The Design of G-quadruplex Ligands as Telomerase Inhibitors

摘要

Guanine-rich repetitive DNA sequences are of particular importance at the ends of chromosomes,nwhere they are associated with a number of proteins to form telomeres. Their function is in large part to protectnchromosomal ends from unwanted degradation and chromosomal fusions, although in normal somatic cellsntelomeres progressively shorten, eventually becoming non-proliferating and consequently these cells have anfinite lifetime. By contrast tumour cell telomeres are maintained in length so that tumour cells are effectivelynimmortalised. The reverse transcriptase enzyme telomerase is activated in over 80% of tumour cells, and itnundertakes the synthesis of further telomeric DNA repeats, so directly maintaining telomeres. The inhibition ofntelomerase leads to the senescence and eventual apoptosis of tumour cells, and thus telomerase is an attractiventarget for selective chemotherapy. This review describes an approach to the inhibition of telomerase thatninvolves the folding of telomeric DNA into a four-stranded quadruplex structure, held together by Hoogsteennhydrogen-bonded arrays of guanine bases. The formation of a quadruplex structure at the 3' end of telomericnDNA effectively hinders telomerase from adding further repeats. A number of small-molecule ligands arendescribed that stabilise quadruplex formation, and which result in telomerase inhibition. Implications for anti-ntumour therapy with such molecules are discussed, and the particular challenges and problems discussed.