title: Optimization of peptidomimetic boronates bearing a P3 bicyclic scaffold as proteasome inhibitors.
abstract: A new series of pseudopeptide boronate proteasome inhibitors (2-3) was developed, through optimization of our previously described analogs of bortezomib, bearing a bicyclic 1,6-naphthyridin-5(6H)-one scaffold as P3 fragment (1). The biological evaluation on human 20S proteasome displayed a promising inhibition profile, especially for compounds bearing a P2 ethylene fragment, which exhibited Ki values in the nanomolar range for the ChT-L activity (e.g. 2a, Ki = 0.057 μM) and considerable selectivity for proteasome over bovine pancreatic α-chymotrypsin. Docking experiments into the yeast 20S proteasome revealed that the ligands are accommodated predominantly into the ChT-L site and that they covalently bind to the active site threonine residue via boron atom. Within the cellular assays performed against a 60 cancer cell line panel, compounds 3e and 3f demonstrated also good antiproliferative activity and compound 3f emerged as promising lead compound for the development of anticancer agents targeting melanoma and non-small cell lung cancer.
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Troiano
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy.
authors.forename: Kety
authors.initials: K
authors.lastname: Scarbaci
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy. Electronic address: roberta.ettari@unimi.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ettari
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Micale
authors.affiliation: Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Cerchia
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, D-55099 Mainz, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.affiliation: Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Messina, Via F. Stagno D'Alcontres 31, 98166 Messina, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Grasso
authors.affiliation: Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli Federico II, Via Domenico Montesano 49, 80131 Napoli, Italy. Electronic address: antonio.lavecchia@unina.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.affiliation: Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, Viale Annunziata, 98168 Messina, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Zappalà
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001897:Boronic Acids / Q000737:chemistry*; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D062105:Molecular Docking Simulation; D057786:Peptidomimetics / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D059748:Proteolysis / Q000187:drug effects; D011719:Pyrazines / Q000737:chemistry*; D014357:Trypsin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D057786:Peptidomimetics; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D010450:Endopeptidases; D014357:Trypsin; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; C114177:peptidylglutamylpeptide hydrolase
keywords: Docking studies; Peptidomimetic boronates; Proteasome inhibitors