Summers J B, Kim K H, Mazdiyasni H, Holms J H, Ratajczyk J D, Stewart A O, Dyer R D, Carter G W
Immunosciences Research and Computer Assisted Molecular Design Areas, Abbott Laboratories, Illinois 60064.
J Med Chem. 1990 Mar;33(3):992-8. doi: 10.1021/jm00165a017.
An evaluation of the quantitative structure-activity relationships (QSAR) for more than 100 hydroxamic acids revealed that the primary physicochemical feature influencing the in vitro 5-lipoxygenase inhibitory potencies of these compounds is the hydrophobicity of the molecule. A significant correlation was observed between the octanol-water partition coefficient of the substituent attached to the carbonyl of the hydroxamate and in vitro inhibitory activity. This correlation held for hydroxamic acids of diverse structure and with potencies spanning 4 orders of magnitude. Although the hydrophobicity may be packaged in a variety of structural ways and still correlate with potency, the QSAR study revealed two major exceptions. Specifically, the hydrophobicity of portions of compounds in the immediate vicinity of the hydroxamic acid functionality does not appear to contribute to increased inhibition and the hydrophobicity of fragments beyond approximately 12 A from the hydroxamate do not influence potency. The QSAR study also demonstrated that inhibitory activity was enhanced when there was an alkyl group on the hydroxamate nitrogen, when electron-withdrawing substituents were present and when the hydroxamate was conjugated to an aromatic system. These observations provide a simple description of the lipoxygenase-hydroxamic acid binding site.
对100多种异羟肟酸的定量构效关系（QSAR）评估显示，影响这些化合物体外5-脂氧合酶抑制效力的主要物理化学特征是分子的疏水性。在连接到异羟肟酸羰基的取代基的正辛醇-水分配系数与体外抑制活性之间观察到显著相关性。这种相关性适用于结构多样、效力跨越4个数量级的异羟肟酸。尽管疏水性可能以多种结构方式呈现且仍与效力相关，但QSAR研究揭示了两个主要例外。具体而言，异羟肟酸官能团紧邻区域内化合物部分的疏水性似乎不会导致抑制作用增强，且距离异羟肟酸约12 Å以外片段的疏水性不会影响效力。QSAR研究还表明，当异羟肟酸氮上有烷基、存在吸电子取代基以及异羟肟酸与芳香体系共轭时，抑制活性会增强。这些观察结果为脂氧合酶-异羟肟酸结合位点提供了一个简单描述。
