Furanose-pyranose isomerization of reduced pyrimidine and cyclic urea ribosides

J Med Chem. 1986 Nov;29(11):2351-8. doi: 10.1021/jm00161a034.


Tetrahydrouridine (THU, 2) and other fully reduced cyclic urea ribofuranosyl nucleosides undergo a rapid, acid-catalyzed isomerization to their more stable ribopyranosyl form. This isomerization is characterized by a change in spectral properties and by a greater than 10-fold decrease in potency for those nucleosides that act as potent inhibitors of cytidine deaminase in their ribofuranose form. 1-(beta-D-Ribopyranosyl)hexahydropyrimidin-2-one (7) was synthesized and used in conjunction with its furanose isomer 6 as a model compound for more extensive 1H and 13C NMR, mass spectral, and kinetic studies of this isomerization. The 0.4 delta upfield shift and 4-Hz increase in the J1',2' coupling constant for the pyranose anomeric proton in the 1H NMR spectrum is indicative of a pyranose beta-CI conformation in which the aglycon and C-2' and C-4' hydroxyls are equatorial. The mass spectra of trimethylsilylated pyranose nucleosides also show a characteristic large shift in the m/z 204-217 abundance and the appearance of two new rearrangement ions at M-133 and M-206. For furanose 6 the rate of isomerization is pH and temperature dependent with pyranose 7 predominating by a factor of 6-9 equilibrium. At pH 1 and 37 degrees C, furanose 6 has an initial half-life of less than 12 min. Accordingly, this isomerization may explain the observed lack of enhanced ara-C levels in studies evaluating the oral administration of an ara-C and THU combination to species with an acidic stomach content.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cytarabine / metabolism
  • Cytidine Deaminase / antagonists & inhibitors*
  • Gas Chromatography-Mass Spectrometry
  • Gastric Acidity Determination
  • Hydrogen-Ion Concentration
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Nucleoside Deaminases / antagonists & inhibitors*
  • Nucleosides / pharmacology*
  • Tetrahydrouridine / pharmacology*
  • Uridine / analogs & derivatives*


  • Nucleosides
  • Cytarabine
  • Tetrahydrouridine
  • Nucleoside Deaminases
  • Cytidine Deaminase
  • Uridine