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 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.
Vassiliou
Stamatia
S
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece.
Xeilari
Metaxia
M
Yiotakis
Athanasios
A
Grembecka
Jolanta
J
Pawełczak
Małgorzata
M
Kafarski
Paweł
P
Mucha
Artur
A
D001665:Binding Sites; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D007931:Leucyl Aminopeptidase / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004151:Dipeptides; D008024:Ligands; D010721:Phosphinic Acids; D007931:Leucyl Aminopeptidase