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Studies on Transformations of H-Phosphonates into DNA Analogues Containing P-S or P-C Bonds
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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 [en]
Organisk kemi
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-202ISBN: 91-7265-935-1 (print)OAI: oai:DiVA.org:su-202DiVA: diva2:190876
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
List of papers
1. The Case for Configurational Stability of H-Phosphonate Diesters in the Presence of Diazabicyclo[5.4.0]undec-7-ene (DBU)
Open this publication in new window or tab >>The Case for Configurational Stability of H-Phosphonate Diesters in the Presence of Diazabicyclo[5.4.0]undec-7-ene (DBU)
2001 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, Vol. 9, no 9, 2315-2322 p.Article in journal (Refereed) Published
Abstract [en]

Configurational stability of dinucleoside H-phosphonates and the stereochemical course of their sulfurisation in the presence of diazabicyclo[5.4.0]undec-7-ene (DBU) were investigated using 31P NMR spectroscopy. It was found that under the reaction conditions and irrespective of the type of protecting groups present in the nucleoside moieties, the H-phosphonate diesters investigated did not undergo any detectable epimerisation at the phosphorus centre, and their sulfurisation with elemental sulfur in the presence of DBU, proceeded stereospecifically. Thus, we could not confirm reports from another laboratory on a stereoselective course of sulfurisation of H-phosphonate diesters and the corresponding acylphosphonates in the presence of DBU.

Place, publisher, year, edition, pages
Elsevier, 2001
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-23234 (URN)10.1016/S0968-0896(01)00140-7 (DOI)
Note
Part of urn:nbn:se:su:diva-202Available from: 2004-08-19 Created: 2004-08-19 Last updated: 2010-01-05Bibliographically approved
2. 2-Pyridylphosphonates: A New type of Modification for Nucleotide Analogues
Open this publication in new window or tab >>2-Pyridylphosphonates: A New type of Modification for Nucleotide Analogues
2001 (English)In: Tetrahedron Letters, ISSN 0040-4039, Vol. 42, no 11, 2217-2220 p.Article in journal (Refereed) Published
Abstract [en]

Suitably protected dithymidine H-phosphonates afforded the corresponding dinucleoside 2-pyridylphosphonates upon treatment with N-methoxypyridinium tosylate in acetonitrile in the presence of 1,8-diazabicylo[5.4.0]undec-7-ene (DBU). The reaction was rapid (ca. 5 min), practically quantitative and proceeded stereospecifically, most likely with retention of configuration at the phosphorus centre.

A simple and efficient protocol for the preparation of a new type of oligonucleotide analogue bearing a 2-pyridylphosphonate internucleotide linkage was developed

Place, publisher, year, edition, pages
Elsevier, 2001
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-23235 (URN)10.1016/S0040-4039(01)00115-0 (DOI)
Note
Part of urn:nbn:se:su:diva-202Available from: 2004-08-19 Created: 2004-08-19 Last updated: 2010-01-05Bibliographically approved
3. Nucleoside H-phosphonates.: Part 19. Efficient entry to novel nucleotide analogues with 2-pyridyl and 4-pyridylphosphonothioate internucleotide linkages
Open this publication in new window or tab >>Nucleoside H-phosphonates.: Part 19. Efficient entry to novel nucleotide analogues with 2-pyridyl and 4-pyridylphosphonothioate internucleotide linkages
2004 (English)In: Tetrahedron, ISSN 0040-4020, Vol. 60, no 2, 389-395 p.Article in journal (Refereed) Published
Abstract [en]

Synthetic and 31P NMR spectroscopy studies resulted in the development of efficient protocols for the stereospecific synthesis of a novel type of nucleotide analogues, 2-pyridyl- and 4-pyridylphosphonothioates. The underlying chemistry involves formation of the P–C bond via a base-promoted reaction of suitably protected dithymidine H-phosphonothioates with N-methoxypyridinium tosylate in acetonitrile, or with trityl chloride in pyridine, to produce high yields of nucleotide analogues with a 2-pyridyl- or 4-pyridyl moiety directly bound to the phosphorus centre.

Place, publisher, year, edition, pages
Elsevier, 2004
National Category
Inorganic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-23236 (URN).1016/j.tet.2003.11.010 (DOI)
Note
Part of urn:nbn:se:su:diva-202Available from: 2004-08-19 Created: 2004-08-19 Last updated: 2010-01-05Bibliographically approved
4. Synthesis of Dinucleoside Pyridylphosphonates Involving Palladium(0)-catalysed Phosphorus-carbon Bond Formation as a Key Step
Open this publication in new window or tab >>Synthesis of Dinucleoside Pyridylphosphonates Involving Palladium(0)-catalysed Phosphorus-carbon Bond Formation as a Key Step
2001 (English)In: Chemical Communications, ISSN 1359-7345, no 24, 2564-2565 p.Article in journal (Refereed) Published
Abstract [en]

Dinucleoside 3-pyridylphosphonates, as well as their 2- and 4-pyridyl positional isomers, have been synthesised using a palladium(0)-catalysed cross coupling strategy

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2001
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-23237 (URN)10.1039/b108857m (DOI)
Note
Part of urn:nbn:se:su:diva-202Available from: 2004-08-19 Created: 2004-08-19 Last updated: 2010-01-05Bibliographically approved
5. Towards Nucleotide Analogues with Metal Complexing Proprties. Synthesis of Dinucleoside Terpyridyl- and Bipyridylphosphonates
Open this publication in new window or tab >>Towards Nucleotide Analogues with Metal Complexing Proprties. Synthesis of Dinucleoside Terpyridyl- and Bipyridylphosphonates
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-23238 (URN)
Note
Part of urn:nbn:se:su:diva-202Available from: 2004-08-19 Created: 2004-08-19 Last updated: 2010-01-13Bibliographically approved
6. Novel DNA Analogues with 2-, 3- and 4-Pyridylphosphonate Internucleotide Bonds: Synthesis and Hybridisation Properties
Open this publication in new window or tab >>Novel DNA Analogues with 2-, 3- and 4-Pyridylphosphonate Internucleotide Bonds: Synthesis and Hybridisation Properties
Show others...
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
Keyword
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:nbn:se:su:diva-23239 (URN)10.1039/b305689a (DOI)
Note
Part of urn:nbn:se:su:diva-202Available from: 2004-08-19 Created: 2004-08-19 Last updated: 2010-01-05Bibliographically approved
7. Synthesis of a Nucleotide Unit for the Incorporation of a Terminal 5'-pyridylphosphonate Moiety into Oligonucleotides
Open this publication in new window or tab >>Synthesis of a Nucleotide Unit for the Incorporation of a Terminal 5'-pyridylphosphonate Moiety into Oligonucleotides
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-23240 (URN)
Note
Part of urn:nbn:se:su:diva-202Available from: 2004-08-19 Created: 2004-08-19 Last updated: 2010-01-13Bibliographically approved

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