Drag Marcin, Grembecka Jolanta, Pawełczak Małgorzata, Kafarski Paweł
Institute of Organic Chemistry, Biochemistry and Biotechnology, University of Technology, Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland.
Eur J Med Chem. 2005 Aug;40(8):764-71. doi: 10.1016/j.ejmech.2005.02.011. Epub 2005 Apr 20.
The synthesis and biological activity studies of the series of structurally different alpha-aminoalkylphosphonates were performed in order to optimise the shape of the side chain of the potential inhibitors in S1 pocket of leucine aminopeptidase [E.C.3.4.11.1]. Analysis of a series of compounds with aromatic, aliphatic and alicyclic P1 side chains enabled to find out the structural features, optimal for that fragment of inhibitors of LAP. The most active among all investigated compounds were the phosphonic analogues of homo-tyrosine (K(i)=120 nM) and homo-phenylalanine (K(i)=140 nM), which even as racemic mixtures were better inhibitors in comparison with the best till now-phosphonic analogue of l-leucine (230 nM). Additional comparison of the inhibitory activity obtained for aminopeptidase N (APN, E.C.3.4.11.2) give insight into structural preferences of both enzymes.
为了优化亮氨酸氨肽酶[S1口袋中潜在抑制剂侧链的形状，对一系列结构不同的α-氨基烷基膦酸酯进行了合成和生物活性研究。[E.C.3.4.11.1]。对一系列具有芳香族、脂肪族和脂环族P1侧链的化合物进行分析，从而找出对亮氨酸氨肽酶抑制剂该片段最为理想的结构特征。在所有研究的化合物中，活性最高的是高酪氨酸的膦酸类似物（K(i)=120 nM）和高苯丙氨酸的膦酸类似物（K(i)=140 nM），即使作为外消旋混合物，它们也是比目前最好的L-亮氨酸膦酸类似物（230 nM）更好的抑制剂。对氨肽酶N（APN，E.C.3.4.11.2）的抑制活性进行的额外比较，有助于深入了解这两种酶的结构偏好。
