Abstract

Background

The ends of chromosomes within animal and human cells possess a guanine rich overhang (telomere). During cell division a number of these guanine groups are lost. Eventually the number of Guanine groups is reduced to the point that cell defence mechanisms destroy the cell.^1,2

Within cancer cells an enzyme called telomerase adds additional guanine bases on the ends of the chromosomes making them theoretically immortal. As telomerase is expressed in over 80% of all tumour cells it has become an increasingly important target in the search for better anti-cancer drugs.^3,4,5

Method and Results

We report the optimisation of a High-throughput ¹H Diffusion Ordered Spectroscopy (DOSY) technique to evaluate the G-quadruplex binding efficacy of small molecules and the synthesis of a series of novel anthracene-based G-quadruplex ligands.

Using in vitro preparations of a G-quadruplex forming oligonucleotide, we are able to observe the interaction of planar small molecules within the stacked G-tetrad structure of the quadruplex. Based on the structure of known, effective G-quadruplex ligands a number of diacrylamido anthracene derivatives have been synthesised via a modified Heck Reaction, which according to the ¹H DOSY NMR show good binding to the in vitro G-quadruplex formed and potential as a new class of ligand with anti-cancer properties.

References

[1] McClintock, B.; Genetics, 1941, 26, 234-282.

[2] Zhu, J.; Wang. H.; Bishop, J.; Blackburn, E. H.; Proc Nat. Acad. Sci. USA.