Tetrasubstituted naphthalene diimide ligands with selectivity for telomeric G-quadruplexes and cancer cells

A series of tetrasubstituted naphthalene diimide compounds with N-methylpiperazine end groups has been synthesized and evaluated as G-quadruplex ligands. They have high affinity and selectivity for telomeric G-quadruplex DNA over duplex DNA. CD studies show that they induce formation of a parallel G-quadruplex topology. They inhibit the binding of hPOT1 and topoisomerase IIIα to telomeric DNA and inhibit telomerase activity in MCF7 cells. The compounds have potent activity in a panel of cancer cell lines, with typical IC50 values of ∼0.1 μM, and up to 100-fold lower toxicity in a normal human fibroblast cell line.

Modelled structure of a naphthalene diimide derivative with four N-methylpiperazine end-groups, bound to a parallel form of the human intramolecular telomeric G-quadruplex.Figure optionsDownload as PowerPoint slide