title: Phosphonic pseudopeptides as human neutrophil elastase inhibitors--a combinatorial approach.
abstract: Here we present a simple and rapid method for the construction of phosphonic peptide mimetic inhibitor libraries-products of Ugi and Passerini multicomponent condensations-leading to the selection of new biologically active phosphonic pseudopeptides. As the starting isonitriles, 1-isocyanoalkylphosphonate diaryl ester derivatives were applied. The structure of the synthesized inhibitors was designed to target human neutrophil elastase, a serine protease whose uncontrolled activity may lead to development of several pathophysiological states such as rheumatoid arthritis, cystic fibrosis or tumor growth and invasion. After screening the inhibitory activity of our constructed libraries, the most active compounds were synthesized as single molecules. One of the obtained inhibitors, Cbz-Met-O-Met-Val(P)(OC(6)H(4)-p-Cl)(2), displayed apparent second-order inhibition value at 40,105M(-1)s(-1) as the diastereomers mixture. Inhibition potency and selectivity of action toward other serine proteases as well as the results of initial in vitro experiments regarding inhibitors influence on cancer cell proliferation are presented.
authors.affiliation: Division of Medicinal Chemistry and Microbiology, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland. marcin.sienczyk@pwr.wroc.pl
authors.forename: Marcin
authors.initials: M
authors.lastname: Sieńczyk
authors.forename: Dawid
authors.initials: D
authors.lastname: Podgórski
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Błażejewska
authors.forename: Julita
authors.initials: J
authors.lastname: Kulbacka
authors.forename: Jolanta
authors.initials: J
authors.lastname: Saczko
authors.forename: Józef
authors.initials: J
authors.lastname: Oleksyszyn
mesh_terms: D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D005347:Fibroblasts; D005881:Gingiva / Q000166:cytology; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D063065:Organophosphonates / Q000032:analysis / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism; D057057:Serine Proteases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014357:Trypsin / Q000378:metabolism
chemical_list: D063065:Organophosphonates; D053491:Proteinase Inhibitory Proteins, Secretory; D015842:Serine Proteinase Inhibitors; D057057:Serine Proteases; D012697:Serine Endopeptidases; D002918:Chymotrypsin; D019272:Leukocyte Elastase; D014357:Trypsin