Smart Brian P, Pan Ying H, Weeks Amanda K, Bollinger James G, Bahnson Brian J, Gelb Michael H
Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA 98195, USA.
Bioorg Med Chem. 2004 Apr 1;12(7):1737-49. doi: 10.1016/j.bmc.2004.01.022.
Structure-guided design was employed in a search for potent and selective inhibitors of mammalian secreted phospholipases A(2) (sPLA(2)s). Using the X-ray structures of human groups IIA and X sPLA(2)s (hGIIA and hGX) as templates, homology structural models were made for the other human and mouse sPLA(2)s (hGIB, mGIB, mGIIA, mGIIC, hGIID, mGIID, hGIIE, mGIIE, hGIIF, mGIIF, hGV, mGV, and mGX). Me-Indoxam is a previously discovered indole analogue that binds tightly to many sPLA(2)s, and the X-ray structure of the hGX-Me-Indoxam complex was determined at a resolution of 2.0 A. Modeling suggests that the residues near the N(1)-substituent of Me-Indoxam vary significantly among the mammalian sPLA(2)s, and therefore a library of 83N(1)-variants was prepared by parallel synthesis. Several Me-Indoxam analogues bearing a 4-(2-oxy-ethanoic acid) side chain were potent inhibitors (IC(50) <0.05 microM) of hGIIA, mGIIA, mGIIC, hGIIE, mGIIE, hGV, and mGV, while they displayed intermediate potency (0.05-5 microM) against hGIB, mGIB, hGX, and mGX, and poorly inhibited (>5 microM) hGIID, mGIID, hGIIF, and mGIIF. Me-Indoxam analogues bearing a 5-(4-oxy-butanoic acid) side chain were generally less potent inhibitors. Although no compounds were found to be highly specific for a single human or mouse sPLA(2), combinations of Me-Indoxam analogues were discovered that could be used to distinguish the action of various sPLA(2)s in cellular events. For example, Me-Indoxam and compound 5 are approximately 5-fold more potent on hGIIA than on hGV, and compound 21 is 10-fold more potent on hGV versus hGIIA.
采用结构导向设计来寻找哺乳动物分泌型磷脂酶A2（sPLA(2)s）的强效和选择性抑制剂。以人IIA组和X组sPLA(2)s（hGIIA和hGX）的X射线结构为模板，构建了其他人和小鼠sPLA(2)s（hGIB、mGIB、mGIIA、mGIIC、hGIID、mGIID、hGIIE、mGIIE、hGIIF、mGIIF、hGV、mGV和mGX）的同源结构模型。甲吲酰胺是一种先前发现的吲哚类似物，它能与多种sPLA(2)s紧密结合，hGX-甲吲酰胺复合物的X射线结构在2.0 Å分辨率下得以确定。建模表明，甲吲酰胺N(1)取代基附近的残基在哺乳动物sPLA(2)s之间有显著差异，因此通过平行合成制备了一个包含83种N(1)变体的文库。几种带有4-(2-氧代-乙酸)侧链的甲吲酰胺类似物是hGIIA、mGIIA、mGIIC、hGIIE、mGIIE、hGV和mGV的强效抑制剂（IC(50)<0.05 μM），而它们对hGIB、mGIB、hGX和mGX表现出中等效力（0.05 - 5 μM），对hGIID、mGIID、hGIIF和mGIIF的抑制作用较弱（>5 μM）。带有5-(4-氧代-丁酸)侧链的甲吲酰胺类似物通常是效力较低的抑制剂。尽管没有发现对单一人类或小鼠sPLA(2)具有高度特异性的化合物，但发现了甲吲酰胺类似物的组合，可用于区分各种sPLA(2)s在细胞事件中的作用。例如，甲吲酰胺和化合物5对hGIIA的效力比对hGV高约5倍，化合物21对hGV的效力比对hGIIA高10倍。
