Deoxyribonucleic Acid Topoisomerase Inhibitors

Abstract

Drugs that inhibit the action of topoisomerase enzymes (regulatory enzymes that catalyze the breakage and religation of DNA) are an important class of anticancer drugs. The drugs bind reversibly to form ternary drug/DNA/enzyme complexes that result in cytotoxic DNA breaks, primarily by preventing the relegation step. The drugs are usually classified by their spectrum of inhibition, as inhibitors of topo I, topo II, or of both enzymes (dual topo I/II inhibitors). The majority of the topo II and dual topo I/II inhibitors are DNA intercalators, where a flat polyaromatic drug chromophore intercalates between the base pairs, driven primarily by stacking and electrostatic interactions. There is also a substantial and diverse class of drugs with little direct DNA affinity but which nevertheless form ternary complexes. Inhibitors of topo I are primarily of the latter type, most being analogues of the natural product camptothecin. The major deficiencies of this class are the instability of the essential E ring lactone and the susceptibility of the drugs to cell efflux mechanisms, and the majority of the new analogues attempt to improve these. Inhibitors of topo II are mostly DNA intercalators, with the major deficiencies being cardiotoxicity and, again, susceptibility to cell efflux pumps. While the cardiotoxicity issue has been quite well addressed, many topo II drugs are still susceptible to transport-mediated resistance. There is evidence that some of the newer topo II inhibitors may act by additional mechanisms. Finally, the dual topo I/II inhibitors represent the newest class of topoisomerase-active drugs. While it is still not clear if such dual inhibition is an advantage, the class has considerable structural diversity, with some members inhibiting topoisomerase in a novel manner, and others suspected of working primarily by non-topoisomerase mechanisms.