Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
Faculty of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland.
Biomolecules. 2020 Sep 14;10(9):1319. doi: 10.3390/biom10091319.
A library of novel phosphonic acid analogues of homophenylalanine and phenylalanine, containing fluorine and bromine atoms in the phenyl ring, have been synthesized. Their inhibitory properties against two important alanine aminopeptidases, of human (hAPN, CD13) and porcine (pAPN) origin, were evaluated. Enzymatic studies and comparison with literature data indicated the higher inhibitory potential of the homophenylalanine over phenylalanine derivatives towards both enzymes. Their inhibition constants were in the submicromolar range for hAPN and the micromolar range for pAPN, with 1-amino-3-(3-fluorophenyl) propylphosphonic acid (compound ) being one of the best low-molecular inhibitors of both enzymes. To the best of our knowledge, P1 homophenylalanine analogues are the most active inhibitors of the APN among phosphonic and phosphinic derivatives described in the literature. Therefore, they constitute interesting building blocks for the further design of chemically more complex inhibitors. Based on molecular modeling simulations and SAR (structure-activity relationship) analysis, the optimal architecture of enzyme-inhibitor complexes for hAPN and pAPN were determined.
已经合成了一系列新型的苯膦酸同型苯丙氨酸和苯丙氨酸类似物，它们的苯环中含有氟原子和溴原子。评估了它们对两种重要的丙氨酸氨肽酶（人源（hAPN，CD13）和猪源（pAPN））的抑制特性。酶学研究和与文献数据的比较表明，同型苯丙氨酸衍生物对两种酶的抑制潜力均高于苯丙氨酸衍生物。它们对 hAPN 的抑制常数在亚微摩尔范围内，对 pAPN 的抑制常数在微摩尔范围内，其中 1-氨基-3-（3-氟苯基）丙基膦酸（化合物）是两种酶的最佳低分子量抑制剂之一。据我们所知，在文献中描述的 APN 的膦酸和膦酸衍生物中，P1 同型苯丙氨酸类似物是最活跃的 APN 抑制剂。因此，它们是进一步设计化学结构更复杂抑制剂的有趣构建模块。基于分子建模模拟和 SAR（构效关系）分析，确定了 hAPN 和 pAPN 酶-抑制剂复合物的最佳结构。
