DNA interstrand cross-link formation by reductive activation of dehydropyrrolizidine progenitors

Pyrrolizidine alkaloids (PAs) are potent hepatotoxins and carcinogens isolated from a wide variety of plants. The hepatotoxicity of these agents is a manifestation of the initial production and release of the reactive dehydropyrrolizidine, which is the DNA-cross-linking species, generated in the liver by the mixed function cytochrome P450 oxidases. A separate class of DNA cross-linkers, including the clinically significant mitomycins and the related FR900482 and congeners are reductively activated in vivo forming a very similar pyrrolic-type intermediate responsible for the DNA cross-linking reactivity of these substances. We report here the synthesis and DNA cross-linking studies of a reductively activated dehydromonocrotaline progentior and its dicarbamate derivative.