Gemcitabine analogues with 4-N-alkyl chain modified with fluoromethyl ketone group

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• Synthesis of 2′-[18F]-labelled gemcitabine from the protected 2′-ketouridine or 2′-ketocytidine employing deoxodifluorination method with DAST/[18F]fluoride/K222 were attempted but gave mono 18F-labeled gemcitabine in very low radiochemical yield (0.2–0.3%) and reproducibility: Meyer, J.P. Synthetic Routes to 18F-labelled gemcitabine and related 2′-fluoronucleosides. Ph.D., Cardiff University, 2014.
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• Lipophilic 4-N-alkyl gemcitabine analogues lack hydrolysis in the cell and are not substrate for deoxycytidine kinase (dCK); thus they have lower anticancer activity than their 4-N-acyl counterparts. On the other hand, 4-N-alkyl modified gemcitabine does not undergo deamination by deoxycytidine deaminase (DCA) into toxic derivatives (see Ref. 11). However, 4-N-alkanoyl and 4-N-alkyl analogues had comparable antiproliferative activities in the HEK293 cells, which have high levels of CDA expression (see Ref 30).
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• Positron-emission tomography (PET) imaging in mice showed the biodistribution of [18F]-J to have initial concentration in the liver, kidneys and GI tract followed by increasing signal in the bone (see Ref. 30).
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• We thank you one of the reviewers for suggesting to use a solid-supported amine for the deprotection conditions, so any imine/sulfonate displacement by-product is trapped on the resin, which may ease purification during synthesis of 18F-radiolabeling tracers.
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