Abstract
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 15c) 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.
Highlights
Zinc-dependent mammalian neutral aminopeptidases (APN/CD13) are considered pivotal targets for treatment diseases, characterized by their overexpression
In this paper we describe series of phosphonic acid analogues of homophenylalanine and phenylalanine fluorinated and brominated in aromatic ring
We evaluated their inhibitory activities towards two aminopeptidases: human and porcine
Summary
Zinc-dependent mammalian neutral aminopeptidases (APN/CD13) are considered pivotal targets for treatment diseases, characterized by their overexpression. In this paper we describe series of phosphonic acid analogues of homophenylalanine and phenylalanine fluorinated and brominated in aromatic ring. We evaluated their inhibitory activities towards two aminopeptidases: human (hAPN, CD13) and porcine (pAPN). Development of the new targeted compounds is in-online with scanning low-molecular sets of compounds of similar structure as the first step to rational search for new building blocks for potential drugs. This method is enforced by computer-aided studies, by means molecular docking simulations. The crystallographic structures of the pAPN and hAPN have been characterized [3,11] and the molecular modeling was used for better understanding of structural preferences for effective inhibition
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