title: Phosphoramidate ProTides of the anticancer agent FUDR successfully deliver the preformed bioactive monophosphate in cells and confer advantage over the parent nucleoside.
abstract: The fluorinated pyrimidine family of nucleosides continues to represent major current chemotherapeutic agents for treating solid tumors. We herein report their phosphate prodrugs, ProTides, as promising new derivatives, which partially bypass the dependence of the current drugs on active transport and nucleoside kinase-mediated activation. They are also resistant to metabolic deactivation by phosphorolytic enzymes. We report 39 ProTides of the fluorinated pyrimidine FUDR with variation in the aryl, ester, and amino acid regions. Notably, only certain ProTide motifs are successful in delivering the nucleoside monophosphate into intact cells. We also find that the ProTides retain activity in mycoplasma infected cells, unlike FUDR. Data suggest these compounds to be worthy of further progression.
authors: Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK. mcguigan@cardiff.ac.uk
authors: Christopher
authors: C
authors: McGuigan
authors: Paola
authors: P
authors: Murziani
authors: Magdalena
authors: M
authors: Slusarczyk
authors: Blanka
authors: B
authors: Gonczy
authors: Johan
authors: J
authors: Vande Voorde
authors: Sandra
authors: S
authors: Liekens
authors: Jan
authors: J
authors: Balzarini
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics; D005467:Floxuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D045790:Mycoplasma hyorhinis / Q000201:enzymology; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D057845:Pyrimidine Phosphorylases / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D033721:Equilibrative Nucleoside Transporter 1; D009943:Organophosphorus Compounds; D011355:Prodrugs; C438649:SLC29A1 protein, human; D005467:Floxuridine; D057845:Pyrimidine Phosphorylases