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Several studies are conducted to determine the structural and conformational requisites that are required for the DNA quadruplex groove binding. Distamycin A is shown to be the only compound exhibiting a pure groove binding.

A structure-based virtual screening campaign is performed by using the X-ray structure of the [[d(TGGGGT)].sub.4] quadruplex with the aim of detecting new and structurally diverse groove binders. Six brand new different molecular entities have interacted with the groove through NMR experiments.

Targeting of DNA secondary structures, such as G-quadruplexes, is now considered an appealing opportunity for drug intervention in anticancer therapy. So far, efforts made in the discovery of chemotypes able to target G-quadruplexes mainly succeeded in the identification of a number of polyaromatic compounds featuring end-stacking binding properties. Against this general trend, we were persuaded that the G-quadruplex grooves can recognize molecular entities with better drug-like and selectivity properties. From this idea, a set of small molecules was identified and the structural features responsible for G-quadruplex recognition were delineated. These compounds were demonstrated to have enhanced affinity and selectivity for the G-quadruplex over the duplex structure. Their ability to induce selective DNA damage at telomeric level and to induction of apoptosis and senescence on tumor cells is herein experimentally proven.