title: Development of novel selective peptidomimetics containing a boronic acid moiety, targeting the 20S proteasome as anticancer agents.
abstract: This paper describes the design, synthesis, and biological evaluation of peptidomimetic boronates as inhibitors of the 20S proteasome, a validated target in the treatment of multiple myeloma. The synthesized compounds showed a good inhibitory profile against the ChT-L activity of 20S proteasome. Compounds bearing a β-alanine residue at the P2 position were the most active, that is, 3-ethylphenylamino and 4-methoxyphenylamino (R)-1-{3-[4-(substituted)-2-oxopyridin-1(2H)-yl]propanamido}-3-methylbutylboronic acids (3 c and 3 d, respectively), and these derivatives showed inhibition constants (Ki ) of 17 and 20 nM, respectively. In addition, they co-inhibited post glutamyl peptide hydrolase activity (3 c, Ki=2.57 μM; 3 d, Ki=3.81 μM). No inhibition was recorded against the bovine pancreatic α-chymotrypsin, which thus confirms the selectivity towards the target enzyme. Docking studies of 3 c and related inhibitors into the yeast proteasome revealed the structural basis for specificity. The evaluation of growth inhibitory effects against 60 human tumor cell lines was performed at the US National Cancer Institute. Among the selected compounds, 3 c showed 50% growth inhibition (GI50) values at the sub-micromolar level on all cell lines.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli, 25, 20133 Milano (Italy).
authors.forename: Kety
authors.initials: K
authors.lastname: Scarbaci
authors.forename: Valeria
authors.initials: V
authors.lastname: Troiano
authors.forename: Roberta
authors.initials: R
authors.lastname: Ettari
authors.forename: Andrea
authors.initials: A
authors.lastname: Pinto
authors.forename: Nicola
authors.initials: N
authors.lastname: Micale
authors.forename: Carmen
authors.initials: C
authors.lastname: Di Giovanni
authors.forename: Carmen
authors.initials: C
authors.lastname: Cerchia
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Maria
authors.initials: M
authors.lastname: Zappalà
authors.forename: Silvana
authors.initials: S
authors.lastname: Grasso
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D057786:Peptidomimetics; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D057786:Peptidomimetics; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: anticancer agents; boronates; bortezomib; docking studies; inhibitors; peptidomimetics; proteasomes