G-Quadruplex DNA Structures and Organic Chemistry: More Than One Connection

G-Quadruplexes represent a group of unusual DNA secondary structures, based on Hoogsteen G-G paired hydrophobic planar rings consisting of four guanine units. Many studies have shown that G-quadruplex structures appear to be involved in several important biological processes, such as DNA replication, gene expression and recombination, as well as cell transformation. For these reasons, in the last few years G-quadruplexes have become the main research interest of many eminent scientists in different fields: from molecular to cellular biologists, from physicians to chemists. In this respect, organic chemists can play fundamental roles in many different areas. First of all, research into specific G-quadruplex ligands as potential drugs, in particular as telomerase inhibitors and thus potential anticancer drugs, has attracted strong attention. The rational design of and the various synthetic approaches toward these kinds of ligands represent two specific fields of interest for organic chemists. The molecules capable of stabilizing G-quadruplexes covered in this review are each characterized by an aromatic core that favours stacking interactions with the G-tetrads and, in most cases, by basic side chains that interact with DNA grooves. First generations and new classes of synthetic G-quadruplex ligands, as well as natural compounds, are presented. Moreover, because the specificities of the interactions between the studied ligands and different DNA structures (both duplex and quadruplex) are without doubt a main concern, determining the different biological effects of these compounds, several chemists are involved in developing approaches to explore this important subject. The last part of this review is devoted to a brief introduction of new fields of application of G-quadruplex structures with open synthetic challenges: quadruplex-forming modified oligonucleotides and nanostructures based on the G-quadruplex. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)