7-Azaindole-1-carboxamides as a new class of PARP-1 inhibitors

Raffaella Cincinelli; Loana Musso; Lucio Merlini; Giuseppe Giannini; Loredana Vesci; Ferdinando M Milazzo; Nives Carenini; Paola Perego; Sergio Penco; Roberto Artali; Franco Zunino; Claudio Pisano; Sabrina Dallavalle

doi:10.1016/j.bmc.2013.12.031

7-Azaindole-1-carboxamides as a new class of PARP-1 inhibitors

Bioorg Med Chem. 2014 Feb 1;22(3):1089-103. doi: 10.1016/j.bmc.2013.12.031. Epub 2013 Dec 22.

Affiliations

¹ Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università di Milano, via Celoria 2, 20133 Milano, Italy.
² R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.,via Pontina Km 30, 400, I-00040 Pomezia (RM), Italy.
³ Molecular Pharmacology Unit, Dept. Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, via Amadeo 42, I-20133 Milan, Italy.
⁴ Scientia Advice, di Roberto Artali, 20832 Desio (MB), Italy.
⁵ 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.

PMID: 24398383
DOI: 10.1016/j.bmc.2013.12.031

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.

Keywords: 7-Azaindoles; Antitumor; Molecular modelling; PARP inhibitors; Synthesis.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
BRCA1 Protein / genetics
BRCA2 Protein / genetics
Breast Neoplasms / drug therapy
Breast Neoplasms / genetics
Drug Resistance, Multiple / drug effects
Drug Resistance, Neoplasm / drug effects*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Female
HeLa Cells / drug effects
Homologous Recombination
Humans
Indoles / chemistry
Mice
Mice, Nude
Models, Molecular
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

7-azaindole dimer
ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
BRCA1 Protein
BRCA1 protein, human
BRCA2 Protein
BRCA2 protein, human
Enzyme Inhibitors
Indoles
Poly(ADP-ribose) Polymerase Inhibitors
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1