[Acronycine revisited: development of benzo[b]acronycine antitumor agents].
Palabras clave
Abstracto
The acridone alkaloid acronycine, isolated from several Sarcomelicopespecies (Rutaceae) was shown to exhibit a promising activity against a broad spectrum of solid tumors. Nevertheless, subsequent clinical trials gave limited results, probably due to the moderate potency and poor water solubility 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. 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 prompted us to develop benzo[b]acronycine analogs possessing an additional aromatic ring linearly fused on the natural alkaloid basic skeleton. In vivo, 1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine esters and diesters, exemplified by cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine developed 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.