Synthesis of 5'-functionalized nucleosides: S-Adenosylhomocysteine analogues with the carbon-5' and sulfur atoms replaced by a vinyl or halovinyl unit

Bioorg Med Chem. 2008 May 15;16(10):5424-33. doi: 10.1016/j.bmc.2008.04.017. Epub 2008 Apr 12.

Abstract

Adenosine and uridine analogues functionalized with alkenyl or fluoroalkenyl chain at C5' were prepared employing cross-metathesis, Negishi couplings, and Wittig reactions. Metathesis of the protected 5'-deoxy-5'-methyleneadenosine or uridine analogues with six-carbon amino acids (homoallylglycines) in the presence of Grubbs catalysts gave nucleoside analogues with the C5'-C6' double bond. Alternatively, the Pd-catalyzed cross-coupling between the protected 5'-deoxy-5'-(iodomethylene) nucleosides and suitable alkylzinc bromides also provided analogues with alkenyl unit. Stereoselective Pd-catalyzed monoalkylation of 5'-(bromofluoromethylene)-5'-deoxyadenosine with alkylzinc bromides afforded adenosylhomocysteine analogues with a 6'-(fluoro)vinyl motif. The vinylic adenine nucleosides produced time-dependent inactivation of the S-adenosyl-l-homocysteine hydrolases.

Publication types

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

MeSH terms

  • Adenosylhomocysteinase / antagonists & inhibitors
  • Adenosylhomocysteinase / chemistry
  • Alkylation
  • Carbon / chemistry*
  • Catalysis
  • Humans
  • Molecular Structure
  • Nucleosides / chemical synthesis*
  • Nucleosides / chemistry
  • Nucleosides / pharmacology
  • Palladium / chemistry
  • S-Adenosylhomocysteine / chemical synthesis*
  • S-Adenosylhomocysteine / chemistry
  • Stereoisomerism
  • Sulfur / chemistry*
  • Vinyl Compounds / chemistry*

Substances

  • Nucleosides
  • Vinyl Compounds
  • Palladium
  • Sulfur
  • Carbon
  • S-Adenosylhomocysteine
  • Adenosylhomocysteinase