Wechselwirkung von Metallkomplexen mit G‐Quadruplex‐DNA

Abstract

Guaninreiche DNA‐Sequenzen können sich zu viersträngigen Aggregaten anordnen, die als G‐Quadruplexe bezeichnet werden. Man nimmt an, dass diese DNA‐Sekundärstrukturen an der Regulation verschiedener biologischer Schlüsselprozesse beteiligt sind. Im menschlichen Genom kommen guaninreiche Sequenzen mit dem Potenzial zur Bildung von G‐Quadruplexen beispielsweise im Telomer sowie in den Promoterregionen bestimmter Onkogene vor. Die Identifizierung dieser Sequenzen als neue Zielstrukturen für Tumortherapeutika hat großes Interesse an der Entwicklung von Verbindungen ausgelöst, die mit Quadruplex‐DNA wechselwirken können. Die meisten bekannten Quadruplex‐DNA‐Bindungssubstanzen beruhen zwar auf rein organischen Templaten, später wurde aber nachgewiesen, dass auch viele Metallkomplexe mit dieser DNA‐Sekundärstruktur effiziente Wechselwirkungen eingehen. Dieser Aufsatz gibt einen Überblick über die wichtigen Funktionen, die Metallkomplexe als Quadruplex‐DNA‐Bindungssubstanzen haben können, und diskutiert die besonderen Eigenschaften von Metallzentren auf diese Verbindungen.

Platinum(II) Phenanthroimidazoles for Targeting Telomeric G‐Quadruplexes

“…Georgiades et al recently reviewed metal complexes and their abilities to bind G4 DNA. [15] In particular, platinum(II) complexes can introduce a square planar geometry unavailable to carbon compounds and can act as electron-withdrawing groups to further increase positive character on the ligand. They can also simplify synthetic access to G4 binders and allow the modular generation of compound libraries in a minimal number of steps.…”

“…To date, many compounds with varying degrees of efficacy in their ability to target this higher-order DNA structure have been reported. [14,15] Based on this wealth of empirical data obtained not only from binding studies, but also from molecular modeling and crystal structure determination of G4-ligand complexes, [16,17] several clues about the rational design of G4 binders have been uncovered, including the need for an electron-poor aromatic p-surface, positive charges in the scaffold, and the presence of positively charged side arms.…”

NMR Structure of a Triangulenium‐Based Long‐Lived Fluorescence Probe Bound to a G‐Quadruplex

“…[4] The majority of G-quadruplex optical probes reported to date, rely on changes in their emission intensity upon interaction with DNA. [5] Recently, we reported a small-molecule optical probe based on trianguleniums (DAOTA- Figure 1a) that can image its interaction with G-quadruplexes in live cells using Fluorescence Lifetime Imaging Microscopy. [6] The key feature of this probe is that it has significantly longer fluorescence lifetimes, when bound to G-quadruplex DNA than when it binds to other topologies such as duplex or single-stranded DNA.…”

Determinants for Tight and Selective Binding of a Medicinal Dicarbene Gold(I) Complex to a Telomeric DNA G‐Quadruplex: a Joint ESI MS and XRD Investigation

“…[15][16][17][18] Interestingly,f ormation of quadruplexes causes an et decrease in the activity of the enzyme telomerase,w hich is responsible for maintaining the length of telomeres. [26,27] However, structural information on adducts formed between metal complexes and G4-DNAi sl imited and would be of great help to develop selective G4 stabilizers.T od ate,c rystal structures have only been reported for adducts of copper(II) and nickel(II) salphen complexes with human telomeric DNA. [20][21][22][23] While the majority of quadruplex DNAbinders reported to date contain planar organic heteroaromatic systems, av ariety of metal complexes (mostly bearing extended planar motifs) were also shown to exhibit large affinities for DNAG -quadruplexes.…”