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

被引：12

作者：

Honzawa, Shinobu ^{[1
]}

Takahashi, Naoyuki ^{[1
]}

Yamashita, Atsushi ^{[2
]}

Sugiura, Takayuki ^{[2
]}

Kurihara, Masaaki ^{[3
]}

Arai, Midori A. ^{[1
]}

Kato, Shigeaki ^{[4
]}

Kittaka, Atsushi ^{[1
]}

机构：

[1] Teikyo Univ, Fac Pharmaceut Sci, Dept Pharmaceut Chem, Kanagawa 2290195, Japan

[2] Teikyo Univ, Fac Pharmaceut Sci, Dept Hyg Chem & Nutr, Kanagawa 2290195, Japan

[3] Natl Inst Hlth Sci, Tokyo 1588501, Japan

[4] Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo 1130032, Japan

来源：

TETRAHEDRON | 2009年 / 65卷 / 34期

基金：

日本学术振兴会;

关键词：

Vitamin D analogue; Vitamin D receptor; Mutant vitamin D receptor; Structure-function relationships; A-RING; BIOLOGICAL EVALUATION; NUCLEAR RECEPTOR; STEP SYNTHESIS; DESIGN; EFFICIENT; 1-ALPHA; 25-DIHYDROXYVITAMIN-D-3; ANTAGONISTS; AGONISTS; 2-ALPHA-(3-HYDROXYPROPYL);

D O I：

10.1016/j.tet.2009.06.029

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

Vitamin D-3 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 1 alpha-OH of 1 alpha,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, 2 alpha-(3-hydroxypropyl)-1 alpha-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 1 alpha,25-dihydroxyvitamin D-3 (1). (C) 2009 Elsevier Ltd. All rights reserved,

引用

页码：7135 / 7145

页数：11

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