Synthesis of docosahexaenoic acid derivatives designed as novel PPARγ agonists and antidiabetic agents
Synthesis of docosahexaenoic acid derivatives designed as novel PPARγ agonists and antidiabetic agents
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DOI：
10.1016/j.bmc.2005.07.074
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发表时间：
2006-01-01
影响因子：
3.5
通讯作者：
Yamamoto, K
中科院分区：
文献类型：
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作者：
Itoh, T;Murota, I;Yamamoto, K
为了发现新的过氧化物酶体增殖体激活受体γ (PPAR γ)激动剂，我们设计了二十二碳六酸（DHA）衍生物（2和3），它们在PPAR γ的配体结合袋的晶体结构的C(4)位置具有亲水性取代基。这些化合物是通过碘乳酸作为关键中间体合成的。我们发现，两种DHA衍生物（2和3）的PPAR γ转激活高于或与吡格列酮相当，吡格列酮是一种用作抗糖尿病药的TZD衍生物。并合成了与这些强效化合物2和3相关的DHA衍生物，以研究其构效关系。此外，4-OH - DHA 2表现出较强的PPAR γ转录活性，以光学纯形式分离。(c) 2005 Elsevier Ltd版权所有。
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.