title: alpha-Aminoalkylphosphonates as a tool in experimental optimisation of P1 side chain shape of potential inhibitors in S1 pocket of leucine- and neutral aminopeptidases.
abstract: 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.
authors.affiliation: Institute of Organic Chemistry, Biochemistry and Biotechnology, University of Technology, Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland. marcin.drag@pwr.wroc.pl
authors.forename: Marcin
authors.initials: M
authors.lastname: Drag
authors.forename: Jolanta
authors.initials: J
authors.lastname: Grembecka
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Pawełczak
authors.forename: Paweł
authors.initials: P
authors.lastname: Kafarski
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000201:enzymology; D007930:Leucine / Q000737:chemistry*; D007931:Leucyl Aminopeptidase / Q000037:antagonists & inhibitors / Q000737:chemistry; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D063065:Organophosphonates; D000626:Aminopeptidases; D007931:Leucyl Aminopeptidase; D007930:Leucine