5-氢过氧-6,8,11,14-二十碳四烯酸类似物的合成及其5-脂氧合酶抑制活性

Synthesis and 5-lipoxygenase inhibitory activity of 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid analogues.

作者信息

Kerdesky F A, Schmidt S P, Holms J H, Dyer R D, Carter G W, Brooks D W

出版信息

J Med Chem. 1987 Jul;30(7):1177-86. doi: 10.1021/jm00390a010.

Abstract

A series of eicosatetraenes (2-24) were designed, synthesized, and evaluated in vitro for inhibitory activity against 5-lipoxygenase (20000g supernatant from homogenized rat basophilic leukemia cells). All compounds were found to be active with the potencies (IC50's) ranging from 0.19 to 97 microM. Compounds containing the hydroxamic acid functionality (10-12) exhibited the best activity (IC50 = 0.19-2.8 microM). The most potent inhibitor was 5-[(hydroxyamino)carbonyl]methyl]-6,8,11,14-eicosatetraenoic acid (11), which was 10 times more active than the C-1 hydroxamates of arachidonic acid or 5-HETE. Cyclization of the linear eicosanoids 2 and 14 in the C-1 to C-5 region produced compounds (21 and 24, respectively) with several-fold greater potency.

摘要

设计、合成了一系列二十碳四烯酸（2 - 24），并在体外评估了它们对5 - 脂氧合酶（来自大鼠嗜碱性白血病细胞匀浆的20000g上清液）的抑制活性。发现所有化合物均具有活性，其效力（IC50）范围为0.19至97 microM。含有异羟肟酸官能团的化合物（10 - 12）表现出最佳活性（IC50 = 0.19 - 2.8 microM）。最有效的抑制剂是5 - [（羟氨基）羰基]甲基]-6,8,11,14 - 二十碳四烯酸（11），其活性比花生四烯酸或5 - HETE的C - 1异羟肟酸酯高10倍。在C - 1至C - 5区域将线性类二十烷酸2和14环化分别产生了活性提高数倍的化合物（分别为21和24）。