Synthesis and Biological Activity of N-Sulfonyltripeptides with C-Terminal Arginine as Potential Serine Proteases Inhibitors

Agnieszka Markowska,Magdalena Bruzgo,Arkadiusz Surażyński,Ewa Gorodkiewicz

doi:10.1007/s10989-012-9338-4

Abstract

Tripeptides of the general X-SO2-d-Ser-AA-Arg-CO-Y formula, where X = α-tolyl, p-tolyl, 2,4,6-triisopropylphenyl; AA = alanine, glycine, norvaline and Y = OH, NH-(CH2)5NH2 were obtained and tested for their effect on the amidolytic activities of urokinase, thrombin, trypsin, plasmin, t-PA and kallikrein. The most active compound towards urokinase was PhCH2SO2-d-Ser-Gly-Arg-OH with Ki value 5.4 μM and the most active compound toward thrombin was PhCH2SO2-d-Ser-NVa-Arg-OH with Ki value 0.82 μM. The peptides were nontoxic against porcine erythrocytes in vitro. PhCH2SO2-d-Ser-Gly-Arg-OH showed cytotoxic effect against DLD cell lines with IC50 values of 5 μM. For the highly selective determination of the interaction of some of the synthesised acids of tripeptides with urokinase and plasmin the Surface Plasmon Resonance Imaging sensor has been applied. These compounds bind to urokinase and plasmin in 0.05 mM concentration.

Highlights

The proteolytic degradation of the extracellular matrix is essential for the processes of tissue remodelling
The peptides were nontoxic against porcine erythrocytes in vitro
We examined the interaction of some of the synthesised acids of tripeptides with urokinase and plasmin through a Surface Plasmon Resonance Imaging (SPRI)

Summary

Introduction

The proteolytic degradation of the extracellular matrix is essential for the processes of tissue remodelling. These processes take place in a number of distinct physiological events in the healthy organism such as matrix degradation, cell motility, angiogenesis and wound healing, as well as in the critical mechanisms in tumor invasion and metastasis. The plasminogen activation system has an important role as a proteolytic cascade in these degradation reactions (Irigoyen et al 1999). UPA accumulates plasminogen activation activity at cell surfaces (Ossowski and AguirreGhiso 2000). UPA is the primary cellular activator which converts the pro-enzyme plasminogen into its active form plasmin (Irigoyen et al 1999). Urokinase has become an attractive therapeutic target in a variety of tumor

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