Oligonucleotides containing the modification 2-fluoro-2-deoxy-beta-D-arabinose (2'F-ANA) were synthesized via solid phase synthesis in order to investigate their ability to bind to nucleic acids (DNA and RNA). The ability of this modification to serve as a suitable antisense oligonucleotide construct was also evaluated. / All four nucleobase monomers (thymine, cytosine, adenine and guanine) were prepared for solid phase oligonucleotide synthesis, from which homopolymeric and heteropolymeric base sequences were assembled. These molecules bound with very good affinities to both DNA and RNA targets. Structural studies via NMR experiments demonstrated that in a 2'F-ANA/RNA duplex the 2'F-ANA residues adopt an O4' -endo conformation, similar to what has been proposed for the structure of DNA in a DNA/RNA hybrid. / A 2'F-ANA oligopyrimidylate formed a triple-helical complex with duplex DNA and hybrid DNA(Pu):RNA(Py) with an affinity higher than that of a corresponding DNA strand. Also, a cytosine-rich 2' F-ANA strand was found to form a complex at acidic pH which has properties similar to that of i-motif DNA. / Finally, 2'F-ANA strands when hybridized to RNA were found to activate RNase H, an enzyme that is involved in the mechanism of action of antisense drugs. 2'F-ANA is the first example of an antisense analogue that demonstrates improved binding to RNA relative to DNA and still retains the ability to elicit RNase H activity.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.36730 |
| Date | January 1999 |
| Creators | Wilds, Christopher James. |
| Contributors | Damha, Masad Jose (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Chemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001745456, proquestno: NQ64692, Theses scanned by UMI/ProQuest. |
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