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

白三烯是由花生四烯酸产生的，在过敏反应中从细胞中释放出来。其中一些激活了白细胞的功能。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症的化学中间体。由于白三烯的生物合成是由5-脂氧合酶的反应启动的，因此抑制该酶可以抑制白三烯的产生，该抑制剂可能用于治疗过敏性疾病，如哮喘。本研究的目的是寻找5-脂氧合酶的选择性抑制剂，并对其进行衍生化，以期得到更有效、更有选择性的抑制剂，并测试它们的体内外效应。在早期观察到黄芩素和槲皮素等黄酮类化合物抑制兔过敏性呼吸道阻力增加的基础上，我们筛选了几种天然黄酮类化合物，发现其为5-脂氧合酶(&lt；IC_(50)&gt；=0.1&lt；Micro&gt；M)的有效抑制剂。抑制12脂氧合酶需要更高浓度的环氧合酶，而环氧合酶几乎不受影响。Cirsiliol抑制抗原诱导的致敏兔肺碎片中白三烯的释放。Cirsiliol被衍生为更有效和更有选择性的抑制剂。测试了在A环的-5或-6位具有不同碳数的烷基链的各种衍生物。含烷氧基5-10个碳的黄酮衍生物对5-脂氧合酶的抑制作用较小，约为10 nM；IC_(50)&gt；

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.