Abstract 2674: Interaction of natural alkaloids with G-quadruplex structures: biophysical and pharmacological implications

Abstract

Abstract DNA sequences rich in guanines can fold up to form peculiar structures, known as a G-quadruplex, deriving from pairing of four guanines by Hoogsteen-like hydrogen bonds. Nowadays, these structure(s) are being exploited as suitable targets for anti-cancer drug design. Indeed, G-quadruplexes can be formed at the telomers, the ends of human chromosomes as well as in the promoters of several important oncogenes such as c-myc, bcl-2, c-kit and VEGF. At physiological conditions an equilibrium between different conformations builds up. It has been shown that the interconversion between folded-unfolded conformation can be used by the cell to modulate the oncogene transcriptional state. Up-to-date, several classes of compounds have been tested and identified as efficient G-quadruplex binders. DNA recognition occurs mainly through stacking on a terminal G-tetrad, thus, these ligands share a general consensus structural motif based on a large flat aromatic surface. Several natural compounds characterized by cytotoxic activity present this structural motif. Here, we selected several structurally related natural derivatives of plant origin characterized by four fused rings with different degree of π electron delocalization. Among them, Berberine, Sanguinarine and Cheleritrine were identified as the most efficient stabilizers for G-quadruplex structures. Their interaction with various nucleic acid conformations was examined in detail in terms of affinity constant and mode of binding by NMR studies, spectroscopic (fluorometric and CD) and ITC titrations. In particular, we focussed our attention on the role of DNA sequence and structure on binding geometry and affinity. Biophysical data were then related to the cytotoxic response of each derivative. From these data we could asses the potential of the tested ligands as G-quadruplex binders (and prospective drug response) at physiological conditions. 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 2674.