Stereodefined synthesis of O3'-labeled uracil nucleosides. 3'-[(17)O]-2'-Azido-2'-deoxyuridine 5'-diphosphate as a probe for the mechanism of inactivation of ribonucleotide reductases

J Org Chem. 2002 Mar 22;67(6):1816-9. doi: 10.1021/jo010899i.

Abstract

Thermolysis of a 2'-[(16)O]-O-benzoyl-[(17)O]-5'-O-(tert-butyldimethylsilyl)-O(2),3'-cyclouridine derivative gave the more stable 3'-[(17)O]-O-benzoyl-[(16)O]- 5'-O-(tert-butyldimethylsilyl)-O(2),2'-cyclouridine isomer, which was converted into 3'-[(17)O]-2'-azido-2'-deoxyuridine by deprotection and nucleophilic ring opening at C2' with lithium azide. The 5'-diphosphate was prepared by nucleophilic displacement of the 5'-O-tosyl group with tris(tetrabutylammonium) hydrogen pyrophosphate. Model reactions gave (16)O and (18)O isotopomers, and base-promoted hydrolysis of an O(2),2'-cyclonucleoside gave stereodefined access to 3'-[(18)O]-1-(beta-D-arabinofuranosyl)uracil. Inactivation of ribonucleoside diphosphate reductase with 2'-azido-2'-deoxynucleotides results in appearance of EPR signals for a nitrogen-centered radical derived from azide, and 3'-[(17)O]-2'-azido-2'-deoxyuridine 5'-diphosphate provides an isotopomer to perturb EPR spectra in a predictable manner.

Publication types

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

MeSH terms

  • Azides / chemistry*
  • Catalysis
  • Chemistry, Organic / methods*
  • Chromatography, High Pressure Liquid
  • Deoxyuracil Nucleotides / chemistry*
  • Electron Spin Resonance Spectroscopy
  • Escherichia coli / enzymology*
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Nitrogen / metabolism
  • Oxygen Isotopes / chemical synthesis
  • Oxygen Isotopes / chemistry
  • Ribonucleoside Diphosphate Reductase / antagonists & inhibitors*
  • Spectrophotometry, Ultraviolet
  • Stereoisomerism
  • Uridine / analogs & derivatives*
  • Uridine / chemical synthesis*
  • Uridine / chemistry

Substances

  • 3'-(O)-2'-azido-2'-deoxyuridine 5'-diphosphate
  • Azides
  • Deoxyuracil Nucleotides
  • Oxygen Isotopes
  • Ribonucleoside Diphosphate Reductase
  • Nitrogen
  • Uridine