Gorins G, Kuhnert L, Johnson C R, Marnett L J
Department of Chemistry, Wayne State University, Detroit, Michigan 48202-3489, USA.
J Med Chem. 1996 Dec 6;39(25):4871-8. doi: 10.1021/jm9606047.
A series of (carboxyalkyl)benzyl propargyl ethers was synthesized and tested as inhibitors of 12-lipoxygenase (12-LO) from porcine leukocyte cytosol. Optimum activity was displayed by 3-[4-[(2-tridecynyloxy)methyl]phenyl]propanoic acid. Altering the length of the alkyl side chain attached to the acetylenic group reduced activity. Changing the substitution pattern in the (carboxyalkyl)benzyl group from para to meta or ortho also reduced activity. Analogs in which the triple bond was replaced by a double bond or an allene displayed reduced activity, whereas fully saturated analogs were inactive. High concentrations (10 microM) of the most potent acetylenic (carboxylalkyl)benzyl ethers did not inhibit human platelet 12-LO, human neutrophil 5-LO, rabbit reticulocyte 15-LO, or soybean 15-LO. Thus, this class of compounds represents the first example of isoform specific LO inhibitors.
合成了一系列（羧基烷基）苄基炔丙基醚，并作为猪白细胞胞质溶胶中12-脂氧合酶（12-LO）的抑制剂进行了测试。3-[4-[(2-十三炔氧基)甲基]苯基]丙酸表现出最佳活性。改变连接在炔基上的烷基侧链长度会降低活性。将（羧基烷基）苄基中的取代模式从对位变为间位或邻位也会降低活性。其中三键被双键或丙二烯取代的类似物活性降低，而完全饱和的类似物则无活性。高浓度（10 microM）的最有效的炔属（羧基烷基）苄基醚不抑制人血小板12-LO、人中性粒细胞5-LO、兔网织红细胞15-LO或大豆15-LO。因此，这类化合物代表了同工型特异性LO抑制剂的首个实例。
