Gemcitabine (2',2'-difluoro-2'-deoxycytidine, dFdC) is a potent chemotherapeutic nucleoside analogue in the treatment of cancers and solid tumors. Coupling of gemcitabine (NMM/HOBt/EDCI) with varying carboxylic acids of different chain lengths (C9-C13) afforded the 4-N-alkanoylgemcitabine analogues (1 ) bearing a hydroxyl, fluoro, chloro or alkene functional group suitable for further chemical modification. Displacement of p-toluenesulfonylamido group in 4-N-tosylgemcitabine with 11-aminoundecanol or 10-undecenyl amine gave the 4-N-alkylgemcitabines (2 ). The analogues bearing a terminal hydroxyl group on the 4-N-alkanoyl or 4-N-alkyl chain were efficiently fluorinated either with DAST or under conditions that are compatible with synthetic protocols for 18F labeling. The 4-N-alkanoylgemcitabines 1  displayed potent cytostatic activities against L1210, CEM, HeLa and MCF-7 tumor cell lines with IC50 values in the nM range, while activities for the 4-N-alkylgemcitabines 2  were in the �M range.

Synthesis and cytostatic evaluation of 4-<i>N</i>-alkanoyl and 4-<i>N</i>-alkyl gemcitabine analogs

247th National Meeting (2014)

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Synthesis and cytostatic evaluation of 4-N-alkanoyl and 4-N-alkyl gemcitabine analogs