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Development of Fluorophosphoramidate as a Biocompatibly Transformable Functional Group and its Application as a Phosphate Prodrug for Nucleoside Analogs.

Yuki YoshidaTi ZhengWataru TanabeFumiaki TomoikeFumitaka HashiyaTetsuro SuzukiShuto HirotaYuriko SaikiAkira HoriiAkiyoshi HirayamaTomoyoshi SogaYasuaki KimuraHiroshi Abe
Published in: ChemMedChem (2022)
Synthetic phosphate-derived functional groups are important for controlling the function of bioactive molecules in vivo. Herein we describe the development of a new type of biocompatible phosphate analog, a fluorophosphoramidate (FPA) functional group that has characteristic P-F and P-N bonds. We found that FPA with a primary amino group was relatively unstable in aqueous solution and was converted to a monophosphate, while FPA with a secondary amino group was stable. Furthermore, by improving the molecular design of FPA, we developed a reaction in which a secondary amino group is converted to a primary amino group in the intracellular environment and clarified that the FPA group functions as a phosphate prodrug of nucleoside. Various FPA-gemcitabine derivatives were synthesized and their toxicity to cancer cells were evaluated. One of the FPA-gemcitabine derivatives showed superior toxicity compared with gemcitabine and its ProTide prodrug, which methodology is widely used in various nucleoside analogs, including anti-cancer and anti-virus drugs.
Keyphrases
  • oxidative stress
  • cancer therapy
  • drug release
  • squamous cell carcinoma
  • aqueous solution
  • structure activity relationship