Design, synthesis and X-ray crystallographic study of new nonsecosteroidal vitamin D receptor ligands

被引：18

作者：

Demizu, Yosuke ^{[1
]}

Takahashi, Takeo ^{[1
]}

Kaneko, Fumiya ^{[1
]}

Sato, Yukiko ^{[1
]}

Okuda, Haruhiro ^{[2
]}

Ochiai, Eiji ^{[2
]}

Horie, Kyohei ^{[2
]}

Takagi, Ken-ichiro ^{[2
]}

Kakuda, Shinji ^{[2
]}

Takimoto-Kamimura, Midori ^{[2
]}

Kurihara, Masaaki ^{[1
]}

机构：

[1] Natl Inst Hlth Sci, Div Organ Chem, Setagaya Ku, Tokyo 1588501, Japan

[2] Teijin Pharma Ltd, Teijin Inst Biomed Res, Tokyo 1918512, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 20期

关键词：

Vitamin D receptor; Nonsecosteroidal ligand; X-ray crystallographic analysis; LG190178; MUTANT; VDR;

D O I：

10.1016/j.bmcl.2011.08.047

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We designed and synthesized nonsecosteroidal vitamin D receptor (VDR) ligands that formed H-bonds with six amino acid residues (Tyr143, Ser233, Arg270, Ser274, His301 and His393) of the VDR ligand-binding domain. The ligand YR335 exhibited potent transcriptional activity, which was comparable to those of 1 alpha,25-dihydroxyvitamin D-3 and YR301. The crystal structure of the complex formed between YR335 and the VDR ligand-binding domain was solved, which revealed that YR335 formed H-bonds with the six amino acid residues mentioned above. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：6104 / 6107

页数：4

共 17 条

[1] Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3
Boehm, MF
Fitzgerald, P
Zou, AH
Elgort, MG
Bischoff, ED
Mere, L
Mais, DE
Bissonnette, RP
Heyman, RA
Nadzan, AM
Reichman, M
Allegretto, EA
[J]. CHEMISTRY & BIOLOGY, 1999, 6 (05): : 265 - 275
[2] THE VITAMIN-D STORY - A COLLABORATIVE EFFORT OF BASIC SCIENCE AND CLINICAL MEDICINE
DELUCA, HF
[J]. FASEB JOURNAL, 1988, 2 (03) : 224 - 236
[3] Facile Synthesis of Stereoisomers of the Non-Secosteroidal Ligand LG190178 and their Evaluation Using the Mutant Vitamin D Receptor
Demizu, Yosuke
Nakatsu, Aki
Sato, Yukiko
Honzawa, Shinobu
Yamashita, Atsushi
Sugiura, Takayuki
Kittaka, Atsushi
Kato, Shigeaki
Okuda, Haruhiro
Kurihara, Masaaki
[J]. LETTERS IN ORGANIC CHEMISTRY, 2011, 8 (01) : 43 - 47
[4] Coot:: model-building tools for molecular graphics
Emsley, P
Cowtan, K
[J]. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2004, 60 : 2126 - 2132
[5] Feldman D, 2005, VITAMIN D: VOLS 1 AND 2, 2ND EDITION, P1
[6] NUCLEAR HORMONE RECEPTORS ACTIVATE DIRECT, INVERTED, AND EVERTED REPEATS
FORMAN, BM
EVANS, RM
[J]. STEROID RECEPTORS AND ANTIHORMONES, 1995, 761 : 29 - 37
[7] (2S,2′R)-analogue of LG190178 is a major active isomer
Hakamata, Wataru
Sato, Yukiko
Okudaa, Haruhiro
Honzawa, Shinobu
Saito, Nozomi
Kishimoto, Seishi
Yamashita, Atsushi
Sugiura, Takayuki
Kittaka, Atsushi
Kurihara, Masaaki
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (01) : 120 - 123
[8] Ligands with dual vitamin D3-agonistic and androgen-antagonistic activities
Hosoda, S
Tanatani, A
Wakabayashi, K
Nakano, Y
Miyachi, H
Nagasawa, K
Hashimoto, Y
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (19) : 4327 - 4331
[9] Current understanding of the molecular actions of vitamin D
Jones, G
Strugnell, SA
DeLuca, HF
[J]. PHYSIOLOGICAL REVIEWS, 1998, 78 (04) : 1193 - 1231
[10] Structure of the ligand-binding domain of rat VDR in complex with the nonsecosteroidal vitamin D3 analogue YR301
Kakuda, Shinji
Okada, Kazuhisa
Eguchi, Hiroshi
Takenouchi, Kazuya
Hakamata, Wataru
Kurihara, Masaaki
Takimoto-Kamimura, Midori
[J]. ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS, 2008, 64 : 970 - 973

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