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

选择性花生四烯酸5-脂氧合酶抑制剂的研制及应用

基本信息

批准号：
59870012
负责人：
YAMAMOTO Shozo
金额：
$ 4.48万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research
财政年份：
1984
资助国家：
日本
起止时间：
1984 至 1985
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-59870012/
关键词：
Leukotriene Anaphylaxy 5-lipoxygenase Flavone Cirsiliol アラキドン酸

项目摘要

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.

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。其中一些激活白细胞功能。其他增强血管渗透性，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-脂氧合酶的反应引发的，因此抑制该酶可以抑制白三烯的产生，并且该抑制剂可以在临床上用于过敏性疾病如支气管哮喘。本课题的目的是寻找5-脂氧合酶的选择性抑制剂，并对其进行衍生化，以获得更有效、更有选择性的抑制剂，并对其体内外效应进行测试，在早期观察到黄芩素和槲皮素等黄酮类化合物抑制过敏性家兔气道阻力增加的基础上，筛选出了一些天然黄酮类化合物，并发现了小蓟醇（3 '，4'，5-三羟基-6，7-二甲氧基黄酮）是5-脂氧合酶的有效抑制剂（IC_（50）> = <micro>0.1M）。抑制12-脂氧合酶需要更高浓度的小蓟醇，而对环氧合酶几乎没有影响。Cirsiliol抑制致敏兔肺碎片中抗原诱导的白三烯释放。将Cirsiliol衍生为更有效和选择性的抑制剂。测试了多种在A环-5或-6位具有不同碳数烷基链的衍生物。含5-10个碳的烷氧基的黄酮衍生物抑制5-脂氧合酶，其<IC_（50）>值约为10 nM。