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Synthesis and Structure of Novel Conformationally Constrained 1‘,2‘-Azetidine-Fused Bicyclic Pyrimidine Nucleosides: Their Incorporation into Oligo-DNAs and Thermal Stability of the Heteroduplexes
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för bioorganisk kemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för bioorganisk kemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för bioorganisk kemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för bioorganisk kemi.
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2006 (engelsk)Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 71, nr 1, s. 299-314Artikkel i tidsskrift (Fagfellevurdert) Published
sted, utgiver, år, opplag, sider
2006. Vol. 71, nr 1, s. 299-314
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URN: urn:nbn:se:uu:diva-96311DOI: 10.1021/jo052115xOAI: oai:DiVA.org:uu-96311DiVA, id: diva2:170843
Tilgjengelig fra: 2007-10-18 Laget: 2007-10-18 Sist oppdatert: 2017-12-14bibliografisk kontrollert
Inngår i avhandling
1. Conformationally Constrained Nucleosides: Design, Synthesis, and Biochemical Evaluation of Modified Antisense Oligonucleotides
Åpne denne publikasjonen i ny fane eller vindu >>Conformationally Constrained Nucleosides: Design, Synthesis, and Biochemical Evaluation of Modified Antisense Oligonucleotides
2007 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

This thesis is concerned with synthesis, structure and biochemical analysis of chemically modified oligonucleotides with potential therapeutic applications. The three types of chemical modifications described here are: (a) A North-East locked 1',2'-azetidine nucleoside (b) A North locked 2',4'-cyanomethylene bridged nucleoside and (c) A 2',4'-aza-ENA-T nucleoside. The synthesis of the 1',2'-azetidine fused nucleosides was described using two different approaches. A highly strained 2',4'-cyanomethylene locked nucleoside was synthesized but could not be converted to the phosphoramidite derivative due to instability during derivatization. The key cyclization step in the aza-ENA-T nucleoside synthesis gave rise to two separable diastereomers due to chirality at the exocyclic nitrogen. Conversion of diastereomer 55 to 56 occurred with a large free energy of activation (ΔG = 23.4 kcal mol-1 at 298 K in pyridine-d5). Of the two isomers the equatorial NH product was more stable than the axial one due to reduced 1,3 diaxial interactions. As a result, all NH axial product was converted to the equatorial isomer during subsequent steps in the synthesis. NMR and ab initio experiments confirmed the North-East structure of the 1',2'-azetidine locked nucleoside and North conformation of aza-ENA-T locked nucleosides with a chair conformation of the piperidine ring.

The amino modified nucleosides were incorporated into different positions of a 15mer oligonucleotide. The azetidine modified AONs did not form stable duplexes with complementary RNA (ΔTm ~-1 to -4 °C), but they performed better than previously synthesized isosequential 1',2'-oxetane modified oligonucleotides. The 2',4'-aza-ENA-T modified oligonucleotide, on the other hand, showed excellent target affinity with complementary RNA (ΔTm ~+4 °C). The azetidine and aza-ENA-T modified oligonucleotides showed significant stability in the presence of human serum and snake venom phosphodiesterase (3'-exonuclease) as compared to the unmodified native sequence. The singly modified 15mer oligonucleotides were also subjected to RNase H promoted digestion in order to evaluate their potential as effective antisense agents. The effective enzyme activity (kcat/Km) was found to be lower in the modified AONs due to reduced enzyme-substrate binding. However, the catalytic activity of RNase H with these modified-AON:RNA duplexes were higher than observed with the native duplex.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2007. s. 60
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 354
Emneord
Organic chemistry, chemically modified oligonucleotides, azetidine, aza-ENA-T, cyanomethylene locked, free energy of activation, diaxial interactions, chair conformation, stable duplex, human serum, snake venom phosphodiesterase, antisense agents, RNase H, Organisk kemi
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-8266 (URN)978-91-554-6992-4 (ISBN)
Disputas
2007-11-09, B7:113a, BMC, Husargatan 3, Uppsala, 13:30 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2007-10-18 Laget: 2007-10-18 Sist oppdatert: 2012-08-03bibliografisk kontrollert

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