The novel napthoquinone adduct 12,13-Dihydro-N-methyl-5,11,13-trioxo-5H-benzo[4,5]cyclohepta[1,2-b]napthalen-5,12-imine (TU100) was synthesized as a potential chemotherapeutic agent.  TU100 is structurally similar to anthracyclines and isoquinones.  TU100 is a potent topoisomerase I and II inhibitor, but unlike anthracyclines, does not intercalate DNA. Pre-incubation of topoisomerase II with TU100 shows the drug is a slow acting topoisomerase II inhibitor that works in the absence of DNA.  Diluting the pre-incubated TU100 and topoisomerase II failed to alleviate inhibition suggesting covalent modifcation of the enzyme.  Cystenine thiols have been identified as the potential target due to the ability of reducing agents to reverse TU100 inhibition.  Consistent with this thought, TU100 protected topoisomerase II from activation by the sulfhydryl modifying agent N-ethylmaleimide (NEM).   These results indicate that TU100 inactivates free topoisomerase II through alkylation of cysteine residues.  With its unique mechanism of inhibition and specific targeting, it is hopeful TU100 can be developed as a new form of chemotherapeutics.

Mechanism of topoisomerase II inhibition by a novel naphthonquinone adduct

243rd National Meeting (2012)

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