Podophyllotoxin aza-analogue, a novel DNA topoisomerase II inhibitor.
The pendant E-ring moiety of the podophyllotoxin aza-analogue 1 that is a potent inhibitor of microtubule assembly was modified in order to acquire inhibitory activity of DNA topoisomerase II. The monophenolic analogue 2 did not exhibit human topoisomerase II inhibition, while the ortho-quinone 3 that was obtained by oxidation of 2 inhibited its catalytic activity (decatenation) in a dose-dependent manner and stimulated double strand DNA breaks in supercoiled circular plasmid DNA, resulting in the production of linear DNA. These results showed that the topoisomerase II inhibition of the ortho-quinone 3 is due to stabilization of the topoisomerase II-DNA covalent binary complex. On the other hand, the ortho-quinone 3 did not inhibit the relaxation process of supercoiled DNA by topoisomerase I at concentrations up to 400 microM, nor was intercalation observed in unwinding measurements of 3. Therefore, the ortho-quinone 3 was shown to be a novel nonintercalative topoisomerase II specific inhibitor that stabilizes the cleavable complex. The present results suggest that the 4'-free hydroxyl group on the E-ring and the sugar moiety on the C-ring are not a prerequisite for topoisomerase II inhibition by podophyllotoxin derivatives.
Iida
A
A
Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Kano
M
M
Kubota
Y
Y
Koga
K
K
Tomioka
K
K
D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008956:Models, Chemical; D009690:Nucleic Acid Conformation; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D059005:Topoisomerase II Inhibitors
D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D004247:DNA; D011034:Podophyllotoxin