Synthesis and characterization of oligonucleotides containing conformationally constrained bicyclo[3.1.0]hexane pseudosugar analogs

Nucleic Acids Res. 2004 Jul 9;32(12):3642-50. doi: 10.1093/nar/gkh667. Print 2004.

Abstract

Oligodeoxyribonucleotides containing pseudorotationally locked sites derived from bicyclo[3.1.0]hexane pseudosugars have been synthesized using adenosine, thymidine and abasic versions of North- and South-methanocarba nucleosides. The reaction conditions for coupling and oxidation steps of oligonucleotide synthesis have been investigated and optimized to allow efficient and facile solid-phase synthesis using phosphoramidite chemistry. Our studies demonstrate that the use of iodine for P(III) to P(V) oxidation leads to strand cleavage at the sites where the pseudosugar is North. In contrast, the same cleavage reaction was not observed in the case of South pseudosugars. Iodine oxidation generates a 5'-phosphate oligonucleotide fragment on the resin and releases the North pseudosugar into the solution. This side reaction, which is responsible for the extremely low yields observed for the incorporation of the North pseudosugar analogs, has been studied in detail and can be easily overcome by replacing iodine with t-butylhydroperoxide as oxidant.

MeSH terms

  • Base Sequence
  • Bridged Bicyclo Compounds / chemistry*
  • Carbohydrates / chemistry
  • Molecular Structure
  • Nucleic Acid Conformation
  • Oligodeoxyribonucleotides / chemical synthesis*
  • Oligodeoxyribonucleotides / chemistry*
  • Organophosphorus Compounds / chemistry
  • Oxidation-Reduction
  • tert-Butylhydroperoxide / chemistry

Substances

  • Bridged Bicyclo Compounds
  • Carbohydrates
  • Oligodeoxyribonucleotides
  • Organophosphorus Compounds
  • phosphoramidite
  • bicyclo(3.1.0)hexane
  • tert-Butylhydroperoxide