Antitumor Agents. 164. Podophenazine, 2‘‘,3‘‘-Dichloropodophenazine, Benzopodophenazine, and Their 4β-p-Nitroaniline Derivatives as Novel DNA Topoisomerase II Inhibitors

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Abstract
We report here the synthesis and biological evaluation of novel DNA topoisomerase II inhibitors, podophenazine (8), 2‘‘,3‘‘-dichloropodophenazine (9), and benzopodophenazine (10), and their 4β-p-nitroaniline derivatives 13−15. Among these, 4‘-O-demethyl-4β-(4‘‘‘-nitroanilino)-4-desoxypodophenazine (13) and 4‘-O-demethyl-2‘‘,3‘‘-dichloro-4β-(4‘‘‘-nitroanilino)-4-desoxypodophenazine (14) were found to inhibit KB cells at sub-micromolar concentrations (IC50 = 0.11 ± 0.03 and 0.48 ± 0.17 μM, respectively). Against KB/7d cells (a pleiotrophic multiple drug-resistant subclone selected with etoposide which has reduced level of topoisomerase II), only compound 13 out of a target series maintained activity in the sub-micromolar concentration range with a IC50 value of 0.56 ± 0.13 μM. The differential toxicity ratio for 13 [IC50(KB/7d)/IC50(KB)] was ∼5. Unlike etoposide and its congeners, compounds 13 and 14 were found to be weak inhibitors of the catalytic activity of topoisomerase II (IC100 = >100 and >150 μM, respectively). In vitro protein-linked DNA complex formation assay revealed that 13 and 14, respectively, induced marginal response (13 at 1 μM, 320.3 ± 124.5 cpm; 13 at 50 μM, 308.8 ± 139.9 cpm; 13 at 100 μM, 446.0 ± 153.5 cpm) and no response (14 at 1 μM, 104.9 ± 52.6 cpm; 14 at 50 μM, 103.3 ± 42.6 cpm; 14 at 100 μM, 101.4 ± 35.2 cpm) compared to the enzyme control. On the basis of these results, we conclude that the mechanism of enzyme inhibition of these compounds is distinct from that of etoposide and its congeners. We are currently investigating the mechanism(s) of action of compounds 13 and 14 as well as synthesizing other derivatives in order to better characterize structure−activity relationships of this series of compounds.