Stabilization of quadruplex DNA and inhibition of telomerase by square planar metal complexes

INOR 151

Anna Arola1, Stephen Neidle, stephen.neidle@ulsop.ac.uk2, Julie E. Reed1, and Ramon Vilar, r.vilar@imperial.ac.uk1. (1) Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom, (2) Cancer Research UK Biomolecular Structure Group, School of Pharmacy, University of London, 29-39 Brunswick square, London, WC1N 1AX, United Kingdom
Telomerase maintains the integrity of the ends of chromosomes preventing critical shortening of the telomere so that cells cannot reach crisis points of senescence and apoptosis. This enzyme is present in 85-90% of cancer cells but not expressed in normal somatic cells. Therefore, its inhibition has been identified as an attractive target for cancer chemotherapy. Human telomeric DNA consists of the tandem repeat sequence TTAGGG, the 3' terminal 100-200 bases being single-stranded. Since the substrate of telomerase is the 3'-single-stranded overhang, stabilization of quadruplex DNA by small molecules can inhibit telomerase, therefore interfering with telomere maintenance in tumor cells. In this communication we will present our latest results in the development of a series of square planar metal complexes with a remarkable ability to induce stabilization of quadruplex DNA while having little effect in melting temperature of duplex DNA. These complexes have also shown to be excellent telomerase inhibitors.
 

Bioinorganic Chemistry: DNA and RNA
1:30 PM-5:30 PM, Sunday, August 19, 2007 BCEC -- 211, Oral

Division of Inorganic Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007