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

Abstract

Gemcitabine analogues with a lipophilic 4-N-alkyl chain bearing a terminal β-keto sulfonate moiety suitable for fluorination compatible with ¹⁸F-radiolabeling have been explored. Displacement of p-toluenesulfonylamino in protected 4-N-tosylgemcitabine with 1-amino-10-undecene gave 4-N-(10-undecenyl)-3',5'-di-O-benzoyl-2'-deoxy-2',2'-difluorocytidine. Oxidation of the terminal double bond in the latter with OsO₄/NMO afforded 4-N-(10,11-dihydroxyundecanyl) derivative. Regioselective sulfonation of primary hydroxyl followed by oxidation of secondary hydroxyl with Collin's reagent yielded desired β-keto sulfonate analogues 8 or 9. Subsequent displacement of the mesylate or tosylate group with KF in the presence of Kryptofix 2.2.2. or 18-crown-6 ether followed by deprotection with NH₃/MeOH gave 4-N-(11-fluoro-10-oxoundecanyl)-2'-deoxy-2',2'-difluorocytidine 11.

Keywords: anticancer nucleosides; fluorination; gemcitabine; nucleoside synthesis; prodrugs.