A synthetic method for diversification of the P1′ substituent in phosphinic dipeptides as a tool for exploration of the specificity of the S1′ binding pockets of leucine aminopeptidases

A novel, general, and versatile method of diversification of the P1′ position in phosphinic pseudodipeptides, presumable inhibitors of proteolytic enzymes, was elaborated. The procedure was based on parallel derivatization of the amino group in the suitably protected phosphinate building blocks with...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry Vol. 15; no. 9; pp. 3187 - 3200
Main Authors:	Vassiliou, Stamatia, Xeilari, Metaxia, Yiotakis, Athanasios, Grembecka, Jolanta, Pawełczak, Małgorzata, Kafarski, Paweł, Mucha, Artur
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 01-05-2007 Elsevier Science
Subjects:	Alkylation Analytical, structural and metabolic biochemistry Binding Sites Biological and medical sciences Cross-coupling Dipeptides - chemical synthesis Dipeptides - chemistry Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Hydrogen Bonding Hydrolases LAP inhibitors Leucyl Aminopeptidase - chemistry Ligands Medical sciences Miscellaneous Models, Molecular Molecular Structure P1′ diversification Pharmacology. Drug treatments Phosphinic Acids - chemical synthesis Phosphinic Acids - chemistry Phosphinic pseudodipeptides Stereoisomerism Structure-Activity Relationship LAP inhibitors Cross-coupling Phosphinic pseudodipeptides P1′ diversification Alkylation Phosphinic acids Leucyl aminopeptidase Active site Selectivity Modeling PI' diversification Structure activity relation Molecular model Binding mode Chemical synthesis Enzyme Aminopeptidases Phosphopeptide Enzyme inhibitor Inhibitor enzyme complex In vitro Pseudopeptide Peptidases Dipeptides Hydrolases Hydrogen bond
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Summary:	A novel, general, and versatile method of diversification of the P1′ position in phosphinic pseudodipeptides, presumable inhibitors of proteolytic enzymes, was elaborated. The procedure was based on parallel derivatization of the amino group in the suitably protected phosphinate building blocks with appropriate alkyl and aryl halides. This synthetic strategy represents an original approach to phosphinic dipeptide chemistry. Its usefulness was confirmed by obtaining a series of P1′ modified phosphinic dipeptides, inhibitors of cytosolic leucine aminopeptidase, through computer-aided design basing on the structure of homophenylalanyl-phenylalanine analogue (hPheP[CH 2]Phe) bound in the enzyme active site as a lead structure. In this approach novel interactions between inhibitor P1′ fragment and the S1′ region of the enzyme, particularly hydrogen bonding involving Asn330 and Asp332 enzyme residues, were predicted. The details of the design, synthesis, and activity evaluation toward cytosolic leucine aminopeptidase and aminopeptidase N are discussed. Although the potency of the lead compound has not been improved, marked selectivity of the synthesized inhibitors toward both studied enzymes was observed.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2007.02.042