Inhibition of uridine kinase and the salvage of uridine by modified pyrimidine nucleosides.
Uridine kinase can play a crucial role in the provision of pyrimidine nucleotides for cellular nucleic acid synthesis, particularly when de novo synthesis is inhibited by chemotherapeutic agents. Therefore, uridine kinase is an attractive target for drug development. We examined a series of 29 analogs of uridine, most with modifications at the 5'-position, as inhibitors of uridine kinase in vitro and of uridine salvage by intact L1210 cells. Substitution at the 5'-position resulted in decreased efficacy as inhibitors of uridine kinase, particularly if the substituent was large. None of the analogs with 5'-position modifications effectively inhibited salvage of uridine by intact L1210 cells. Four carbocyclic pyrimidine nucleoside analogs (one series) were all effective competitive inhibitors of uridine kinase and of uridine salvage by intact L1210 cells. Cyclopentenyl uracil 19 shows promise for further development as it inhibits uridine salvage at nontoxic concentrations.
D000818:Animals; D002460:Cell Line; D007939:Leukemia L1210 / Q000378:metabolism; D051379:Mice; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D011741:Pyrimidine Nucleosides / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014529:Uridine / Q000378:metabolism*; D014541:Uridine Kinase / Q000037:antagonists & inhibitors*
D011741:Pyrimidine Nucleosides; D010770:Phosphotransferases; D014541:Uridine Kinase; D014529:Uridine