Diketopyrrolo[3,4-c]pyrrole derivative as a promising ligand for the stabilization of G-quadruplex DNA structures

[Display omitted] •The cationic diketopyrrolo[3,4–c]pyrrole derivative (DPP(PyMe)2 showed high affinity to G-quadruplex DNA structures and remarkable selectivity for the oncogene promotors c-MYC and KRAS;•molecular dynamics studies revealed different binding modes depending on the G4 structure.•PCR stop assays confirmed the ability of DPP(PyMe)2 to block Taq polymerase activity.•DPP(PyMe)2 is an attractive ligand for the development of G4 labelling probes. Telomerase, oncogenes and tumor suppressors are closely associated with tumour occurrence, therefore these structures are being recognized as targets for the development of new anticancer drugs. The efficacy of several molecules in telomerase inhibition and regulation of genes expression, by adduct formation with G-quadruplexes (G4), has been studied by biophysical and biochemical methods with promising results. We report here the synthesis and structural characterization of a small positively charged diketopyrrolo[3,4–c]pyrrole derivative, identified as DPP(PyMe)2, that showed very promising results as G4 stabilizing ligand. The data obtained from UV–Vis and fluorescence experiments suggest that DPP(PyMe)2 presents high affinity to G4 structures. Docking studies and molecular dynamics simulations unraveled the binding modes of the ligand with four G4 structures. The obtained results also allowed us to conclude that the DPP(PyMe)2 ligand binds into the top G-tetrad or in a mixed binding mode depending on the GQ structure. A remarkable selectivity of DPP(PyMe)2 for c-MYC and KRAS 32R in the presence of ds26 was observed by circular dichroism (CD) and fluorescence resonance energy transfer (FRET) melting experiments. CD titrations revealed a stabilization higher than 30 °C in the case of c-MYC G4 structure and, for the same sequence, DPP(PyMe)2 showed the ability to block the activity of Taq polymerase in a dose-dependent manner. The subcellular localization obtained with confocal microscopy corroborates the results obtained by the other techniques and the obtained data suggest that DPP(PyMe)2 is an attractive ligand for the development of G4 labelling probes.