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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（PUFAs）介导的信号转导已引起越来越多的关注。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这种PUFA介导的信号传导，我们合成了Bhc-笼状PUFA衍生物，花生四烯酸，油酸和亚油酸，发现Bhc-花生四烯酸（Bhc-AA）被光解，量子产率为0.05，总光敏性，量子产率和摩尔吸光系数的乘积约为400。酶促试验表明，BHC-花生四烯酸对环氧合酶-2（考克斯-2）没有残留活性，而COX-2被认为在肿瘤发生中起重要作用，并将AA转化为拟南芥素。此外，在银的作用下，通过在3α-OH上选择性引入2-硝基苄基，合成了4个胆汁酸的光不稳定衍生物。所有衍生物在水溶液中照射（350 nm）后均表现出令人满意的光反应性。3-NB-CA在甲醇中的光解产生了前所未有的稳定的亚硝基半缩醛中间体，其NMR光谱可以在室温下测量。笼胆酸的酶法测定显示，这些化合物将是有用的化学工具，以研究生物过程中，胆汁酸发挥关键作用。