Novel PARP-1 inhibitors based on a 2-propanoyl-3H-quinazolin-4-one scaffold.

Giannini, Giuseppe; Battistuzzi, Gianfranco; Vesci, Loredana; Milazzo, Ferdinando M; De Paolis, Francesca; Barbarino, Marcella; Guglielmi, Mario Berardino; Carollo, Valeria; Gallo, Grazia; Artali, Roberto; Dallavalle, Sabrina

Giannini, Giuseppe; Battistuzzi, Gianfranco; Vesci, Loredana; Milazzo, Ferdinando M; De Paolis, Francesca; Barbarino, Marcella; Guglielmi, Mario Berardino; Carollo, Valeria; Gallo, Grazia; Artali, Roberto; Dallavalle, Sabrina.

Afiliación

Giannini G; 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.
Battistuzzi G; R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
Vesci L; R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
Milazzo FM; R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
De Paolis F; R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
Barbarino M; R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
Guglielmi MB; R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
Carollo V; R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
Gallo G; R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia (RM), Italy.
Artali R; Scientia Advice di Roberto Artali, 20832 Desio (MB), Italy.
Dallavalle S; Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università di Milano, Via Celoria 2, 20133 Milano, Italy.

Bioorg Med Chem Lett ; 24(2): 462-6, 2014 Jan 15.

Article en En | MEDLINE | ID: mdl-24388690

RESUMEN

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.

Asunto(s)

Antineoplásicos/química; Inhibidores de Poli(ADP-Ribosa) Polimerasas; Quinazolinonas/química; Animales; Antineoplásicos/farmacología; Línea Celular Tumoral; Inhibidores Enzimáticos/química; Inhibidores Enzimáticos/farmacología; Femenino; Humanos; Ratones; Ratones SCID; Poli(ADP-Ribosa) Polimerasa-1; Poli(ADP-Ribosa) Polimerasas/metabolismo; Quinazolinonas/farmacología; Relación Estructura-Actividad; Ensayos Antitumor por Modelo de Xenoinjerto/métodos

Palabras clave

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

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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Quinazolinonas / Inhibidores de Poli(ADP-Ribosa) Polimerasas / Antineoplásicos Límite: Animals / Female / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2014 Tipo del documento: Article

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