the replicative life span of most somatic cells to about 50 rounds of mitosis. Germline cells, proliferative stem
cells, and tumour cells need to circumvent this limit on cell replication to achieve longer life times, and over-
come telomere shortening by expressing the enzyme telomerase. This enzyme, discovered by Elizabeth
Blackburn in 1985, is a multisubunit ribonucleoprotein complex that has reverse transcriptase activity.
Several studies have indicated that 80–90% of human tumours exhibit elevated levels of telomerase
activity. One approach to telomerase inhibition was initiated by Thomas Cech and David Prescott, who
realised that when telomeric DNA is folded into a quadruplex secondary structure, it cannot act as a tem-
plate for telomerase.^64 This suggested that small molecules might be used to induce quadruplex formation
in telomeres and prevent telomerase from carrying out its function.
There have been several recent advances in development of ligands that are capable of quadruplex-
specific recognition and telomerase inhibition,59,61,65as well as a number of NMR and X-ray crystallographic
studies, of inter- and intramolecular quadruplexes.66–72Nearly all quadruplex architectures are built upon
the guanine quartet (Figure 9.21). However, there is a large degree of structural heterogeneity in the arrange-
ment of the four strands and the loops that connect them.
376 Chapter 9
M+Figure 9.21 (a) Hydrogen-bonding arrangement of an individual guanine–tetrad. This type of guanine–guanine
interaction leads to the formation of a central pore with negative electrostatic potential due to the car-
bonyl oxygen atoms. Quadruplex DNA folds only in the presence of monovalent cations, which coordinate
in the central pore as shown. (b) NMR-derived view of the actual structure of a G-tetrad. (c) Planar nature
of a G-tetrad. (d) Schematic of the folding topology adopted by a 22-nucleotide sequence containing
the human telomere repeat unit TTAGGG in the presence of sodium ions