Mechanism of Nucleophilic Activation of (-)-Lomaiviticin A

(-)-Lomaiviticin A (1) is a C₂-symmetric cytotoxin that contains two diazofluorene functional groups and which induces double-strand breaks (DSBs) in DNA. Evidence suggests DNA cleavage is initiated by hydrogen atom abstraction from the deoxyribose backbone. Here we demonstrate the formation of the vinyl radicals 1· and 2· from 1 by 1,7-addition of thiols to the diazofluorenes. These radicals can affect hydrogen atom abstraction from methanol and acetone. The first addition of thiol to 1 proceeds at a much greater rate than the second. The diazosulfide 5 formed en route to 1· has been detected at -50 °C and undergoes decomposition to 1· with a half-life of 110 min at -20 °C under air. These data, which constitute the first direct evidence for the generation of 1· and 2· from 1, provide insights into the mechanism of DNA cleavage by 1.