期刊
CHEMMEDCHEM
卷 17, 期 17, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202200188
关键词
nucleoside analogs; prodrugs; anti-cancer drugs; antiviral drugs; phosphate
资金
- AMED [JP21fk0310102, JP20fk0108520, JP21ak0101119]
- Takeda Science Foundation
- KAKENHI [20K21249]
- Grants-in-Aid for Scientific Research [20K21249] Funding Source: KAKEN
In this study, we have developed a new type of biocompatible phosphate analog (fluorophosphoramidate, FPA) and investigated its function in vivo. By improving the molecular design of FPA, we found that it can function as a phosphate prodrug of nucleoside. Additionally, one of the synthesized FPA-gemcitabine derivatives showed superior toxicity to cancer cells.
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.
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