Naphthalene diimide scaffolds with dual reversible and covalent interaction properties towards G-quadruplex

Selective recognition and alkylation of G-quadruplex oligonucleotides has been achieved by substituted naphathalene diimides (NDIs) conjugated to engineered phenol moieties by alkyl-amido spacers with tunable length and conformational mobility. FRET-melting assays, circular dichroism titrations and gel electrophoresis analysis have been carried out to evaluate both reversible stabilization and alkylation of the G-quadruplex. The NDIs conjugated to a quinone methide precursor (NDI-QMP) and a phenol moiety by the shortest alkyl-amido spacer exhibited a planar and fairly rigid geometry (modelled by DFT computation). They were the best irreversible and reversible G-quadruplex binders, respectively. The above NDI-QMP was able to alkylate the telomeric G-quadruplex DNA in the nanomolar range and resulted 100–1000 times more selective on G-quadruplex versus single- and double-stranded oligonucleotides. This compound was also the most cytotoxic against a lung carcinoma cell line.

► Recognition and alkylation of G-quadruplex structures. ► Substituted Naphathalene Diimides acting as hybrid ligand/alkylating binders. ► FRET-melting assays, circular dichroism titrations and gel electrophoresis. ► Telomeric G-quadruplex DNA alkylation in the low nanomolar range. ► G-quadruplex versus single- and double-stranded oligonucleotides selectivity.