A valuable approach to interfere with telomerase activity is to stabilize the G-quadruplex folded structure of telomeres. To reach this goal, compounds containing extended planar ring systems have been widely used. These compounds are effective DNA binders due to favourable stacking within the the G-quadruplex system. Among them, a prominent position from a pharmacological point of view is covered by perylenes. Many indications suggest that they stabilize G-quadruplex structures by face recognition on the terminal G-quartet of the folded telomere. With the aim to further investigate the role of drug structure in driving the DNA conformation recognition and the binding mode, we have synthesized and studied a series of perylene-related compounds. As leading compound we choose PIPER, a well known telomerase inhibitor. In this work, we modified the basicity of the nitrogens in the side chains, hence modulating the protonation state and the extent of drug aggregation at physiological conditions. Additionally, we modified the extension of the planar system, changing the number of condensed aromatic rings. Selective interaction with quadruplex vs. other DNA folded arrangements was preliminary assessed by comparing IC50s for inhibition of telomerase (TRAP assay) and TAQ polymerase respectively. To investigate in deeper detail the molecular basis for DNA-binding selectivity, the interactions of the new compounds with several DNA structures were further characterized by electrophoretic and chiroptical techniques using PIPER as a reference. Finally, cytotoxic properties of the test drugs were evaluated. The results allowed us to define structure-selective recognition-activity relationships for the examined derivatives for future rational design.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]