Antiproliferative Properties and G-Quadruplex-Binding of Symmetrical Naphtho[1,2-b:8,7-b’]dithiophene Derivatives
Antonino Lauria,
Gabriele La Monica,
Alessio Terenzi,
Giuseppe Mannino,
Riccardo Bonsignore,
Alessia Bono,
Anna Maria Almerico,
Giampaolo Barone,
Carla Gentile,
Annamaria Martorana
Affiliations
Antonino Lauria
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze—Ed. 17, 90128 Palermo, Italy
Gabriele La Monica
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze—Ed. 17, 90128 Palermo, Italy
Alessio Terenzi
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze—Ed. 17, 90128 Palermo, Italy
Giuseppe Mannino
Plant Physiology Unit, Department of Life Sciences and Systems Biology, University of Turin, Via Quarello 15/A, 10135 Turin, Italy
Riccardo Bonsignore
Department of Chemistry, Technical University of Munich, Lichtenbergstr. 4, 85747 Garching, Germany
Alessia Bono
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze—Ed. 17, 90128 Palermo, Italy
Anna Maria Almerico
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze—Ed. 17, 90128 Palermo, Italy
Giampaolo Barone
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze—Ed. 17, 90128 Palermo, Italy
Carla Gentile
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze—Ed. 17, 90128 Palermo, Italy
Annamaria Martorana
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche “STEBICEF”, University of Palermo, Viale delle Scienze—Ed. 17, 90128 Palermo, Italy
Background: G-quadruplex (G4) forming sequences are recurrent in telomeres and promoter regions of several protooncogenes. In normal cells, the transient arrangements of DNA in G-tetrads may regulate replication, transcription, and translation processes. Tumors are characterized by uncontrolled cell growth and tissue invasiveness and some of them are possibly mediated by gene expression involving G-quadruplexes. The stabilization of G-quadruplex sequences with small molecules is considered a promising strategy in anticancer targeted therapy. Methods: Molecular virtual screening allowed us identifying novel symmetric bifunctionalized naphtho[1,2-b:8,7-b’]dithiophene ligands as interesting candidates targeting h-Telo and c-MYC G-quadruplexes. A set of unexplored naphtho-dithiophene derivatives has been synthesized and biologically tested through in vitro antiproliferative assays and spectroscopic experiments in solution. Results: The analysis of biological and spectroscopic data highlighted noteworthy cytotoxic effects on HeLa cancer cell line (GI50 in the low μM range), but weak interactions with G-quadruplex c-MYC promoter. Conclusions: The new series of naphtho[1,2-b:8,7-b’]dithiophene derivatives, bearing the pharmacophoric assumptions necessary to stabilize G-quadruplexes, have been designed and successfully synthesized. The interesting antiproliferative results supported by computer aided rational approaches suggest that these studies are a significant starting point for a lead optimization process and the isolation of a more efficacious set of G-quadruplexes stabilizers.
