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Synthesis, physicochemical and biochemical studies of 1',2'-oxetane constrained adenosine and guanosine modified oligonucleotides, and their comparison with those of the corresponding cytidine and thymidine analogs
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
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In: Journal of American Chemical SocietyArticle in journal (Refereed) Submitted
URN: urn:nbn:se:uu:diva-91710OAI: oai:DiVA.org:uu-91710DiVA: diva2:164532
Available from: 2004-04-26 Created: 2004-04-26 Last updated: 2015-05-19Bibliographically approved
In thesis
1. Chemically Modified Oligonucleotides: Synthesis, Physicochemical and Biochemical Properties of their Duplexes with DNA and RNA
Open this publication in new window or tab >>Chemically Modified Oligonucleotides: Synthesis, Physicochemical and Biochemical Properties of their Duplexes with DNA and RNA
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is based on 9 papers dealing with the synthesis, physicochemical and biochemical properties of two types of chemically modified oligonucleotides which have the potential to down-regulate gene expression: (i) The first set is comprised of antisense oligonucleotides (AONs) conjugated with different chromophores of varying size, charge and π-electron density. Conjugation of the chromophores at the 3'- or 5'-end enhanced the target RNA binding affinity and RNase H recruitment capabilities compared to the native counterpart without changing the global helical conformation of their AON/RNA hybrid duplexes. The 3'-dipyridophenazine (DPPZ) has emerged as the most promising non-toxic chromophore in this series. (ii) The second set encompasses a new class of AONs containing North-East conformationally constrained 1',2'-oxetane-nucleosides. The introduction of oxetane-T and -C units imparts lowering of the Tm by ~ 6º and ~ 3 ºC/modification, respectively, of the AON/RNA hybrids, whereas the incorporation of the corresponding oxetane-A and-G units into AONs did not alter the thermostability in comparison with that of the native hybrid duplex. The oxetane-modified AONs have been found to possess enhanced serum stability compared to that of the native, whereas oxetane-T and -C containing AONs were more endonuclease-resistant than oxetane-A and-G modified AONs. All oxetane-modified mixmer AON/ RNA hybrid duplexes were, however, found to be excellent substrates for RNase H cleavage, which has been analyzed by Michaelis-Menten kinetics. The oxetane-modified mixmer AONs have shown effective down-regulation of the proto-oncogene c-myb mRNA in the K562 human leukemia cells, which was analyzed by QRT-PCR and Western Blot. Based on the amount of AON uptake after delivery, determined by slot blot, it was apparent that the oxetane-modified AONs are 5-6 times more effective antisense agents than the corresponding isosequential phosphorothioate analogues. The electrochemical assay based on sensitive nucleic acid mediated charge transport (CT) has revealed that the presence of oxetane-T unit causes more stacking perturbations in a DNA/DNA duplex than in a DNA/RNA duplex.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 56 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 973
Bioorganic chemistry, Antisense oligonucleotides, Dipyridophenazine, Oxetane, RNase H, Gene down-regulation, DNase 1, Charge transport, Bioorganisk kemi
National Category
Organic Chemistry
urn:nbn:se:uu:diva-4247 (URN)91-554-5957-9 (ISBN)
Public defence
2004-05-21, Floor 3, C10: 301, Biomedical Centre (BMC), Uppsala, 13:30
Available from: 2004-04-26 Created: 2004-04-26Bibliographically approved

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Plashkevych, Oleksandr
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