Design and synthesis of new caged compounds for lipid mediators

脂质介质新型笼状化合物的设计与合成

基本信息

批准号：
13640545
负责人：
FURUTA Toshiaki
金额：
$ 1.92万
依托单位：
Toho University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

Signaling mediated by polyunsaturated fatty acids (PUFAs) has been attracted growing interests. Arachidonic acid (AA) is an essential polyunsaturated fatty acid, and is metabolized to prostaglandins and leukotrienes. To develop a chemical tool to investigate the signaling mediated by such PUFAs, we synthesized Bhc-caged derivatives of PUFAs, arachidonic acid, oleic acid and linoleic acid and found that Bhc-arachidonic acid (Bhc-AA) was photolyzed with quantum yield of 0.05 and overall photosensitivity, the product of quantum yield and molar absorptivity, of about 400. Enzymatic test reveals that Bhc-arachidonic acid has no residual activity against cyclooxygenase-2 (COX-2) which is believed to play important role in carcinogenesis and converts AA to prostaglandins. Furthermore, the enzymatic activity against COX-2 was restored after photo-irradiation (350nm), which also confirms the release of parent arachidonic acid.Furthermore, four photolabile derivatives of bile acids were synthesized through the silver oxide-mediated selective introduction of a 2-nitrobenzyl group to 3α-OH. All of the derivatives showed satisfactory photoreactivity upon irradiation (350 nm) in aqueous solution. Photolysis of 3-NB-CA in methanol produced an unprecedentedly stable nitroso-hemiacetal intermediate whose NMR spectrum could be measured at room temperature. Enzymatic assays of the caged cholic acids revealed that these compounds would be useful as chemical tools to investigate biological processed in which bile acids play key roles.

多不饱和脂肪酸 (PUFA) 介导的信号引起了越来越多的兴趣，花生四烯酸 (AA) 是一种必需的多不饱和脂肪酸，可代谢为前列腺素和白三烯。为了开发一种化学工具来研究此类 PUFA 介导的信号。合成了 PUFA、花生四烯酸、油酸和亚油酸的 Bhc 笼状衍生物，并发现Bhc-花生四烯酸 (Bhc-AA) 被光解，量子产率为 0.05，总光敏度（量子产率与摩尔吸收率的乘积）约为 400。酶测试表明，Bhc-花生四烯酸对环氧化酶-2 无残留活性（ COX-2）被认为在致癌作用中发挥着重要作用，并将 AA 转化为前列腺素。光照射（350nm）后恢复了对COX-2的抵抗力，这也证实了母体花生四烯酸的释放。此外，通过氧化银介导的2-硝基苄基选择性引入到3α上合成了四种对光不稳定的胆汁酸衍生物。 -OH。所有衍生物在甲醇水溶液中的照射（350 nm）下均表现出令人满意的光反应性。产生了一种前所未有的稳定的亚硝基半缩醛中间体，其核磁共振谱可以在室温下测量笼状胆酸的酶分析表明，这些化合物可用作生物加工的化学工具，其中胆汁酸起着关键作用。