444 MEDICINAL CHEMISTRY
through its amino groups. Above (and below) this intercalated ethidium molecule lies
another one, which is simply stacked and does not interact with the phosphate in an
ionic bond. The phenyl and ethyl groups of the interacting ethidium molecule lie outside
(in the minor groove of) the double helix; only the planar tricyclic ring interacts with
the nucleotides. As a result, the base pairs of the helix are twisted by 10° and separated
by 0.67 nm, and the helix unwinds by −26° at the intercalation site. Since this distorts
the double helix, the replication and transcription of genes are compromised.
Ethidium is a model compound for these studies. In human pharmacology, two
classes of natural products (actinomyces, anthracyclines) provide prototypic molecules
as DNA intercalating agents. (Planar molecules tend to insert well into the stacked
nucleic acids, which accounts for the carcinogenic potential of polyaromatic hydrocarbons;
see figure 7.5.)