Synthesis of docosahexaenoic acid derivatives designed as novel PPARγ agonists and antidiabetic agents

被引:38
作者
Itoh, T
Murota, I
Yoshikai, K
Yamada, S
Yamamoto, K
机构
[1] Tokyo Med & Dent Univ, Inst Biomat & Bioengn, Chiyoda Ku, Tokyo 1010062, Japan
[2] Maruha Corp, Cent Res Inst, Tsukuba, Ibaraki 3004295, Japan
关键词
PPAR gamma agonist; docosahexaenoic acid; antidiabetic agent; lodolactonization;
D O I
10.1016/j.bmc.2005.07.074
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
To discover novel peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists that Could be used as antidiabetic agents, we designed docosahexacnoic acid (DHA) derivatives (2 and 3), which have a hydrophilic substituent at the C(4)-position, based on the crystal structure of the ligand-binding pocket of PPAR gamma. These compounds were synthesized via iodolactolic as a key intermediate. We found that both DHA derivatives (2 and 3) showed PPAR gamma transactivation higher than, or comparable to, that of pioglitazone, which is a TZD derivative used as an antidiabetic agent. DHA derivatives related to these potent Compounds 2 and 3 were also synthesized to study structure-activity relationships. Furthermore, 4-OH DHA 2, which shows strong PPAR gamma transcriptional activity, was separated as an optically pure form. (c) 2005 Elsevier Ltd. All rights reserved.
引用
收藏
页码:98 / 108
页数:11
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