Summers J B, Mazdiyasni H, Holms J H, Ratajczyk J D, Dyer R D, Carter G W
J Med Chem. 1987 Mar;30(3):574-80. doi: 10.1021/jm00386a022.
The hydroxamic acid functionality can be incorporated in a variety of simple molecules to produce potent inhibitors of 5-lipoxygenase. As an example of this, the structure-activity relationships in a series of omega-phenylalkyl and omega-naphthylalkyl hydroxamic acids are presented. Among the features described are the influence of hydrophobicity, aryl substitution, and modifications of the hydroxamate group on enzyme inhibitory potency. To assist in the selection of more potent hydroxamic acid inhibitors, a simple hypothesis about the nature of enzyme-inhibitor binding was devised. In this hypothesis, the structures of compounds were matched to a proposed geometry of arachidonic acid when bound to the enzyme. Compounds that match best without extending into disfavored regions were predicted to be the best inhibitors. Three series of hydroxamates selected according to this approach are described. Within these series are some of the most potent inhibitors of 5-lipoxygenase reported to date.
异羟肟酸官能团可引入多种简单分子中，以制备5-脂氧合酶的强效抑制剂。作为这方面的一个例子，本文介绍了一系列ω-苯基烷基和ω-萘基烷基异羟肟酸的构效关系。所描述的特征包括疏水性、芳基取代以及异羟肟酸基团修饰对酶抑制效力的影响。为了帮助选择更有效的异羟肟酸抑制剂，设计了一个关于酶-抑制剂结合本质的简单假说。在这个假说中，将化合物的结构与花生四烯酸与酶结合时的假定几何结构进行匹配。预测在不延伸至不利区域的情况下匹配最佳的化合物是最佳抑制剂。描述了根据该方法选择的三个异羟肟酸系列。在这些系列中，有一些是迄今为止报道的最有效的5-脂氧合酶抑制剂。
