Introduction of a fluorine atom at C3 of 3-deazauridine shifts its antimetabolic activity from inhibition of CTP synthetase to inhibition of orotidylate decarboxylase, an early event in the de novo pyrimidine nucleotide biosynthesis pathway.
The antimetabolite prodrug 3-deazauridine (3DUrd) inhibits CTP synthetase upon intracellular conversion to its triphosphate, which selectively depletes the intracellular CTP pools. Introduction of a fluorine atom at C3 of 3DUrd shifts its antimetabolic action to inhibition of the orotidylate decarboxylase (ODC) activity of the UMP synthase enzyme complex that catalyzes an early event in pyrimidine nucleotide biosynthesis. This results in concomitant depletion of the intracellular UTP and CTP pools. The new prodrug (designated 3F-3DUrd) exerts its inhibitory activity because its monophosphate is not further converted intracellularly to its triphosphate derivative to a detectable extent. Combinations with hypoxanthine and adenine markedly potentiate the cytostatic activity of 3F-3DUrd. This is likely because of depletion of 5-phosphoribosyl-1-pyrophosphate (consumed in the hypoxanthine phosphoribosyl transferase/adenine phosphoribosyl transferase reaction) and subsequent slowing of the 5-phosphoribosyl-1-pyrophosphate-dependent orotate phosphoribosyl transferase reaction, which depletes orotidylate, the substrate for ODC. Further efficient anabolism by nucleotide kinases is compromised apparently because of the decrease in pK(a) brought about by the fluorine atom, which affects the ionization state of the new prodrug. The 3F-3DUrd monophosphate exhibits new inhibitory properties against a different enzyme of the pyrimidine nucleotide metabolism, namely the ODC activity of UMP synthase.
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. jan.balzarini@rega.kuleuven.be
Jan
J
Balzarini
Federico
F
Gago
Wim
W
Kulik
André B P
AB
van Kuilenburg
Anna
A
Karlsson
Matt A
MA
Peterson
Morris J
MJ
Robins
D015092:3-Deazauridine / Q000031:analogs & derivatives / Q000737:chemistry*; D000818:Animals; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D005461:Fluorine / Q000737:chemistry*; D054879:Halogenation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011741:Pyrimidine Nucleosides / Q000096:biosynthesis*
D011741:Pyrimidine Nucleosides; D015092:3-Deazauridine; D005461:Fluorine; D009964:Orotidine-5'-Phosphate Decarboxylase; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase