title: 7-Azaindole-1-carboxamides as a new class of PARP-1 inhibitors.
abstract: 7-Azaindole-1-carboxamides were designed as a new class of PARP-1 inhibitors. The compounds displayed a variable pattern of target inhibition profile that, in part, paralleled the antiproliferative activity in cell lines characterized by homologous recombination defects. A selected compound (1l; ST7710AA1) showed significant in vitro target inhibition and capability to substantially bypass the multidrug resistance mediated by Pgp. In antitumor activity studies against the MX1 human breast carcinoma growth in nude mice, the compound exhibited an effect similar to that of Olaparib in terms of tumor volume inhibition when used at a lower dose than the reference compound. Treatment was well tolerated, as no deaths or significant weight losses were observed among the treated animals.
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: Raffaella
authors.initials: R
authors.lastname: Cincinelli
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: Loana
authors.initials: L
authors.lastname: Musso
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: Lucio
authors.initials: L
authors.lastname: Merlini
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.,via Pontina Km 30, 400, I-00040 Pomezia (RM), Italy.
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: 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: Molecular Pharmacology Unit, Dept. Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, via Amadeo 42, I-20133 Milan, Italy.
authors.forename: Nives
authors.initials: N
authors.lastname: Carenini
authors.affiliation: Molecular Pharmacology Unit, Dept. Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, via Amadeo 42, I-20133 Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Perego
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.,via Pontina Km 30, 400, I-00040 Pomezia (RM), Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Penco
authors.affiliation: Scientia Advice, di Roberto Artali, 20832 Desio (MB), Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Artali
authors.affiliation: Molecular Pharmacology Unit, Dept. Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, via Amadeo 42, I-20133 Milan, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.,via Pontina Km 30, 400, I-00040 Pomezia (RM), Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.affiliation: Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università di Milano, via Celoria 2, 20133 Milano, Italy. Electronic address: sabrina.dallavalle@unimi.it.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dallavalle
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells / Q000187:drug effects; D059765:Homologous Recombination; D006801:Humans; D007211:Indoles / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C023422:7-azaindole dimer; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004791:Enzyme Inhibitors; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: 7-Azaindoles; Antitumor; Molecular modelling; PARP inhibitors; Synthesis