The nucleus of every human cell possesses 46 chromosomes (23 pairs), each
chromosome consisting of one large DNA molecule. Each chromosome is composed of
several thousand DNA segments called genes; the sum of all genes in a human cell is
the human genome. Often a gene will begin in one small section of meaningful DNA
called an exon, and then be interrupted by a seemingly nonsensical segment called
anintron.
The nucleic acids DNA and RNA have justifiably stood at the centre of contempo-
rary biology and biochemistry for the past 50 years. Their remarkable structure and the
ever-increasing insight into their intricate functions triggered the major scientific revo-
lution labeled “molecular biology.” Since medicinal chemistry and molecular pharma-
cology are at the confluence of physical chemistry and molecular biology, nucleic acids
have been investigated and recognized as the targets of several major groups of drugs.
Some antibiotics, numerous antiparasitic agents, many antineoplastic (antitumour)
drugs, and most of the antiviral compounds exert their varied actions on different phases
of nucleic acid function.
From the perspective of a drug designer, a fundamental question concerns the rele-
vance of nucleic acids as a druggable target for rational drug design. Despite the over-
whelming importance of DNA and RNA to cell heredity, the number of pathological
processes in which nucleic acids play a central role is surprisingly low. Cancer is the
major human disease in which nucleic acid biochemistry is crucial. Since cancer arises
from uncontrolled cellular reproduction and proliferation, it is understandable that
nucleic acids would exert an important influence in the etiology and pathogenesis of
cancer.
The other important disease states in which DNA/RNA targets are crucial for drug
design are infections. However, there are fundamental differences between targeting
nucleic acids for cancer treatment and targeting them to treat a viral or bacterial infec-
tion. Cancer is a disease of “self ”; the genome of the cancer cell is like the genomes of
every other cell in the patient’s body—targeting the cancer cell is analogous to targeting
the other “healthy” cells in the body. Infections, on the other hand, involve “nonself.”
The genome of the virus or bacterium is different from the genome of the patient’s body
(reflecting the fact that the bacterium is a different life form from the human that it
infects). If the differences between genomes can be understood and exploited at a mol-
ecular level, it is possible to engineer a drug specific for the virus (or bacterium) that
will hopefully spare the genome of the human host organism suffering from the infection.
In recognition of this fundamental difference, drug design for cancer (i.e., for drugs
targeting human genome nucleic acid sequences) is presented in this chapter. Drugs
targeting the nonself genome of exogenous pathogens, such as viruses, bacteria, fungi
or parasites, are discussed in chapter 9. However, given that the basic nucleotide build-
ing blocks are the same for humans as for viruses, many of the drug design concepts are
similar when designing “anti-nucleic acid drugs” for either endogenous cancer or
exogenous infections.
As a putative receptor, nucleic acids are suitable molecules. Nucleic acids, unlike alkyl
chain lipids, are not “bland”; rather, they are reasonably complicated molecules in terms
of possessing heteroatoms and hydrogen-bonding donors and acceptors. Such com-
plexity affords a diversity of opportunities for designing molecules capable of unique
interactions with DNA or RNA. Given the importance of nucleic acids to heredity and
442 MEDICINAL CHEMISTRY