Abstract
Organic small molecules that can recognize and bind to G-quadruplex and i-Motif nucleic acids have great potential as selective drugs or as tools in drug target discovery programs, or even in the development of nanodevices for medical diagnosis. Hundreds of quadruplex-interactive small molecules have been reported, and the challenges in their design vary with the intended application. Herein, we survey the major achievements on the therapeutic potential of such quadruplex ligands, their mode of binding, effects upon interaction with quadruplexes, and consider the opportunities and challenges for their exploitation in drug discovery.
Highlights
The association of nucleic acid sequences into a wide range of secondary and higherorder structures is nowadays well known to be of crucial importance in genome regulation in association with proteins
G4-forming nucleic acid sequences were identified in telomeres and other regions of the genome of many organisms, including humans [42–44], bacteria [45,46], viruses [47–49], plants [50] and parasites [51–53]
According to the reported work [226], one of the ligands stacks on the top of the tetramolecular G4, stabilized by hydrophobic π−π stacking between the quinacridine moiety and the top G-quartet with the two cationic branches binding to the flanking grooves
Summary
The association of nucleic acid sequences into a wide range of secondary and higherorder structures is nowadays well known to be of crucial importance in genome regulation in association with proteins. In the past two decades, G4s have generated a huge interest among the scientific community due to their versatile applicability in nanotechnology and medicinal fields Another important DNA quadruplex (or tetraplex) is formed by the self-assembly of cytosine-rich sequences into an intercalateddouble helix motif, known as i-Motif (iM). This structural arrangement was first reported in the 1990s based on NMR [9] and X-ray crystallographic [10] studies in acidic conditions. Metal-based quadruplex-interactive compounds have been developed and shown relevant properties that can be exploited in the development of probes, diagnostic tools, or therapeutic agents, as recently reviewed elsewhere [14,15]
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