Title
Targeting multiple G-quadruplex–forming DNA sequences: Design, biophysical and biological evaluations of indolo-naphthyridine scaffold derivatives
Author
Raffaella Catalano, Federica Moraca, Jussara Amato, Camilla Cristofari, Riccardo Rigo, Lisa Dalla Via, Roberta Rocca, Antonio Lupia, Annalisa Maruca, Giosuè Costa, Bruno Catalanotti, Anna Artese, Bruno Pagano, Antonio Randazzo, Claudia Sissi, Ettore Novellino, Stefano Alcaro
Year
2019
Journal
European Journal of Medicinal Chemistry
Abstract
It is well recognized that the non-canonical DNA structures known as G-quadruplexes (G4s) have a potential anticancer significance and several compounds have been discovered and evaluated as promising G4 binders with anticancer activity. Here, starting from a promising hit with an indolo-naphthyridine scaffold, a small series of five indolo-naphthyridine based derivatives have been designed and evaluated as G4-targeting compounds. FRET biophysical studies were performed on multiple DNA G4 structures, leading to the identification of a multi-target G4 stabilizer with a slight preference for the c-KIT1 and a good G4 over duplex selectivity. The good affinity of this compound against c-KIT1 G4 was also confirmed by SPR and MST experiments, while biological assays revealed its cytotoxic activity on tumour cells. Finally, Molecular Dynamics simulations helped to elucidate the stabilization effect of the selected compound against the c-KIT1 G4.
Instrument
J-815
Keywords
Circular dichroism, G-quadruplex structure, DNA structure, Ligand binding, Thermal stability, Biochemistry