title: Synthesis and cytostatic evaluation of 4-N-alkanoyl and 4-N-alkyl gemcitabine analogues.
abstract: The coupling of gemcitabine with functionalized carboxylic acids (C9-C13) or reactions of 4-N-tosylgemcitabine with the corresponding alkyl amines afforded 4-N-alkanoyl and 4-N-alkyl gemcitabine derivatives. The analogues with a terminal hydroxyl group on the alkyl chain were efficiently fluorinated under conditions that are compatible with protocols for (18)F labeling. The 4-N-alkanoylgemcitabines showed potent cytostatic activities in the low nanomolar range against a panel of tumor cell lines, whereas cytotoxicity of the 4-N-alkylgemcitabines were in the low micromolar range. The cytotoxicity for the 4-N-alkanoylgemcitabine analogues was reduced approximately by 2 orders of magnitude in the 2'-deoxycytidine kinase (dCK)-deficient CEM/dCK(-) cell line, whereas cytotoxicity of the 4-N-alkylgemcitabines was only 2-5 times lower. None of the compounds acted as efficient substrates for cytosolic dCK; therefore, the 4-N-alkanoyl analogues need to be converted first to gemcitabine to display a significant cytostatic potential, whereas 4-N-alkyl derivatives attain modest activity without measurable conversion to gemcitabine.
authors.affiliation: Department of Chemistry and Biochemistry, ‡Department of Environmental and Occupational Health, Florida International University , Miami, Florida 33199, United States.
authors.forename: Jesse
authors.initials: J
authors.lastname: Pulido
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Sobczak
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Stanislaw F
authors.initials: SF
authors.lastname: Wnuk
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D013329:Structure-Activity Relationship; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000093542:Gemcitabine