Reductive Activation of a Hydroxylamine Hemiacetal Derivative of Dehydromonocrotaline: The First Reductively Activated Pyrrolizidine Alkaloid Capable of Cross-Linking DNA

The acute hepatotoxicity displayed by the pyrrolizidine alkaloids, which obviates their clinical utility, is a result of activation in vivo by cytochrome P450 mediated oxidation. Now the first reductively activated progenitor of the highly cytotoxic dehydropyrrolizidine alkaloid dehydromonocrotaline has been synthesized and demonstrated to mediate interstrand DNA cross-link formation (see scheme); pyrrolizidine alkaloids exert their cytotoxicity through the formation of DNA–DNA interstrand and DNA–protein cross-links.