Cascade Radical Reactions of Isonitriles: A Second-Generation Synthesis of (20S)-Camptothecin, Topotecan, Irinotecan, and GI-147211C

摘要

The camptothecin family of molecules has recently moved to the forefront of research in the treatment of solid tumors by chemotherapy. The parent of this family, (20S)-camptothecin (la), is highly active, and it is thought to operate by interfering with the unwinding of DNA by the enzyme topoisomerase I. Camptothecin's clinical use has been limited by its insolubility, but extensive structure-activity studies have identified many analogs of camptothecin with equal or better antitumor activity and with better solubility properties. Generally speaking, substitution at C7 and C9-C11 is permitted, while substitution at other positions tends to decrease or completely eliminate activity. Several analogs of camptothecin with improved solubility in water,including topotecan (1b), irinotecan (lc), and GI-147211C (1d), are now in various stages of clinical trials around the world.