The
acridone alkaloid acronycine, isolated from several Sarcomelicope species (Rutaceae) was shown to exhibit a promising activity against a broad spectrum of solid
tumors. Nevertheless, clinical trials only gave poor results, probably due to the moderate potency of this
drug. The isolation of the unstable
acronycine epoxide from several New-Caledonian Sarcomelicope led us to a hypothesis of bioactivation of
acronycine by transformation of the 1,2-double bond into the corresponding
oxirane in vivo. Consequently, we synthesized a series of cis-1,2-dihydroxy-1,2-dihydroacronycine diesters which exhibited interesting antitumor properties with a broadened spectrum of activity and an increased potency when compared with
acronycine. The demonstration that
acronycine should interact with
DNA, by some noncovalent process prompted us to develop
benzo[b] acronycine analogs possessing an additional aromatic ring linearly fused on the natural
alkaloid basic skeleton. When tested against a panel of
cancer cell lines in vitro, cis-1,2-dihydroxy-1,2-dihydrobenzo[b]
acronycine diesters exhibited cytotoxic activities within the same range of potency as the most active drugs currently used in
cancer chemotherapy. In vivo, cis-1,2-diacetoxy-1,2-dihydrobenzo[b]
acronycine (S 23906-1), selected for further preclinical development, demonstrated a marked antitumor activity in human orthotopic models of lung, ovarian and
colon cancers xenografted in nude mice.