Rai R, Katzenellenbogen J A
Department of Chemistry, University of Illinois, Urbana 61801.
J Med Chem. 1992 Oct 30;35(22):4150-9. doi: 10.1021/jm00100a021.
We have synthesized four guanidinophenyl-substituted protio enol and iodo enol lactones (3-(4-guanidinophenyl)-6-methylidenetetrahydro-2-pyranone (1), 3-(4-guanidinophenyl)-6-(E)-(iodomethylidene)tetrahydro-2-pyran one (2), 4-(4-guanidinophenyl)-6-methylidenetetrahydro-2-pyranone+ ++ (3), and 4-(4-guanidinophenyl)-6-(E)-(iodomethylidene)tetrahydro-2-pyran one (4)) and tested them for inhibitory activity against some trypsin-like enzymes, namely trypsin, urokinase, tissue plasminogen activator (t-PA), plasmin, and thrombin, as well as alpha-chymotrypsin and human neutrophil elastase (HNE). The beta-aryl-substituted protio lactone 3 was a potent alternate substrate inhibitor of trypsin and urokinase. The alpha-aryl-substituted iodo lactone 2 was a permanent inactivator of urokinase, plasmin, t-PA, thrombin, and alpha-chymotrypsin, exhibiting a relatively high specificity for the former two enzymes. In general, these compounds showed a preference for inactivating trypsin-like enzymes over alpha-chymotrypsin and HNE. Also, within the class of trypsin-like enzymes, there was generally good selectivity of inhibition.
我们合成了四种胍基苯基取代的原烯醇内酯和碘代烯醇内酯（3-(4-胍基苯基)-6-亚甲基四氢-2-吡喃酮(1)、3-(4-胍基苯基)-6-(E)-(碘亚甲基)四氢-2-吡喃酮(2)、4-(4-胍基苯基)-6-亚甲基四氢-2-吡喃酮(3)和4-(4-胍基苯基)-6-(E)-(碘亚甲基)四氢-2-吡喃酮(4)），并测试了它们对一些类胰蛋白酶的抑制活性，即胰蛋白酶、尿激酶、组织型纤溶酶原激活剂(t-PA)、纤溶酶和凝血酶，以及α-糜蛋白酶和人中性粒细胞弹性蛋白酶(HNE)。β-芳基取代的原烯醇内酯3是胰蛋白酶和尿激酶的有效替代底物抑制剂。α-芳基取代的碘代内酯2是尿激酶、纤溶酶、t-PA、凝血酶和α-糜蛋白酶的永久性失活剂，对前两种酶表现出相对较高的特异性。一般来说，这些化合物对失活类胰蛋白酶的偏好高于α-糜蛋白酶和HNE。此外，在类胰蛋白酶中，通常具有良好的抑制选择性。
