One of the most important factors that influences folding topology is the type of monovalent cation
present during folding. For example, in the fold of the human telomeric sequence (Figure 9.21), which is
based on an NMR study in the presence of Na(Figure 9.22)^67 the TTA loops are arranged in a lateral and
diagonal conformation, and the strands alternate between parallel and antiparallel. By contrast, a recent
X-ray structure in the presence of Kions shows that all four strands are parallel and the TTA loops are
extended out from the sides of the G-quartets.
It has been suggested that the antiparallel fold observed in an NMR study is solely a consequence of the
presence of sodium ions, and the presence of potassium ions induces a transition to the parallel arrange-
ment. The different conformations adopted by quadruplex structures in different cationic environments
have a direct impact on the binding of drug molecules. In fact recent biophysical studies reveal consider-
able complexity in quadruplex unfolding and show that multiple species coexist in equilibrium across the
temperature range. Thus there is no single static structure for the folded quadruplex and hence targeting
quadruplex DNA with small molecules is not straightforward.
Despite these difficulties, several different classes of ligand have shown promise as structure-specific,
quadruplex-binding agents and as telomerase inhibitors (Figure 9.23). Most of these compounds have
telomerase inhibitory effectswith IC 50 values in the low micromolar range but specific binding to quadru-
plex DNA over duplex is, at best, only modest.
Laurence Hurley has developed some cationic porphyrins for targeting quadruplex DNA and to effect
telomerase inhibition. The structure of an archetypal porphyrin, [tetra-(N-methyl-4-pyridyl)-porphine]
TMPyP4 (Figure 9.23) illustrates the planar arrangement of the aromatic rings, which give rise to a ligand that
has similar molecular dimensions to a G-tetrad intercalation site. This has led to the proposal that compounds
of this type will bind to quadruplex DNA through intercalative stacking. UV spectroscopy, circular dichroism,
Reversible Small Molecule–Nucleic Acid Interactions 377
Figure 9.22 NMR solution structure of the human telomeric sequence 5 -AGGGTTAGGGTTAGGGTTAGGG in the
presence of Na(PDB: 143D). Guanine residues are in red, thymines in grey, adenines in black, and a
grey ribbon highlights the DNA backbone