Design and synthesis of new caged compounds for lipid mediators

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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.