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

doi:10.1016/j.jsbmb.2013.09.001

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 journal › Review article › peer-review

10 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 language	English
Pages (from-to)	201-203
Number of pages	3
Journal	Journal of Steroid Biochemistry and Molecular Biology
Volume	144
Issue number	PART A
DOIs	https://doi.org/10.1016/j.jsbmb.2013.09.001
Publication status	Published - Oct 2014
Externally published	Yes

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jsbmb.2013.09.001

Cite this

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, 144(PART A), 201-203. https://doi.org/10.1016/j.jsbmb.2013.09.001

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

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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)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'.",

keywords = "2α-Functionalized vitamin D, Binding affinity, Transactivation, Vitamin D receptor, X-ray cocrystallographic analysis",

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

note = "Funding Information: This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (Nos. 23790021 and 25860011 to M.T.) as well as a Grant-in-Aid from the Japan Society for the Promotion of Science (No. 24590021 to A.K.).",

year = "2014",

month = oct,

doi = "10.1016/j.jsbmb.2013.09.001",

language = "English",

volume = "144",

pages = "201--203",

journal = "Journal of Steroid Biochemistry and Molecular Biology",

issn = "0960-0760",

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TY - JOUR

T1 - Design and synthesis of 2α-(tetrazolylethyl)-1α,25- dihydroxyvitamin D3 as a high affinity ligand for vitamin D receptor

AU - Matsuo, Miki

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

N1 - Funding Information: This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (Nos. 23790021 and 25860011 to M.T.) as well as a Grant-in-Aid from the Japan Society for the Promotion of Science (No. 24590021 to A.K.).

PY - 2014/10

Y1 - 2014/10

N2 - 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'.

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'.

KW - 2α-Functionalized vitamin D

KW - Binding affinity

KW - Transactivation

KW - Vitamin D receptor

KW - X-ray cocrystallographic analysis

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DO - 10.1016/j.jsbmb.2013.09.001

M3 - Review article

C2 - 24036313

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SN - 0960-0760

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JO - Journal of Steroid Biochemistry and Molecular Biology

JF - Journal of Steroid Biochemistry and Molecular Biology

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