DNA Cross-Linking by a Phototriggered Dehydromonocrotaline Progenitor

A wide variety of pyrrolizidine alkaloids, such as monocrotaline, and the clinically significant mitomycins and the related FR-900482, FK 973, and FR-66979 exert their cytotoxicity through the formation of DNA−DNA interstrand cross-links and DNA−protein cross-links. These naturally occurring antitumor antibiotics are generally either oxidatively or reductively activated in vivo forming a highly reactive pyrrolic-type intermediate, which is responsible for the ultimate DNA cross-linking reaction. These oxidative and reductive pathways, however, often lead to a variety of undesirable toxic events. With the increasing demand for new and less cytotoxic antitumor agents and the recent success of clinically significant photopheresis technologies, we describe here the semisynthesis and DNA cross-linking of the first photochemically triggered progenitor of dehydromonocrotaline.