A new strategy to improve the metabolic stability of lactone: discovery of (20S,21S)-21-fluorocamptothecins as novel, hydrolytically stable topoisomerase I inhibitors

J Med Chem. 2013 Oct 24;56(20):7902-10. doi: 10.1021/jm400906z. Epub 2013 Oct 9.


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 (20S,21S)-21-fluorocamptothecins as hydrolytically stable topoisomerase I inhibitors. A highly potent camptothecin derivative, 8l, was successfully identified, which showed excellent in vitro and in vivo antitumor activities and represents a promising lead for the discovery of novel antitumor agents. Interestingly, this study also provided a new structure-activity relationship for the C21-carbonyl group of camptothecin, which has been regarded as an essential pharmacophore. Our results revealed that the conserved C21-carbonyl group can be replaced by a fluorine substituent. α-Fluoro ether may have general application in improving the metabolic stability of lactone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Camptothecin / analogs & derivatives
  • Camptothecin / chemical synthesis
  • Camptothecin / chemistry*
  • Camptothecin / pharmacology
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA Topoisomerases, Type I / metabolism
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Drug Stability
  • Humans
  • Lactones / chemistry*
  • Lactones / metabolism
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Chemical
  • Molecular Structure
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors / chemical synthesis
  • Topoisomerase I Inhibitors / chemistry*
  • Topoisomerase I Inhibitors / pharmacology
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays


  • 7-cyclohexylfluorocamptothecin
  • Antineoplastic Agents
  • Lactones
  • Topoisomerase I Inhibitors
  • DNA Topoisomerases, Type I
  • TOP1 protein, human
  • Camptothecin