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, subsequent 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 to a hypothesis of bioactivation of
acronycine by transformation of the 1.2-double bond into the corresponding
oxirane in vivo. This hypothesis and the demonstration that
acronycine should interact with
DNA guided the development of a series of 1.2-dihydroxy-1.2-dihydrobenzo[b]
acronycine esters and diesters as novel anticancer
drug candidates. In vivo, cis-1.2-diacetoxy-1,2-dihydrobenzo[b]
acronycine, selected for further development under the code
S 23906-1, demonstated a marked antitumor activity in human orthotopic models of lung, ovarian and
colon cancers xenografted in nude mice. The cytotoxic and antitumor activities of these compounds were strongly correlated with their ability to give covalent adducts with purified as well as genomic
DNA. Such adducts involve reaction between the exocyclic N-2 amino group of guanines exposed in the minor groove of double helical
DNA and the leaving
ester group at the benzylic position 1 of the
drug.