Furanose-Pyranose Isomerization of Reduced Pyrimidine and Cyclic Urea Ribosides

Article abstract of 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-(β-D-Ribopyranosyl)hexahydropyrimidin-2-one (7) was synthesized and used in conjuction 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 δ upfield shift and 4-Hz increase 1H in the J_1',2' coupling constant for the pyranose anomeric proton in the 1H NMR spectrum is indicative of a pyranose β-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 at equilibrium.At pH 1 and 37 deg 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.