title: Diphenyl phosphonate inhibitors for the urokinase-type plasminogen activator: optimization of the P4 position.
abstract: This paper describes the structure-activity relationship in a series of tripeptidyl diphenyl phosphonate irreversible urokinase plasminogen activator (uPA) inhibitors, originally derived from an arginyltripeptide. uPA is considered an interesting target in anticancer drug design. The selectivity of these inhibitors for uPA is enhanced by the optimization of the P4 position. The most interesting compound shows an IC(50) of 5 nM, with a selectivity index of more than 3000 toward other Arg/Lys-specific proteases such as tissue-type plasminogen activator, plasmin, factor Xa, and thrombin. A synthetic strategy for the preparation of small libraries of diphenyl phosphonate analogues of capped tripeptides is described. It is shown that uPA is irreversibly inhibited, and interactions with the active site were modeled. Finally, a diparacetamol phosphonate analogue was developed to circumvent the release of cytotoxic phenol.
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, BE-2610 Antwerp, Belgium.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
authors.forename: Georgiana
authors.initials: G
authors.lastname: Surpateanu
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lambeir
authors.forename: Ibrahim
authors.initials: I
authors.lastname: El-Sayed
authors.forename: Omar M
authors.initials: OM
authors.lastname: Ali
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.forename: Achiel
authors.initials: A
authors.lastname: Haemers
mesh_terms: D000818:Animals; D001665:Binding Sites; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D009842:Oligopeptides; D063065:Organophosphonates; D014568:Urokinase-Type Plasminogen Activator