Hybrid ligandalkylating agents targeting telomeric G-quadruplex structuresElectronic supplementary information (ESI) available: Details about experimental procedures concerning the synthesis and structural characterization of the intermediates 814, and the NDIs 1, 1Br, 3, 3Br, 4, 5Br, 6, DNA alkylation, telomerase activity assay and western immunoblotting are provided in Supplementary Experimental Procedures. FRET-melting and CD analysis were performed as recently reported (ref. 14). See DOI: 10

The synthesis, physico-chemical properties and biological effects of a new class of naphthalene diimides (NDIs) capable of reversibly binding telomeric DNA and alkylate it through an electrophilic quinone methide moiety (QM), are reported. FRET and circular dichroism assays showed a marked stabilization and selectivity towards telomeric G4 DNA folded in a hybrid topology. NDIQMs alkylating properties revealed a good reactivity on single nucleosides and selectivity towards telomeric G4. A selected NDI was able to significantly impair the growth of melanoma cells by causing telomere dysfunction and down-regulation of telomerase expression. These findings points to our hybrid ligandalkylating NDIs as possible tools for the development of novel targeted anticancer therapies. Naphthalene-diimides tethered to a quinone methide precursor (QMP), capable of binding and alkylating telomeric DNA, were successfully designed.