Dual topoisomerase I/II poisons as anticancer drugs

Abstract

Topoisomerases I and II, intranuclear enzymes that play vital roles in DNA replication and transcription, are attractive targets for cancer chemotherapy. Topoisomerase-active drugs either inhibit the ability of the enzymes to initially cleave DNA (catalytic inhibitors) or stabilise the fragile and normally transient 'cleavable complexes' they form by preventing strand religation (poisons). Many clinically useful drugs exert their cytotoxic effects through poisoning of either topo I or topo II. Because the level and time-course of expression of these enzymes vary in different cell types, and the development of resistance to one type of inhibitor is often accompanied by a concomitant rise in the level of the other enzyme, there is an increasing interest in drugs that can act as dual topo I/II poisons. The major classes of such dual poisons are benzophenanthridine alkaloids, indolocarbazoles and lipophilic bis(naphthalimides), but include anthraquinones, pyridoindoles, indenoquinolones and acridines. No overall structure-activity relationships are discernible for this property, but small structural changes within a particular series appear to markedly alter the relative activities of analogues towards the two enzymes. This observation supports the 'drug stacking' model of interaction, where inhibitors with a 'deep intercalation mode' are responsible for topo I-mediated cleavage and those with an 'outside binding mode' are responsible for topo II-mediated cleavage.