Abstract 3219: Heterocyclic cations: Highlighting the importance of selectivity in biologically relevant quadruplex DNA recognition and binding
Authors: Musetti Caterina , Kumar Arvind , Ismail Mohamed A. , Lucatello Lorena , Munde Manoj , Nanjunda Rupesh K. , Sissi Claudia , Palumbo Manlio , Boykin David W. , Wilson W. David 
Published: February 2011

Small molecules that target G-quadruplex DNA structures represent a potential approach for anticancer drug development. Stabilization of G-quadruplex structures leads to the inhibition of the telomerase enzyme that is overexpressed in the tumor cells resulting in an exciting new anticancer receptor.

The purpose of this study is to explore conformational space in a series of heterocyclic cations in order to discover novel structural motifs that can selectively bind and stabilize specific G-quadruplex structures such as those present in oncogene promoters.

As target DNA sequences we selected the human telomere and the oncogene promoter c myc, which can fold into specific quadruplex arrangements. The compounds investigated, characterized by a curved shape motif, were selected from a preliminary study between linear, partially curved and highly curved heterocyclic compound libraries. Their DNA recognition properties have been investigated by biophysical experiments. Affinity was evaluated by thermal melting experiments, biosensor surface plasmon resonance, circular dichroism, fluorescence displacement assay and mass spectrometry methods. Biological studies as TRAP assay, inhibition of Taq polymerase enzyme and cytotoxicity on two series of cancer cells were also performed to complement the biophysical data.

From our results, compounds with a large number of rings show an impressive selectivity for the G-quadruplex folded c myc oncogene promoter in comparison to the human telomere and to the double helix model systems. The results suggest also a novel binding mechanism which involves the grooves of the folded quadruplex structures. Most of the compounds that have been found to effectively target G-quadruplexes show aromatic arrays that resemble the planar guanine tetrads so “end-stacking” to the G-quartet is the traditionally considered binding mode for this type of ligand. The quadruplex grooves represent attractive targets as they are different from the duplex grooves, and because their dimensions can also vary according to the type of quadruplex sequence. We use these results to explain how the novel class of compounds here presented is able to drive the selectivity not only over duplex but also through different quadruplex conformations. The importance of selectivity and of the evaluation of ligands towards biological relevant sequences is a major issue to be considered in drug design to avoid the important problem of nonspecific cytotoxicity. These results can be useful for the development of new efficient and selective telomerase inhibitors, endowed with pharmacological activity.

Acknowledgements: This work was supported by University of Padova (Italy) and NIH grant AI064200

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3219.