Mini Reviews in Medicinal Chemistry - Volume 3, Issue 1, 2003

The current evidence on prokaryotic linear chromosomes, the eukaryotes that do not use telomerase and quadruplex DNA has been considered. This has lead to the suggestion that quadruplex DNA may have played a role in the evolution of the protection linear chromosomes rather than in overcoming the end replication problem.

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

Telomeric DNA progressively erodes with each round of cell division in cells that do not express telomerase, a specialized reverse transcriptase necessary to fully duplicate the chromosomal ends. Telomerase is expressed in tumor cells but not in most somatic cells and thus telomeres and telomerase may be proposed as attractive targets for the discovery of new anticancer agents. In this paper we will present different strategies to inhibit telomerase activity via an interaction with a telomere / telomerase nucleic acid component, with a special emphasis on quadruplex ligands.

Four different approaches have been reviewed herein: i) nucleoside analogs as mock agents of the reverse transcriptase (hTERT) catalytic site, ii) miscellaneous molecules with unknown mechanism(s) of action, iii) inhibitors of upstream processes of regulation of the hTERT subunit, iiii) immunotherapy against immunogenic hTERT- derived peptides.

The ability of peptide nucleic acids and hammerhead ribozymes, which target different subunits of human telomerase, to efficiently inhibit the enzyme's catalytic activity has been clearly demonstrated in several in vitro studies carried out in human immortalized and cancer cell lines. However, the actual efficacy of these molecules still needs to be validated in in vivo human tumor models, and such validation appears to be largely dependent on the development of reliable systems for their intracellular delivery.