Acronycine derivatives: a promising series of anticancer agents.

The pyranoacridone acronycine (1) exhibits antitumor properties against a large panel of solid tumor models, but its moderate potency and low water solubility severely hampered the subsequent clinical trials. Development of synthetic analogues followed the isolation from several Sarcomelicope species of acronycine epoxide (17), which led to a hypothesis of bioactivation of acronycine by transformation of the 1,2-double bond into the corresponding oxirane. 1,2-Diacyloxy-1,2-dihydroacronycine derivatives exhibited antitumor properties, with a broadened spectrum of activity and an increased potency. The demonstration that acronycine interacted with DNA led to the development of benzo[a], [b], and [c]acronycine analogs. 1,2-Dihydroxy-1,2-dihydrobenzo[b]acronycine esters and diesters were active in human orthotopic models of cancers xenografted in nude mice. The activity of these compounds, exemplified by cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine (49), developed in phase I clinical trials under the code S23906-1, was correlated with their ability to give covalent adducts with DNA, involving reaction between the N-2 amino group of guanines in the minor groove and the ester group at the benzylic position of the drug. The influence of the kinetics of DNA alkylation on the cytotoxic and antitumor properties showed a strong correlation between antiproliferative activity and DNA alkylation kinetics, with the most cytotoxic compounds, appearing as the slowest DNA alkylators. Hybrid compounds associating the acridone or benzo[b]acridone chromophore of acronycine derivatives and the epoxyfuran alkylating unit present in psorospermin also displayed potent antiproliferative activities, alkylating DNA guanine units at position N-7 in the major groove, as natural xanthones belonging to the psorospermin series.

[From acronycine to benzo-[b]-acronycine derivatives: potent antitumor agents]. / De l'acronycine aux dérivés de la benzo-[b]-acronycine, puissants agents antitumoraux.

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.

[Structure activity relationships and mechanism of action of antitumor benzo[b]acronycine antitumor agents]. / Relations structure, activité et mécanisme d'action des antitumoraux de série benzo[b]acronycine.

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.

[Main anticancer substances of vegetable origin]. / Principaux anticancéreux d'origine végétale.

During the last thirty years, the systematic screening of thousands of vegetal extracts has led to the isolation of numerous antitumor agents which belong to various chemical series. This paper only deals with some of them which are either of current clinical use or under advanced clinical experimentation, e.g., ellipticine, homoharringtonine, camptothecine, acronycine and their derivatives. The origin, the biological activity and its mechanism, and the toxicity of each of these alkaloids are described. These examples highlight the interest of the Plant Kingdom as source of biologically active new structures and the importance of a good knowledge of the mechanism of the activity and toxicity of active components. This knowledge gives a rational basis to prepare compounds of increased activity or reduced toxicity and to use them at their best in therapeutic.