Hybrid ligand–alkylating agents targeting telomeric G-quadruplex structures

Dipartimento di Chimica, Università di Pavia, V.le Taramelli 10, 27100 Pavia, Italy.
Organic & Biomolecular Chemistry (Impact Factor: 3.49). 02/2012; 10(14):2798-806. DOI: 10.1039/c2ob06816h
Source: PubMed

ABSTRACT 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. NDI-QMs' 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 ligand-alkylating NDIs as possible tools for the development of novel targeted anticancer therapies.

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