamin D
Functional groups
Transcriptional Activation
Nitrogen
Hormones
Education
X rays
Atoms

Keywords

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

ASJC Scopus subject areas

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

Cite this

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

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 144, No. PART A, 2014, p. 201-203.

Research output: Contribution to journalArticle

Matsuo, M, Hasegawa, A, Takano, M, Saito, H, Kakuda, S, Takagi, K, Ochiai, E, Horie, K, Takimoto-Kamimura, M, Takenouchi, K, Sawada, D & Kittaka, A 2014, 'Design and synthesis of 2α-(tetrazolylethyl)-1α,25- dihydroxyvitamin D3 as a high affinity ligand for vitamin D receptor', Journal of Steroid Biochemistry and Molecular Biology, vol. 144, no. PART A, pp. 201-203. https://doi.org/10.1016/j.jsbmb.2013.09.001
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. / Design and synthesis of 2α-(tetrazolylethyl)-1α,25- dihydroxyvitamin D3 as a high affinity ligand for vitamin D receptor. In: Journal of Steroid Biochemistry and Molecular Biology. 2014 ; Vol. 144, No. PART A. pp. 201-203.
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AU - Hasegawa, Asami

AU - Takano, Masashi

AU - Saito, Hiroshi

AU - Kakuda, Shinji

AU - Takagi, Kenichiro

AU - Ochiai, Eiji

AU - Horie, Kyohei

AU - Takimoto-Kamimura, Midori

AU - Takenouchi, Kazuya

AU - Sawada, Daisuke

AU - Kittaka, Atsushi

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AB - 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'.

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