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

白三烯由花生四烯酸产生，并在过敏反应中从细胞中释放出来。其中一些激活白细胞功能。另一些则增强血管通透性，收缩支气管和肠道。白三烯被认为是过敏反应的化学介质。由于白三烯的生物合成是由5-脂氧合酶的反应启动的，抑制该酶可以抑制白三烯的产生，该抑制剂在临床上可能对支气管哮喘等过敏性疾病有用。本研究项目的目的是寻找5脂氧合酶的选择性抑制剂，衍生出更有效的选择性抑制剂，并测试其体外和体内效果。在早期黄芩素、槲皮素等黄酮类化合物抑制兔过敏反应气道阻力增加的基础上，我们筛选了一些天然黄酮类化合物，发现千里油（3',4'，5-三羟基6,7-二甲氧基黄酮）是一种有效的5-脂氧合酶抑制剂（<IC_(50)> =0.1 <micro> M）。对12脂加氧酶的抑制作用需要较高浓度的纤毛醇，而对环加氧酶的抑制作用几乎不受影响。千禧年醇抑制抗原诱导的白三烯在致敏兔肺碎片中的释放。千禧年醇衍生出更有效和选择性的抑制剂。在A环的-5或-6位置上具有不同碳数的烷基链的各种衍生物进行了测试。含有5-10个碳烷基氧基的黄酮衍生物对5-脂氧合酶的抑制作用在10 nM量级，IC_(50)>值较低。

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.