title: N-Acyl-phosphoramidates as potential novel form of gemcitabine prodrugs.
abstract: Gemcitabine (dFdC) is a cytidine analog remarkably active against a wide range of solid tumors. Inside a cell, gemcitabine is phosphorylated by deoxycytidine kinase to yield gemcitabine monophosphate, further converted to gemcitabine di- and triphosphate. The most frequent form of acquired resistance to gemcitabine in vitro is the deoxycytidine kinase deficiency. Thus, proper prodrugs carrying the 5'-pdFdC moiety may help to overcome this problem. A series of new derivatives of gemcitabine possessing N-acyl(thio)phosphoramidate moieties were prepared and their cytotoxic properties were determined. N-Acyl-phosphoramidate derivatives of gemcitabine have similar cytotoxicity as gemcitabine itself, and have been found accessible to the cellular enzymes. The nicotinic carboxamide derivative of gemcitabine 5'-O-phosphorothioate occurred to be the best inhibitor of bacterial DNA polymerase I and human DNA polymerase α.
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90 363 Lodz, Poland.
authors.forename: Janina
authors.initials: J
authors.lastname: Baraniak
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90 363 Lodz, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pietkiewicz
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90 363 Lodz, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Kaczmarek
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90 363 Lodz, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Radzikowska
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90 363 Lodz, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kulik
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90 363 Lodz, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Krolewska
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90 363 Lodz, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Cieslak
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90 363 Lodz, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Krakowiak
authors.affiliation: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90 363 Lodz, Poland. Electronic address: bnawrot@cbmm.lodz.pl.
authors.forename: Barbara
authors.initials: B
authors.lastname: Nawrot
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D015394:Molecular Structure; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000093542:Gemcitabine
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D010756:Phosphoric Acids; D011355:Prodrugs; D003841:Deoxycytidine; C011067:phosphoramidic acid; D004256:DNA Polymerase I; D000093542:Gemcitabine
keywords: Anticancer therapy; Cytotoxicity; DNA polymerase inhibitor; Gemcitabine; Prodrug