Synthesis and properties of adenosine oligonucleotide analogues containing methylene groups in place of phosphodiester 5'-oxygens.
The ADP analogue in which the 5'-oxygen has been replaced by a methylene group can be prepared by condensing 5'-deoxy-5'-phosphonomethyladenosine with inorganic phosphate. This analogue readily polymerizes onto the primer A-A in the presence of the enzyme polynucleotide phosphorylase and either Mg2+ or Mn2+. The initial products are of the form A-A(-cA)n-cA (where "-" and "-c" stand for the normal phosphodiester linkage and the linkage in which the 5'-oxygen is replaced with the methylene group, respectively). Treatment of these with alkali yields adenosine 2'(3')-phosphate and the series (A(-cA)n-cA containing only phosphonomethylene linkages. The decamer A(-cA)8-cA interacts with two molecules of U(-U)8-U to form a triple-standard structure that has a stability similar to that exhibited by the analogous complex formed from A(-A)8-A and U(-U)8-U. This property, along with the resistance of these oligomer analogues toward nucleases that cleave phosphodiester linkages between the phosphorus and the 5'-oxygen, should provide a strong rationale for application of phosphonomethylene linkages in schemes for therapeutic drug design that use the antisense strategy.
Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907.
R R
RR
Breaker
G R
GR
Gough
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Gilham
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000737:chemistry; D000812:Anhydrides / Q000737:chemistry*; D006868:Hydrolysis; D008274:Magnesium / Q000378:metabolism; D008345:Manganese / Q000378:metabolism; D009691:Nucleic Acid Denaturation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry* / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011117:Polyribonucleotide Nucleotidyltransferase / Q000378:metabolism
D000812:Anhydrides; D009838:Oligodeoxyribonucleotides; D008345:Manganese; D000244:Adenosine Diphosphate; C064434:5'-deoxy-5'-phosphonomethyladenosine phosphate; D011117:Polyribonucleotide Nucleotidyltransferase; D010727:Phosphoric Diester Hydrolases; D008274:Magnesium