bind at adjacent base pair sites in violation of neighbour exclusion, whereas molecules with longer linkers
would bind with at least one base pair separation as dictated by neighbour exclusion (Figure 9.7).
For example, bisacridinewas developed as a transcription inhibitor (Figure 9.8). Structures of this type
can bisintercalate into DNA forming a two base pair sandwich, with threading of the carboxamide side
groups through the helix so that the protonated dimethylammonium groups hydrogen bond with O-6 and
N-7 atoms of guanine. This compound has also been found to bind symmetrically to a DNA quadruplex
that has junction-like properties.^24
Simply by altering the number of methylene groups in the bisacridine, i.e.by varying the number nin
Figure 9.8, it is possible to modulate linker length. Hydrodynamic studies using viscosity measurements
have shown that for n 4 the molecules only monointercalate (Figure 9.7c). When n 6 the molecules
bisintercalate (Figure 9.7b), i.e.in violation of the neighbour exclusion principle. However, when n8,
the molecule bisintercalates without violating neighbour exclusion principles (Figure 9.7a). For molecules
with a linker length of n6, viscosity and NMR data are not in accord. Analysis of imino proton chemical
shifts upon titration of bisacridine to the self-complementary oligonucleotides d(AT) 5 showed that bisin-
tercalationoccurred for 7n10 but only monointercalation was observed when 4n6. The
aliphatic linker in these molecules is highly flexible and therefore it is possible that the n6 molecules
might bind without violating neighbour exclusion if local distortions in the DNA could be induced. If such
356 Chapter 9
Figure 9.8 A flexibly linked bisintercalator formed from two dimethylaminoethylacridine-4-carboxamide moieties
Figure 9.7 The effect of linker length on possible bisintercalator binding modes