[Structure activity relationships and mechanism of action of antitumor benzo[b]acronycine antitumor agents].
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.
Seguin
E
E
Laboratoire de pharmacognosie de l'université de Rouen-Haute Normandie, Faculté de Pharmacie, 22, boulevard Gambetta, F76183 Rouen Cedex 1, France.
Tillequin
Fr
F
D000175:Acronine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D013329:Structure-Activity Relationship
D000972:Antineoplastic Agents, Phytogenic; D000175:Acronine