LABORATORY OF NUCLEOTIDE AND OLIGONUCLEOTIDE ANALOGUES

Head: Adam Kraszewski

Research Staff:
Jacek Stawiński, Małgorzata Bogucka, Jacek Cieślak, Jadwiga Jankowska, Michał Sobkowski, Marzena Szymczak

Ph.D. Students:
Joanna Lutomska, Agnieszka Szymańska

Keywords:
synthesis, H-phosphonate chemistry, nucleotides, oligonucleotides, analogues, antiviral, antisense, oligonucleotides analogues


H-Phosphonates represent a class of phosphorus compounds with unique structure and chemical properties. Due to the presence of a phosphoryl group (P=O) and a tetrahedral structure, H-phosphonates bear strong resemble to phosphates (PV), but the oxidation state (+3) clearly relates them to phosphites (PIII). Considering the mechanisms of chemical trans-formations of H-phospho-nates, in many cases these com-pounds behave similarly to phos-phates but at the same time they preserve characteristic features of phosphites. The above makes H-phosphonates exceptionally useful compounds in the synthesis of phosphorus de-rivatives of natural compounds e.g. carbohydrates, nucleosides or oligonucleotides that are of high interest for chemical and biological studies. Investigating the basic H-phosphonate chemistry enables us to develop many efficient synthetic methods for the preparation of nu-cleotide analogues with P-N, P-S, P-Se and P-C modifications at the phosphorus centre. The biological activity of these compounds and some new analogues of nucleoside 2',3'-cyclic phosphates (e.g. phosphorothioate and phosphoroselenoate derivatives) has been evaluated in various in vitro systems containing thymidylate synthase or RNase A. What is more, syn-thetic and enzymatic studies on new nucleotide analogues, dinucleoside phosphonate-phosphates, have been initiated in our Laboratory. These compounds, bearing antiviral nu-cleoside moieties, can be considered a novel type of potential antiviral and anticancer pro-drugs with tuneable pharmacokinetic and pharmacodynamic properties.


Current research activities:

  • synthetic and mechanistic studies on nucleotide and oligonucleotide analogues;
  • development of new enzyme inhibitors, antiviral pro-drugs, antisense agents, etc., based on modified nucleotides and oligonucleotides.



    SELECTED PUBLICATIONS

    J. Jankowska, M. Wenska, M. Popenda, J. Stawiński, A. Kraszewski
    A new, efficient entry to nucleoside 2', 3'-O,O-cyclophosphorothioates.
    Tetrahedron Lett. 41, 2227-2229 (2000).

    J. Cieślak, J. Jankowska, J. Stawiński, A. Kraszewski
    Aryl H-phosphonates. 12. Synthetic and 31P NMR studies on the preparation of nucleoside H phosphonothioate and nucleoside H-phosphonodithioate monoesters.
    J. Org. Chem. 65, 7049-7054 (2000).

    J. Cieślak, M. Sobkowski, J. Jankowska, M. Wenska, M. Szymczak, B. Imiołczyk, I. Zagórowska, D. Shugar, J. Stawiński, A. Kraszewski
    Nucleoside phosphate analogues of biological interest, and their synthesis via aryl nucleoside H phosphonates as intermediates.
    Acta Biochim. Polon. 48, 429-442 (2001).

    M. Wenska, J. Jankowska, M. Sobkowski, J. Stawiński, A. Kraszewski
    A new method for the synthesis of nucleoside 2',3'-O,O-cyclic phosphorodi-thioates via aryl cyclic phosphites as intermediates.
    Tetrahedron Lett. 42, 8055-8058 (2001).

    B. Gołos, J. M. Dzik, Z. Kazimierczuk, J. Cieśla, Z. Zieliński, J. Jankowska, A. Kraszewski, J. Stawiński, W. Rode, D. Shugar
    Interaction of thymidylate synthase with the 5'-thiophosphates, 5'-dithiophosphates, 5' H phos-phonates and 5'-S-thiosulfates of 2'-deoxyuridine, thymidine and 5-fluoro-2'-deoxyuridine.
    Biol. Chem. 382, 1439-1445 (2001).

    Nilsson, A. Kraszewski and J. Stawiński
    Reinvestigation of the 31P NMR evidence for the formation of diorganyl phosphopyridinium intermediates.
    J. Chem. Soc. Perkin Trans. 2, 2263-2266 (2001).

    J. Cieślak, J. Jankowska, M. Sobkowski, M. Wenska, J. Stawiński, A. Kraszewski
    Aryl H-phosphonates. Part 13. A new, general entry to aryl nucleoside phosphate and aryl nucleoside phosphorothioate diesters.
    J. Chem. Soc. Perkin Trans. 1, 31-37 (2002).

    M. Sobkowski, J. Cieślak, J. Jankowska, J. Stawiński, A. Kraszewski
    Dinucleoside aryl phosphorothioates as building blocks for large scale synthesis of chimeric oligonucleotide analogues.
    Collection Symposium Series 5, 283-289 (2002).

    J. Stawiński and A. Kraszewski
    H-Phosphonates - Chemistry and applications.
    Collection Symposium Series 5, 272-282 (2002).

    J. Nilsson, M. Bolmark, J. Jankowska, M. Wenska, J. Cieślak, A. Kraszewski, J. Stawiński
    New synthetic methods for nucleotide analogues based on H-phosphonate chemistry: A progress report.
    Phosphorus, Sulfur and Silicon 177, 1513-1516 (2002).

    J. Stawiński, A. Kraszewski
    How to get most out of two phosphorus chemistries. Studies on H-phosphonates.
    Accounts of Chemical Research 35, 952-960 (2002).

    M. Bolmark, T. Johansson, M. Kulberg, J. Nilsson, J. Stawiński, J. Cieślak, J. Jankowska, M. Sobkowski, M. Szymczak, M. Wenska, A. Kraszewski
    Developing synthetic methods for bioactive phosphorus compounds using H-phosphonate chemistry: A progress report.
    Nucleosides, Nucleotides and Nucleic Acids 22, 611-615 (2003).

    M. Szymczak, A. Szymańska, J. Stawiński, J. Boryski, A. Kraszewski
    Aryl H-phosphonates. 14. Synthesis of new nucleotide analogues with phosphonate-phosphate internucleosidic linkage.
    Organic Letters 5, 3571-3573 (2003).

    Johan Nilsson, Adam Kraszewski and Jacek Stawiński
    Chemoselectivity in oxidative coupling of bifunctional nucleophiles with dinucleoside H phosphonate and dinucleoside H-phosphonothioate diesters.
    Nucleosides, Nucleotides & Nucleic Acids 22, 1467-1469 (2003).

    Adam Kraszewski, Jacek Stawiński
    Aryl nucleoside H-phosphonates. Versatile intermediates in the synthesis of nucleotides and their analogues.
    Trends in Organic Chemistry 10, 1-19 (2003).