[From acronycine to benzo-[b]-acronycine derivatives: potent antitumor agents].

The acridone alkaloid acronycine, first isolated in 1948, was shown in 1966 to have promising activity against a range of solid tumors. Clinical trials conducted in 1983 gave disappointing results, however, probably owing to the moderate potency of this drug. Our isolation of the unstable molecule acronycine epoxide raised the possibility of bioactivating acronycine by transforming the 1,2-double bond into the corresponding epoxide in vivo. Evidence that acronycine interacts with DNA prompted us to develop analogs in the benzo[b]acronycine series. In vivo, benzo[b]acronycine derivatives show marked activity in nude mouse models of orthotopic human lung, ovarian and colon cancers. Their mechanism of action involves monoalkylation of the 2-amino group of DNA guanine residues. A typical representative--a diacetate designated S 23906--is currently in phase II clinical trials.