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.
Nguyen
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Laboratoire de Pharmacognosie de l'Université Paris Descartes, UMR/CNRS 8638, Faculté de Pharmacie, Paris, France.
Nguyen
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Yougnia
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Gaslonde
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Dufat
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Michel
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Tillequin
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D000175:Acronine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D000175:Acronine