SYNTHESIS OF SPECIFICALLY MODIFIED OLIGONUCLEOTIDES

Project Details

Description

Modified nucleosides present in DNA have been implicated in such diverse
areas as mutagenesis, carcinogenesis, protein-DNA recognition, and
transcription. In addition, it is now known that DNA is conformationally
flexible, and that conformational differences are critically important to
DNA function. In order to begin to understand these effects it is
necessary to have model systems - specifically modified oligonucleotides.
However, such molecules have been largely unavailable due both to the lack
of appropriate modified nucleosides and to the rigors of oligonucleotide
synthesis and purification. The long term goals of this project are to develop and demonstrate the
synthetic strategies and purification methodologies necessary for the
synthesis and utilization of specifically modified oligonucleotides. The
molecules that are proposed will have immediate impact on understanding of
DNA base pairing, conformation, and structure/function relationships. In
addition, the procedures developed will provide access to other modified
oligonucleotides, designed to answer specific questions about DNA. The modified nucleosides to be incorporated will include: 06-methyl- and
06-ethyl deoxyguanosine, N6-methyl- and N6-methoxydeoxyadenosine,
2-aminopurine deoxyriboside, and 15N labelled deoxyadenosine,
deoxyguanosine and 06-alkyldeoxyguanosine. In all cases the routes devised
will be amenable to large scale synthesis so that the modified nucleosides
produced will be usable for oligonucleotide synthesis. In order to incorporate these modified nucleosides into oligonucleotides we
will devise synthetic strategies that are more nucleoside efficient than
are present approaches. The modified oligonucleotides will then be
"paired" with a set of complementary oligonucleotides, so that all possible
combinations with the modified nucleoside and its nearest neighbors will be
present. In addition, we will rigorously examine these synthetic
oligonucleotides to attempt to isolate and identify the minor side
reactions which accompany oligonucleotide synthesis. Side reactions have
been a particular problem with certain modified nucleosides, and also
accompany standard oligonucleotide synthesis.
StatusFinished
Effective start/end date12/31/897/31/99

Funding

  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences

ASJC

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemical Engineering(all)
  • Polymers and Plastics
  • Spectroscopy
  • Cancer Research

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