Topoisomerase is responsible for relaxing DNA supercoiling. Inhibitors of this enzyme are common chemotherapeutic agents for the treatment of cancer, but new less toxic versions are needed. 12,13-Dihydro-N-methyl-6,11,13-trioxo-5H-benzo[4,5]cyclohepta[1,2-b]naphthalen-5,12-imine (hereafter called TU100) was synthesized as a potential drug candidate. To determine if TU100 inhibits topoisomerase, we established an activity assay using partially purified enzyme and supercoiled plasmid DNA. Relaxation of the supercoilded plasmid by topoisomerase can be visualized by agarose gel electrophoresis followed by ethidium bromide staining of the DNA. Initial experiments determined the concentration of enzyme required for efficient plasmid DNA unwinding. Next the ability of TU100 to inhibit the reaction was compared to other well known topoisomerase drugs like camptothecin and etoposide. Current efforts are focused on determining the mechanism of inhibition, which may involve redox regulation of the topoisomerase enzyme.

Characterization of a novel topoisomerase inhibitor

241st National Meeting (2011)

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