Ewelina Węglarz-Tomczak1, Łukasz Berlicki1, Małgorzata Pawełczak2, Bogusław Nocek3, Andrzej Joachimiak3, Artur Mucha4. 1. Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland. 2. Institute of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland. 3. Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, USA. 4. Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland. Electronic address: artur.mucha@pwr.edu.pl.
Abstract
N'-substituted 1,2-diaminoethylphosphonic acids and 1,2-diaminoethylphosphinic dipeptides were explored to unveil the structural context of the unexpected selectivity of these inhibitors of M1 alanine aminopeptidases (APNs) versus M17 leucine aminopeptidase (LAP). The diaminophosphonic acids were obtained via aziridines in an improved synthetic procedure that was further expanded for the phosphinic pseudodipeptide system. The inhibitory activity, measured for three M1 and one M17 metalloaminopeptidases of different sources (bacterial, human and porcine), revealed several potent compounds (e.g., Ki = 65 nM of 1u for HsAPN). Two structures of an M1 representative (APN from Neisseria meningitidis) in complex with N-benzyl-1,2-diaminoethylphosphonic acid and N-cyclohexyl-1,2-diaminoethylphosphonic acid were determined by the X-ray crystallography. The analysis of these structures and the models of the phosphonic acid complexes of the human ortholog provided an insight into the role of the additional amino group and the hydrophobic substituents of the ligands within the S1 active site region.
n class="Chemical">N'-substituted 1,2-diaminoethylphosphonic acids and n class="Chemical">1,2-diaminoethylphosphinic dipeptides were explored to unveil the structural context of the unexpected selectivity of these inhibitors of M1 alanine aminopeptidases (APNs) versus M17 leucine aminopeptidase (LAP). The diaminophosphonic acids were obtained via aziridines in an improved synthetic procedure that was further expanded for the phosphinic pseudodipeptide system. The inhibitory activity, measured for three M1 and one M17 metalloaminopeptidases of different sources (bacterial, human and porcine), revealed several potent compounds (e.g., Ki = 65 nM of 1u for HsAPN). Two structures of an M1 representative (APN from Neisseria meningitidis) in complex with N-benzyl-1,2-diaminoethylphosphonic acid and N-cyclohexyl-1,2-diaminoethylphosphonic acid were determined by the X-ray crystallography. The analysis of these structures and the models of the phosphonic acidcomplexes of the human ortholog provided an insight into the role of the additional amino group and the hydrophobic substituents of the ligands within the S1 active site region.
Authors: Tina S Skinner-Adams; Colin M Stack; Katharine R Trenholme; Chris L Brown; Jolanta Grembecka; Jonathan Lowther; Artur Mucha; Marcin Drag; Pawel Kafarski; Sheena McGowan; James C Whisstock; Donald L Gardiner; John P Dalton Journal: Trends Biochem Sci Date: 2009-09-30 Impact factor: 13.807
Authors: Isel Pascual; Pedro A Valiente; Gabriela García; Mario E Valdés-Tresanco; Yarini Arrebola; Lisset Díaz; Lotfi Bounaadja; Rosa María Uribe; Mae Chappé Pacheco; Isabelle Florent; Jean-Louis Charli Journal: Biochimie Date: 2017-09-28 Impact factor: 4.079