title: Novel PARP-1 inhibitors based on a 2-propanoyl-3H-quinazolin-4-one scaffold.
abstract: Poly(ADP-ribose)polymerase-I (PARP-1) enzyme is involved in maintaining DNA integrity and programmed cell death. A virtual screening of commercial libraries led to the identification of five novel scaffolds with inhibitory profile in the low nanomolar range. A hit-to-lead optimization led to the identification of a group of new potent PARP-1 inhibitors, acyl-piperazinylamides of 3-(4-oxo-3,4-dihydro-quinazolin-2-yl)-propionic acid. Molecular modeling studies highlighted the preponderant role of the propanoyl side chain.
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy. Electronic address: giuseppe.giannini@sigma-tau.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Battistuzzi
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Vesci
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
authors.forename: Ferdinando M
authors.initials: FM
authors.lastname: Milazzo
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Paolis
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Barbarino
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
authors.forename: Mario Berardino
authors.initials: MB
authors.lastname: Guglielmi
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Carollo
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Gallo
authors.affiliation: Scientia Advice di Roberto Artali, 20832 Desio (MB), Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Artali
authors.affiliation: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dallavalle
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D052999:Quinazolinones; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: 3-(4-Oxo-3,4-dihydro-quinazolin-2-yl)-propionamides; Anticancer; Hit-to-lead optimization; Molecular modeling; PARP-1 inhibitors; Virtual screening of commercial libraries