Conformationally Constrained Nucleosides: Design, Synthesis, and Biochemical Evaluation of Modified Antisense Oligonucleotides

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Varghese, Oommen P.,1977-Uppsala universitet,Institutionen för biokemi och organisk kemi (författare)

Conformationally Constrained Nucleosides : Design, Synthesis, and Biochemical Evaluation of Modified Antisense Oligonucleotides

BokEngelska2007

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Uppsala :Acta Universitatis Upsaliensis,2007
60 s.
electronicrdacarrier

Nummerbeteckningar

LIBRIS-ID:oai:DiVA.org:uu-8266
ISBN:9789155469924
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8266URI

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Språk:engelska
Sammanfattning på:engelska

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Ämneskategori:vet swepub-contenttype
Ämneskategori:dok swepub-publicationtype

Serie

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology,1651-6214 ;354

Anmärkningar

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.

Ämnesord och genrebeteckningar

NATURVETENSKAP Kemi hsv//swe
NATURAL SCIENCES Chemical Sciences hsv//eng
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
Chemistry
Kemi

Biuppslag (personer, institutioner, konferenser, titlar ...)

Engman, Lars (preses)
Stawinski, Jacek,ProfessorDepartment of Organic Chemistry, Stockholm University (opponent)
Uppsala universitetInstitutionen för biokemi och organisk kemi (creator_code:org_t)

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NATURVETENSKAP: NATURVETENSKAP; och Kemi

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Av lärosätet: Uppsala universitet

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