The insertion of an intercalation agent appears to occur via either the minor
or major grooves of DNA. Compounds that act as intercalating agents normally
have structures that contain a flat fused aromatic or heteroaromatic ring system
that can fit between the flat structures of the bases of the DNA (Figure 7.13(b) ).
These structures are believed to be held in place in the DNA by hydrogen bonds,
van der Waals’ forces and charge transfer bonds.
7.5.4 Alkylating agents
Alkylating agents are believed to bond to the nucleic acid chains in either the
major or minor grooves. In DNA the alkylating agent frequently forms either
intrastrandorinterstrand links. Intrastrand cross linking agents form a bridge
between two parts of the same chain. This has the effect of distorting the strand,
which inhibits transcription. Interstrand cross links are formed between the two
separate chains of the DNA, which has the effect of locking them together. This
also inhibits transcription, which can ultimately lead to cell death. In both cases
the nucleophilic nature of nucleic acids means that alkylating agents are usually
either electrophiles orin situgive rise to electrophiles. Since the structures of
DNA are relatively easy to model on a computer, the molecular modelling
docking technique (see section 5.5) is a very useful tool for determining whether
a compound is of a suitable size and shape to bind to a section of a nucleic acid.
A wide range of different classes of compounds have been found to act as
nucleic acid alkylating agents (Table 7.6). Their modes of action are not usually
fully understood. However, a large amount of information is available concern-
ing their structure–action relationships.
7.5.5 Antisense drugs
The concept of antisense compounds or sequence defined oligonucleotides
(ONs) offers a new specific approach to designing drugs that target nucleic
acids. The idea underlying this approach is that the antisense compound
contains the sequence of bases complementary to those found in a short
section of the target nucleic acid. The antisense compound binds to the target
nucleic acid by hydrogen bonding between its the bases and the comple-
mentary bases of the target. This inhibits the normal function of the nucleic
acid, which hopefully leads to the desired clinical response. Antisense com-
pounds are able to bind to both RNA and DNA. In the latter case they form
a triple helix.
152 SELECTED EXAMPLES OF DRUG ACTION AT SOME COMMON TARGET AREAS