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Novel DNA Analogues with 2-, 3- and 4-Pyridylphosphonate Internucleotide Bonds: Synthesis and Hybridisation Properties
Polish Acad Sci, Ctr Mol & Macromol Studies.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Polish Acad Sci, Ctr Mol & Macromol Studies.
Polish Acad Sci, Ctr Mol & Macromol Studies.
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2003 (English)In: New Journal of Chemistry, ISSN 1144-0546, Vol. 27, no 12, 1698-1705 p.Article in journal (Refereed) Published
Abstract [en]

Oligothymidylates modified with stereodefined 2-pyridyl-, 3-pyridyl- and 4-pyridylphosphonate moieties at one or two juxtaposed internucleotide positions were prepared, and their avidity towards complementary single stranded DNA and RNA, as well as toward double stranded DNA were evaluated by UV melting temperature and CD studies. It was found that the sense of chirality at the phosphorus centre and the position of the nitrogen atom in the pyridyl ring of a pyridylphosphonate moiety are important factors governing stability of double- and triple-stranded complexes formed by these oligonucleotides. DNA/DNA and DNA/RNA duplexes containing oligothymidylate strands with R-P-pyridylphosphonate units differed only slightly from unmodified reference complexes. In contrast to this, the S-P-pyridylphosphonate derivatives exhibited lower binding affinity than both their R-P-counterparts and the unmodified reference oligonucleotide T-20. Triplexes of oligo(thymidyl pyridylphosphonate)s with hairpin oligomer d(A(21)C(4)T(21)) were found mostly to be thermodynamically slightly more stable in pH 7.4 and less stable in pH 5.0 than non-modified complexes. As expected, oligonucleotides with pyridylphosphonate internucleotide bonds were recognised by 3'- and 5'-exonucleases but the chimeric oligonucleotide chains were not cleaved at the modi. cation sites.

Place, publisher, year, edition, pages
Royal Society of Chemistry , 2003. Vol. 27, no 12, 1698-1705 p.
Keyword [en]
IONIC OLIGONUCLEOSIDE METHYLPHOSPHONATES; MOLECULAR-DYNAMICS SIMULATION; HUMAN-IMMUNODEFICIENCY-VIRUS; H-PHOSPHONOTHIOATE DIESTERS; ANTISENSE OLIGONUCLEOTIDES; STEREOSPECIFIC OXIDATION; PHOSPHATE BACKBONE; MINOR-GROOVE; HUMAN PLASMA; B-DNA
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-23239DOI: 10.1039/b305689aOAI: oai:DiVA.org:su-23239DiVA: diva2:190874
Note
Part of urn:nbn:se:su:diva-202Available from: 2004-08-19 Created: 2004-08-19 Last updated: 2010-01-05Bibliographically approved
In thesis
1. Studies on Transformations of H-Phosphonates into DNA Analogues Containing P-S or P-C Bonds
Open this publication in new window or tab >>Studies on Transformations of H-Phosphonates into DNA Analogues Containing P-S or P-C Bonds
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, mechanistic and synthetic studies on transformations of H-phosphonates into DNA analogues containing P-S or P-C bonds are described.

Configurational stability of dinucleoside H-phosphonates and the stereochemical course of their sulfurisation in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were investigated. In light of these studies, the reported stereoselective sulfurisation of dinucleoside H-phosphonates and benzoylphosphonates in the presence of DBU was proved to be incorrect.

Efficient protocols for the synthesis of new nucleotide analogues with non-ionic C-phosphonate internucleotide linkages were developed. The synthesis of dinucleoside 2-pyridylphosphonates was successfully performed by a DBU-promoted reaction of H-phosphonate diesters with N-methoxypyridinium salts. The thio analogues, 2-pyridyl- and 4-pyridyl phosphonothioate diesters, could be obtained by modifying the reactions developed for their oxo counterparts. Dinucleoside 3-pyridylphosphonates were prepared via a palladium(0)-catalysed cross coupling strategy that could be extended also to the synthesis of nucleotide analogues with metal-complexing properties, i.e. terpyridyl- and bipyridylphosphonate derivatives.

Oligonucleotides modified with pyridylphosphonate internucleotide linkages have been prepared and preliminary studies on their hybridisation properties and resistance towards enzymatic degradation were performed.

Finally, nucleotidic units for the incorporation of pyridylphosphonate groups at the 5’-terminus of oligonucleotides were designed. Condensations of such units with a suitably protected nucleoside afforded after oxidation the expected dinucleoside (3’-5’)-phosphates with pyridylphosphonate monoester functions at the 5’-ends.

Place, publisher, year, edition, pages
Stockholm: Institutionen för organisk kemi, 2004. 61 p.
Keyword
Organisk kemi
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-202 (URN)91-7265-935-1 (ISBN)
Public defence
2004-09-09, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 14:00
Opponent
Supervisors
Available from: 2004-08-19 Created: 2004-08-19Bibliographically approved

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