Synthesis and biological activity of a gemcitabine phosphoramidate prodrug.
A gemcitabine (2',2'-difluorodeoxycytidine, dFdC) phosphoramidate prodrug designed for the intracellular delivery of gemcitabine 5'-monophosphate was synthesized. The prodrug was about an order of magnitude less active than gemcitabine against wild-type cells, and the nucleoside transport inhibitor dipyridamole reduced prodrug activity. The prodrug was more active than gemcitabine against two deoxycytidine kinase-deficient cell lines. The results suggest that the prodrug is a potent growth inhibitor that can bypass dCK deficiency at higher drug concentrations.
Wu
Weidong
W
Department of Medicinal Chemistry and Molecular Pharmacology and Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
Sigmond
Jennifer
J
Peters
Godefridus J
GJ
Borch
Richard F
RF
D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003568:Cytidine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000235:genetics; D004176:Dipyridamole / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D033703:Nucleoside Transport Proteins / Q000037:antagonists & inhibitors; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000093542:Gemcitabine
C523436:5'-(2'-deoxy-2',2'-difluorocytidyl) 5-nitrofurfuryl N-methyl-N-(4-chlorobutyl) phosphoramidate; D000964:Antimetabolites, Antineoplastic; D033703:Nucleoside Transport Proteins; D011355:Prodrugs; D003841:Deoxycytidine; D004176:Dipyridamole; D003842:Deoxycytidine Kinase; D003568:Cytidine Monophosphate; D000093542:Gemcitabine