of aromatic rings is pyrrole–pyrrole (PyPy) for netropsin and pyrrole–pyrrole–pyrrole (PyPyPy) for dis-
tamycin. Dickerson and Lown proposed that replacement of Py moieties in netropsin or distamycin by other
heterocycles, such as 1-methylimidazole (Im), could yield compounds capable of recognising G C base pairs
as well as A T sequences. In netropsin, pyrrole methyl groups are orientated towards the minor groove such
that they make close contact with A T base pairs. In lexitropsins, one or more of the pyrrolerings is replaced by,
for example, an imidazole (Im) ring, which is capable of accepting a hydrogen bond.This alleviates the steric
clash of a pyrrole with a guanine amino group in the minor groove and instead allows a specific hydrogen
bond to form between the guanine amino group and the imidazole nitrogen atom, which facilitates
increased minor groove interactions between the lexitropsin and G C base pairs. DNA interactions with
netropsin (PyPy) as well as an imidazole-containing lexitropsin(ImPyPy) are illustrated in Figure 9.15.
NMR and footprinting studies have confirmed the enhanced interactions between suitably modified lex-
itropsins and G C-containing minor grooves, although the presence of an A T base pair does not interfere
with binding. Other examples of ligands in this group include bis-furanlexitropsins, thiazolecompounds,
and analogues of Hoechst 33258, where benzoxazole or pyridoimidazole groups have replaced the benz-
imidazole rings in Hoechst 33258. Binding studies indicate that whilst most of these lexitropsins lose their
A T specificity, they fail to become properly G C-specific.
9.7.4 Hairpin Polyamides
Hairpin polyamideligands provide important opportunities for development of high affinity, sequence-
specific DNA recognition agents for the control of gene function and as potential anticancer therapeutics.36–43
In the early 1990s, Dervan synthesised a polyamide containing an imidazole ring followed by two pyrrole
moieties (ImPyPy) with the expectation that it would form a 1:1 complex with sequences of the type
5 -XGXXX, in which X can be either A or T. Unexpectedly, ImPyPy was found to bind to a five base pair
Reversible Small Molecule–Nucleic Acid Interactions 365
Figure 9.15 Schematic representation of the specific molecular interactions that occur between (a) netropsin and
(b) a lexitropsin ImPyPy. Dotted lines indicate hydrogen bonds. Double-headed arrows represent
nonbonded van der Waals contacts. The curved line is the floor of the minor groove