title: Highly functionalized 2-oxopiperazine-based peptidomimetics: an approach to PAR1 antagonists.
abstract: A series of pseudodipeptide-based chiral 1,3,4,5-tetrasubstituted-2-oxopiperazines has been designed and synthesized as potential PAR1 antagonists. These highly functionalized piperazines were synthesized from aromatic and basic amino acid derived Ψ[CH(CN)NH]pseudodipeptides through a four step pathway that involves reduction of the cyano group to build the 2-oxopiperazine ring, followed by selective functionalization at the N₄-, N₁-positions, and at the exocyclic moiety at position C5. This regioselective functionalization required the fine tuning of reaction conditions. All new compounds were screened as inhibitors of human platelet aggregation induced by the PAR1 agonist SFLLRN and as cytotoxic agents in human cancer cell lines. Some of the compounds displayed moderate PAR1 antagonist activity, while, others were cytotoxic at μM concentration. No correlation was observed between both types of activities.
authors.affiliation: Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Ángel M
authors.initials: ÁM
authors.lastname: Valdivielso
authors.forename: Pilar
authors.initials: P
authors.lastname: Ventosa-Andrés
authors.forename: Francisco
authors.initials: F
authors.lastname: Tato
authors.forename: M Ángeles
authors.initials: MÁ
authors.lastname: Fernández-Ibañez
authors.forename: Ioannis
authors.initials: I
authors.lastname: Pappos
authors.forename: Nikos E
authors.initials: NE
authors.lastname: Tsopanoglou
authors.forename: M Teresa
authors.initials: MT
authors.lastname: García-López
authors.forename: Marta
authors.initials: M
authors.lastname: Gutiérrez-Rodríguez
authors.forename: Rosario
authors.initials: R
authors.lastname: Herranz
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D008968:Molecular Conformation; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D013329:Structure-Activity Relationship; D010975:Platelet Aggregation Inhibitors
chemical_list: D000970:Antineoplastic Agents; D057786:Peptidomimetics; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors
keywords: 2-Oxopiperazines; Cytotoxicity; PAR1 antagonists; Peptidomimetics; Platelet antiaggregant activity; α-Amino nitriles