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.
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.
Wnuk
Stanislaw F
SF
Department of Chemistry, Florida International University, Miami, Florida 33199, USA. wnuk@fiu.edu
Chowdhury
Saiful M
SM
Garcia
Pedro I
PI
Robins
Morris J
MJ
D001386:Azides / Q000737:chemistry*; D002384:Catalysis; D002625:Chemistry, Organic / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D003856:Deoxyuracil Nucleotides / Q000737:chemistry*; D004578:Electron Spin Resonance Spectroscopy; D004926:Escherichia coli / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009584:Nitrogen / Q000378:metabolism; D010103:Oxygen Isotopes / Q000138:chemical synthesis / Q000737:chemistry; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors*; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
C456484:3'-(O)-2'-azido-2'-deoxyuridine 5'-diphosphate; D001386:Azides; D003856:Deoxyuracil Nucleotides; D010103:Oxygen Isotopes; D012262:Ribonucleoside Diphosphate Reductase; D009584:Nitrogen; D014529:Uridine