Camptothecin and its analogs

The antineoplastic agent camptothecin (CPT) (1) (Figure 2.1) was isolated from extracts of Camptotheca acuminata by Wani and Wall. Preclinical studies revealed that CPT had remarkable activity against L1210 leukemia. The marginal water solubility of CPT encouraged researchers to initiate clinical investigation of the drug with the water-soluble sodium salt (2). Unfortunately, poor tumor suppression and numerous side effects were associated with treatment by 2; consequently, the trials were suspended. Interest in CPT was reestablished with the discovery that topoisomerase I (topo I) was the principal cellular target of the drug. Since this discovery, CPT has been the focus of numerous studies; to date, two analogs have been approved for clinical use — the semisynthetic, water-soluble analogs topotecan (Hycamtin) (3) and irinotecan (Camptosar) (4) (Figure 2.1). This chapter summarizes studies of the mechanism of action of CPT, as well as several of the synthetic studies, and provides an account of the current structure-activity studies. Also discussed briefly is the clinical development of topotecan, irinotecan, and several analogs that are currently in various stages of clinical trials.