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G-quadruplex binding properties of a potent PARP-1 inhibitor derived from 7-azaindole-1-carboxamide.
Dallavalle, Sabrina; Musso, Loana; Artali, Roberto; Aviñó, Anna; Scaglioni, Leonardo; Eritja, Ramon; Gargallo, Raimundo; Mazzini, Stefania.
Afiliación
  • Dallavalle S; Department of Food, Environmental and Nutritional Sciences (DEFENS), University of Milan (Università Degli Studi Di Milano), Milan, Italy.
  • Musso L; Department of Food, Environmental and Nutritional Sciences (DEFENS), University of Milan (Università Degli Studi Di Milano), Milan, Italy.
  • Artali R; Scientia Advice di Roberto Artali, 20832, Desio, MB, Italy.
  • Aviñó A; Institute for Advanced Chemistry of Catalonia (IQAC), CSIC, Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain.
  • Scaglioni L; Department of Food, Environmental and Nutritional Sciences (DEFENS), University of Milan (Università Degli Studi Di Milano), Milan, Italy.
  • Eritja R; Institute for Advanced Chemistry of Catalonia (IQAC), CSIC, Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain.
  • Gargallo R; Department of Chemical Engineering and Analytical Chemistry, University of Barcelona, Barcelona, Spain.
  • Mazzini S; Department of Food, Environmental and Nutritional Sciences (DEFENS), University of Milan (Università Degli Studi Di Milano), Milan, Italy. stefania.mazzini@unimi.it.
Sci Rep ; 11(1): 3869, 2021 02 16.
Article en En | MEDLINE | ID: mdl-33594142
Poly ADP-ribose polymerases (PARP) are key proteins involved in DNA repair, maintenance as well as regulation of programmed cell death. For this reason they are important therapeutic targets for cancer treatment. Recent studies have revealed a close interplay between PARP1 recruitment and G-quadruplex stabilization, showing that PARP enzymes are activated upon treatment with a G4 ligand. In this work the DNA binding properties of a PARP-1 inhibitor derived from 7-azaindole-1-carboxamide, (2-[6-(4-pyrrolidin-1-ylmethyl-phenyl)-pyrrolo[2,3-b]pyridin-1-yl]-acetamide, compound 1) with model duplex and quadruplex DNA oligomers were studied by NMR, CD, fluorescence and molecular modelling. We provide evidence that compound 1 is a strong G-quadruplex binder. In addition we provide molecular details of the interaction of compound 1 with two model G-quadruplex structures: the single repeat of human telomeres, d(TTAGGGT)4, and the c-MYC promoter Pu22 sequence. The formation of defined and strong complexes with G-quadruplex models suggests a dual G4 stabilization/PARP inhibition mechanism of action for compound 1 and provides the molecular bases of its therapeutic potential.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Genes myc / Telómero / G-Cuádruplex / Poli(ADP-Ribosa) Polimerasa-1 / Antineoplásicos Idioma: En Revista: Sci Rep Año: 2021 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Genes myc / Telómero / G-Cuádruplex / Poli(ADP-Ribosa) Polimerasa-1 / Antineoplásicos Idioma: En Revista: Sci Rep Año: 2021 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido