Guanine-rich human telomeric DNA found at the ends of chromosomes plays an important role in maintaining the integrity of the genome. In normal somatic cells, telomeric DNA progressively shortens after each replication cycle due to the lack of template for fully replicating the 3'single-stranded overhang. Such shortening eventually triggers genomic instability and cellular senescence. In contrast, telomeric DNA in cancer cells can be maintained via a reverse transcriptase known as telomerase that is overly expressed in 80-85% cancer cells and is responsible for cancer cells' immortality. This remarkable difference in telomerase activity between normal and cancer cells has attracted much attention to exploit telomerase as a potential therapeutic target in oncology.One of the efficient approaches to inhibit telomerase activity is to block the binding of telomerase via the formation of G-quadruplex structures in telomeric DNA. G-quadruplex structures are formed under physiological conditions and their formation can be greatly facilitated by suitable small molecules. In this present work, we investigated the binding of G-quadruplex DNA with a series of newly developed 5-substituted phenanthroline metal complexes. Their binding affinity and specificity towards G-quadruplex DNA were determined using biophysical techniques including thermal denaturation, fluorescence titration, UV absorbance, and circular dichroism. Our results demonstrated that phenanthroline-metal complexes can selectively bind to G-quadruplex over duplex with high affinities partly due to the enhanced planar complex aromatic surface. Substituents at the 5 positions of phenanthroline derivatives also count for the observed G-quadruplex stabilization effect.

Phenanthroline based metal complexes as G-quadruplex ligands

248th National Meeting (2014)

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