DNA sequence selectivity of topoisomerases and topoisomerase poisons.
Chemical agents able to interfere with DNA topoisomerases are widespread in nature, and some of them have clinical efficacy as antitumor or antibacterial drugs. Drugs which have as a target DNA topoisomerases could be divided into two categories: poisons and catalytic inhibitors. Classical topoisomerase poisons stimulate cleavage in a sequence-selective manner, yielding drug-specific cleavage intensity pattern. The mechanisms of drug interaction with DNA topoisomerases, the DNA sequence selectivity of the action of topoisomerase II poisons and the identification of structural determinants of their activity have suggested that topoisomerase II poisons may fit into a specific pharmacophore, constituted by a planar ring system with DNA intercalation or intercalation-like properties, and protruding side chains interfering with the protein side of the covalent enzyme-DNA complex. The complete definition of the diverse pharmacophores of topoisomerase II poisons will certainly be of value for the design of new agents directed to specific genomic sites, and more effective in the treatment of human cancer.
Capranico
G
G
Division of Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, via Venezian 1, 20133 Milan, Italy. capranico@istitutotumori.mi.it
Binaschi
M
M
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D013379:Substrate Specificity; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004247:DNA