Synthesis of a 1α-C-methyl analogue of 25-hydroxyvitamin D3: interaction with a mutant vitamin D receptor Arg274Leu

Shinobu Honzawa; Naoyuki Takahashi; Atsushi Yamashita; Takayuki Sugiura; Masaaki Kurihara; Midori A. Arai; Shigeaki Kato; Atsushi Kittaka

doi:10.1016/j.tet.2009.06.029

Synthesis of a 1α-C-methyl analogue of 25-hydroxyvitamin D₃: interaction with a mutant vitamin D receptor Arg274Leu

Shinobu Honzawa, Naoyuki Takahashi, Atsushi Yamashita, Takayuki Sugiura, Masaaki Kurihara, Midori A. Arai, Shigeaki Kato, Atsushi Kittaka

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

Vitamin D₃ analogues have been developed for a mutant vitamin D receptor (VDR), Arg274Leu. The mutant VDR has a mutation at Arg274, which forms an important hydrogen bond with 1α-OH of 1α,25-dihydroxyvitamin D₃ to anchor the ligand tightly in the VDR ligand binding pocket. Stereoselective synthesis of the A-ring part of the novel vitamin D analogue, 2α-(3-hydroxypropyl)-1α-methyl-25-hydroxyvitamin D₃ (4), from d-galactose was accomplished with the key steps of the introduction of the methyl and allyl groups to the chiral building blocks. The new analogue 4 is ca. 7.3-fold more active than the natural hormone 1α,25-dihydroxyvitamin D₃ (1).

Original language	English
Pages (from-to)	7135-7145
Number of pages	11
Journal	Tetrahedron
Volume	65
Issue number	34
DOIs	https://doi.org/10.1016/j.tet.2009.06.029
Publication status	Published - 2009 Aug 22
Externally published	Yes

Keywords

Mutant vitamin D receptor
Structure-function relationships
Vitamin D analogue
Vitamin D receptor

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

Access to Document

10.1016/j.tet.2009.06.029

Cite this

@article{e9609165f64c4cdcbf4bf16d015eef47,

title = "Synthesis of a 1α-C-methyl analogue of 25-hydroxyvitamin D3: interaction with a mutant vitamin D receptor Arg274Leu",

abstract = "Vitamin D3 analogues have been developed for a mutant vitamin D receptor (VDR), Arg274Leu. The mutant VDR has a mutation at Arg274, which forms an important hydrogen bond with 1α-OH of 1α,25-dihydroxyvitamin D3 to anchor the ligand tightly in the VDR ligand binding pocket. Stereoselective synthesis of the A-ring part of the novel vitamin D analogue, 2α-(3-hydroxypropyl)-1α-methyl-25-hydroxyvitamin D3 (4), from d-galactose was accomplished with the key steps of the introduction of the methyl and allyl groups to the chiral building blocks. The new analogue 4 is ca. 7.3-fold more active than the natural hormone 1α,25-dihydroxyvitamin D3 (1).",

keywords = "Mutant vitamin D receptor, Structure-function relationships, Vitamin D analogue, Vitamin D receptor",

author = "Shinobu Honzawa and Naoyuki Takahashi and Atsushi Yamashita and Takayuki Sugiura and Masaaki Kurihara and Arai, {Midori A.} and Shigeaki Kato and Atsushi Kittaka",

note = "Funding Information: We are grateful to Ms. Junko Shimode and Ms. Akiko Tonoki (Teikyo University) for the spectroscopic measurements. This work has been supported in part by Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (#17790095 to S.H.), and by Grant-in-Aid from Japan Society for the Promotion of Science (#17590012 to A.K.). A.K. gratefully acknowledges Uehara Memorial Foundation.",

year = "2009",

month = aug,

day = "22",

doi = "10.1016/j.tet.2009.06.029",

language = "English",

volume = "65",

pages = "7135--7145",

journal = "Tetrahedron",

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T1 - Synthesis of a 1α-C-methyl analogue of 25-hydroxyvitamin D3

T2 - interaction with a mutant vitamin D receptor Arg274Leu

AU - Honzawa, Shinobu

AU - Takahashi, Naoyuki

AU - Yamashita, Atsushi

AU - Sugiura, Takayuki

AU - Kurihara, Masaaki

AU - Arai, Midori A.

AU - Kato, Shigeaki

AU - Kittaka, Atsushi

N1 - Funding Information: We are grateful to Ms. Junko Shimode and Ms. Akiko Tonoki (Teikyo University) for the spectroscopic measurements. This work has been supported in part by Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (#17790095 to S.H.), and by Grant-in-Aid from Japan Society for the Promotion of Science (#17590012 to A.K.). A.K. gratefully acknowledges Uehara Memorial Foundation.

PY - 2009/8/22

Y1 - 2009/8/22

N2 - Vitamin D3 analogues have been developed for a mutant vitamin D receptor (VDR), Arg274Leu. The mutant VDR has a mutation at Arg274, which forms an important hydrogen bond with 1α-OH of 1α,25-dihydroxyvitamin D3 to anchor the ligand tightly in the VDR ligand binding pocket. Stereoselective synthesis of the A-ring part of the novel vitamin D analogue, 2α-(3-hydroxypropyl)-1α-methyl-25-hydroxyvitamin D3 (4), from d-galactose was accomplished with the key steps of the introduction of the methyl and allyl groups to the chiral building blocks. The new analogue 4 is ca. 7.3-fold more active than the natural hormone 1α,25-dihydroxyvitamin D3 (1).

AB - Vitamin D3 analogues have been developed for a mutant vitamin D receptor (VDR), Arg274Leu. The mutant VDR has a mutation at Arg274, which forms an important hydrogen bond with 1α-OH of 1α,25-dihydroxyvitamin D3 to anchor the ligand tightly in the VDR ligand binding pocket. Stereoselective synthesis of the A-ring part of the novel vitamin D analogue, 2α-(3-hydroxypropyl)-1α-methyl-25-hydroxyvitamin D3 (4), from d-galactose was accomplished with the key steps of the introduction of the methyl and allyl groups to the chiral building blocks. The new analogue 4 is ca. 7.3-fold more active than the natural hormone 1α,25-dihydroxyvitamin D3 (1).

KW - Mutant vitamin D receptor

KW - Structure-function relationships

KW - Vitamin D analogue

KW - Vitamin D receptor

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