A New Strategy To Improve the Metabolic Stability of Lactone: Discovery of (20S,21S)‑21-Fluorocamptothecins as Novel, Hydrolytically Stable Topoisomerase I Inhibitors

Lactone is a common structural motif in biologically active natural products. However, the metabolic instability of lactone significantly reduces their in vivo potency. In the present investigation, a new strategy to improve the metabolic stability of lactone was provided by the design of α-fluoro ether as a novel bioisostere of lactone. The effectiveness of the α-fluoro ether/lactone replacement was validated by the discovery of …