Structure-activity relationships of 9-anilinoacridines as inhibitors of human DNA topoisomerase II.

A series of 9-anilinoacridines, based on the anticancer drug amsacrine [4'-(9-acridinylamino)methanesulphon-m-anisidide; m-AMSA], were synthesized and evaluated for their ability to inhibit both the growth of Jurkat leukaemia cells and human DNA topoisomerase II in vitro. Inhibition of topoisomerase II activity occurred via one of two mechanisms of drug action: (i) direct inhibition of the strand-passing activity or (ii) stabilization of cleavable complex formation. Although the majority of compounds evaluated inhibited P4 DNA unknotting activity catalysed by DNA topoisomerase II up to 100 microM, derivatives bearing 1'-substituents containing SO2 moieties (e.g. 1'-NHSO2Me and 1'-SO2NH2 groups) were generally the most potent inhibitors of DNA topoisomerase II-mediated DNA religation, being effective at concentrations of 1-5 microM. No obvious correlation was observed between the cytotoxicity of individual drugs and linear DNA formation in the in vitro topoisomerase II assays, either across the whole drug series or within similar subgroups. However, a selected group of drugs with different cytotoxicities (compounds 5, 12 and 30; Table I) stimulated DNA topoisomerase II-mediated DNA strand breaks in intact Jurkat cells by 3.5-, 11- and 2.2-fold, respectively, at a concentration of 10 microM, while compounds 31 and 32 did not produce protein-associated DNA strand breaks in whole cells. There was a good correlation between the ability of these selected compounds to induce topoisomerase II-mediated DNA strand breaks in vitro or in whole cells, and their cytotoxicity to Jurkat cells.