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Camptothecin: current perspectives

2004; Elsevier BV; Volume: 12; Issue: 7 Linguagem: Inglês

10.1016/j.bmc.2003.11.036

1464-3391

Craig J. Thomas, Nicolas J. Rahier, Sidney M. Hecht,

Synthesis and biological activity

This review provides a detailed discussion of recent advances in the medicinal chemistry of camptothecin, a potent antitumor antibiotic. Two camptothecin analogues are presently approved for use in the clinic as antitumor agents and several others are in clinical trials. Camptothecin possesses a novel mechanism of action involving the inhibition of DNA relaxation by DNA topoisomerase I, and more specifically the stabilization of a covalent binary complex formed between topoisomerase I and DNA. This review summarizes the current status of studies of the mechanism of action of camptothecin, including topoisomerase I inhibition and additional cellular responses. Modern synthetic approaches to camptothecin and several of the semi-synthetic methods are also discussed. Finally, a systematic evaluation of novel and important analogues of camptothecin and their contribution to the current structure–activity profile are considered.