to the control of cellular protein synthesis, drug design that targets nucleic acids should be
reserved for major pathologies such as cancer. On the basis of molecular mechanisms,
drugs that act upon nucleic acids can be classified in the following way:
- Drugs interfering with DNA replication
a. Intercalating cytostatic agents
Actinomyces
Anthracyclines
b. Alkylating cytostatic agents
Bis(chloroethyl)amines (nitrogen mustards)
Nitrosoureas
Aziridines
Alkylsulphonates
c. Antimetabolites interfering with DNA synthesis
Folate antagonists
Purine antimetabolites
Pyrimidine antimetabolites
d. Antibacterial agents interfering with DNA topoisomerase - Drugs interfering with transcription and translation
a. Cytostatic platinum complexes and bleomycin
b. Antisense oligomers - Drugs interfering with mitosis
a. Vinca alkaloids
b. Taxane alkaloids
7.8.1 Drugs Interfering with DNA ReplicationThere are several mechanisms by which a drug molecule can interfere with DNA
replication. These range from agents that insert into the DNA structure, altering its
geometry, to compounds that inhibit enzymes crucial to DNA metabolism.
7.8.1.1 Intercalating Cytostatic Agents
Intercalating drugs associate strongly with the DNA in the cell nucleus by slipping
between two base pairs of the double helix and forming charge-transfer complexes with
the nucleotides. This interaction is geometrically controlled, and it has been shown that
some compounds (e.g., daunomycin,7.54, proflavine,7.55) intercalate at the major
grooveof DNA whereas others (e.g., actinomycin D,7.56, or ethidium,7.57) do so only
at the minor grooveof the helix. There are even indications that some intercalating
agents are selective for certain base sequences. By intercalating into the DNA structure,
such agents modify DNA conformation, thereby altering its function.
Intercalation has been studied thoroughly on oligonucleotide models using both
experimental (X-ray crystallography) and theoretical (molecular modeling calculations)
approaches. Such work has studied the complex formed between a model oligonu-
cleotide and ethidium (7.57). The ethidium molecule shown forms a charge-transfer
stack and also interacts with the phosphate anions, forming salt bonds with the latter
ENDOGENOUS CELLULAR STRUCTURES 443