The 4-N-acyl and 4-N-alkyl gemcitabine analogues with silicon-fluoride-acceptor: Application to 18 F-Radiolabeling

Eur J Med Chem. 2018 Mar 25;148:314-324. doi: 10.1016/j.ejmech.2018.02.017. Epub 2018 Feb 12.


The coupling of gemcitabine with functionalized carboxylic acids using peptide coupling conditions afforded 4-N-alkanoyl analogues with a terminal alkyne or azido moiety. Reaction of 4-N-tosylgemcitabine with azidoalkyl amine provided 4-N-alkyl gemcitabine with a terminal azido group. Click reaction with silane building blocks afforded 4-N-alkanoyl or 4-N-alkyl gemcitabine analogues suitable for fluorination. RP-HPLC analysis indicated better chemical stability of 4-N-alkyl gemcitabine analogues versus 4-N-alkanoyl analogues in acidic aqueous conditions. The 4-N-alkanoyl gemcitabine analogues showed potent cytostatic activity against L1210 cell line, but cytotoxicity of the 4-N-alkylgemcitabine analogues was low. However, 4-N-alkanoyl and 4-N-alkyl analogues had comparable antiproliferative activities in the HEK293 cells. The 4-N-alkyl analogue with a terminal azide group was shown to be localized inside HEK293 cells by fluorescence microscopy after labelling with Fluor 488-alkyne. The [18F]4-N-alkyl or alkanoyl silane gemcitabine analogues were successfully synthesized using microscale and conventional silane-labeling radiochemical protocols. Preliminary positron-emission tomography (PET) imaging in mice showed the biodistribution of [18F]4-N-alkyl to have initial concentration in the liver, kidneys and GI tract followed by increasing signal in the bone.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / chemistry
  • Deoxycytidine / pharmacokinetics
  • Fluorides / chemistry*
  • Fluorine Radioisotopes*
  • Gastrointestinal Tract / diagnostic imaging
  • Gastrointestinal Tract / metabolism
  • HEK293 Cells
  • Humans
  • Kidney / diagnostic imaging
  • Kidney / metabolism
  • Liver / diagnostic imaging
  • Liver / metabolism
  • Mice
  • Positron-Emission Tomography
  • Silicon Compounds / chemistry*
  • Tissue Distribution


  • Fluorine Radioisotopes
  • Silicon Compounds
  • Deoxycytidine
  • silicon fluoride
  • gemcitabine
  • Fluorides