acronine and Neoplasms

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.

Topics: Acronine; Alkylation; Animals; Antineoplastic Agents; Cell Proliferation; DNA, Neoplasm; Humans; Mice; Molecular Structure; Neoplasms

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.

Topics: Acronine; Animals; Antineoplastic Agents, Phytogenic; Drug Evaluation, Preclinical; Humans; Molecular Structure; Neoplasms