Development and application of a selective inhibitor of arachidonate 5-lipoxygenase

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Leukotrienes are produced from arachidonic acid, and released from the cells in anaphylactic reactions. Some of them activate the leukocyte functions. Others enhance vascular permeability, and constrict bronchi and intestines. The leukotrienes are considered as chemical mediatros of anaphylaxy. Since the biosynthesis of leukotrienes is initiated by the reaction of 5-lipoxygenase, the inhibition of this enzyme can suppress the leukotriene production, and the inhibitor may be clinically useful for anaphylactic diseases like bronchial asthma. The purposes of this research project are to search for selective inhibitors of 5lipoxygenase, to derivatize them for more potent and selective inhibitors and to test their in vitro and in vivo effects.On the basis of an earlier observation that flavonoids like baicalein and quercetin suppressed the increase in airway resistence in anaphylaxy of rabbit, we screened a number of natural flavones and found cirsiliol (3',4',5-trihydroxy6,7-dimethoxyflavone) to be a potent inhibitor of 5-lipoxygenase ( <IC_(50)> =0.1 <micro> M). A much higher concentration of cirsiliol was required for inhibition of 12lipoxygenase, and cyclooxygenase was hardly affected. Cirsiliol inhibited the antigen-induced release of leukotrienes in the lung fragments of sensitized rabbit. Cirsiliol was derivatized for more potent and selective inhibitors. A variety of derivatives with alkyl chain of various carbon numbers at position-5 or -6 of the A ring were tested. Flavone derivatives with an alkyloxy group of 5-10 carbons inhibited 5-lipoxygenase with lower <IC_(50)> values in the order of 10 nM.