There is considerable interest in the development of sequence-selective
DNA drugs. Chemical agents able to interfere with
DNA topoisomerases - essential nuclear
enzymes- are widespread in nature, and some of them have outstanding therapeutic efficacy in human
cancer and
infectious diseases. Several classes of
antineoplastic drugs, such as
amsacrine,
daunorubicin,
etoposide (acting on type II topoisomerases),
camptothecin and indolocarbazole derivatives of the
antibiotic rebeccamycin (acting on type IB topoisomerases), have been shown to stimulate DNA cleavage by topoisomerases leading to cell death. However, these molecules exhibit little sequence preference. A convenient strategy to confer sequence specificity consists in the attachment of these topoisomerase
poisons to sequence-specific
DNA binding elements. Among sequence-specific
DNA ligands,
oligonucleotides can bind with high specificity of recognition to the major groove of double-helical
DNA, resulting in triple helix formation. In this context, derivatives of
camptothecin, indolocarbazole,
anthracycline and
acridine poisons have been covalently tethered to triple helix-forming
oligonucleotides. The use of triple-helical
DNA structures offers an efficient system to target
topoisomerase I and II-mediated DNA cleavage to specific sequences and to increase the
drug efficacy at these sites. Chemical optimization of the conjugates is essential to the efficacy of drug targeting. Consequently, the rational design of this new class of anti-
cancer agents, conceived from topoisomerase
poisons and triplex-forming
oligonucleotides, may be exploited to improve the efficacy and selectivity of the DNA damage induced by topoisomerases.