The silatecans, a novel class of lipophilic camptothecins

Abstract

Camptothecin, a potent cytotoxic agent that inhibits topoisomerase I, was identified in 1966 as a cytotoxic component in extracts of the Chinese tree Camptotheca acuminata. Initial clinical trials with this agent showed promising antitumour activity but due to unacceptable toxicity the trials were halted. The underlying cause of the toxicity was soon determined to be instability of the δ-lactone present in the structure. As a result, analogues were prepared that overcame the lactone instability, leading eventually to the chemotherapeutic drugs irinotecan and topotecan. Although these drugs proved successful in the clinic, side effects and a narrow spectrum of activity have limited their utility. In the decade since the development of these agents, continued research has greatly improved our understanding of camptothecin stability and pharmacology. From this has emerged several new series of analogues that will produce the next generation camptothecin. Silatecans are novel third generation camptothecin analogues that contain lipophilic silane groups. The incorporation of lipophilic substituents into the camptothecin structure provides enhanced blood stability, increased cell penetration and improved pharmacokinetics. This review will first examine the various mechanisms involved and approaches taken to develop new camptothecin-based drugs followed by an analysis of silatecan patents, example compounds and biological data.

• camptothecin (CPT)
• chemotherapy
• cytotoxic agents
• silatecan
• topoisomerase I (topo I)