Department of Nucleoside and Nucleotide Chemistry


 

Head:
Prof. Dr. Jerzy Boryski

 

 


Staff:
Prof. Dr. Michał Sobkowski,

Dr. Dagmara Baraniak;

Dr. Piotr Januszczyk;

Dr. Joanna Romanowska

 


PhD Students:
Justyna Gołębiewska, M.Sc;

Tomasz Jakubowski, M.Sc;

Magdalena Materna, M.Sc;

Marta Rachwalak, M.Sc


 

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Fig.2

 


 

 

 

 

Affiliated Laboratory:

Laboratory of Synthesis of Nucleic Acid Derivarives

 

Key words:

organic chemistry, reaction mechanisms, nucleic acids, nucleosides, nucleoside analogues, nucleoside synthesis, pronucleoside, acyclic nucleosides, 1,2,3-triazol-nucleosides, antiviral activity, anticancer activity, enzyme-substrate interaction, transglycosylation, glycosylation reaction mechanism, nucleotides, oligonucleotides, nucleotide analogues, oligonucleotide analogues, anti-HIV pronucleotides, AIDS, anticancer pro-nucleotides, H-phosphonates, nucleotide phosphorus atom chemistry

 

Scientific profile:

Our research is focused on synthesis of modified nucleobases, nucleosides and nucleotides, and studies of their structure, chemical properties and their biological activity. One of the main stream of studies is general nucleoside chemistry, which combines investigation on pure chemical problems (new synthetic methods, structure, reaction mechanisms) with the research on their properties as a substrate in reactions catalyzed by enzymes.

The second well developed stream are studies on chemistry of nucleotides and oligonucleotides, with particular emphasis on synthetic methods and properties of various nucleotide analogues. In the chemical thread, which includes basic research, the main research area comprises nucleoside H-phosphonates, their synthesis, properties, stereochemistry of their reactions and some structural issues. The knowledge acquired in these studies is employed for construction, initially virtual, then material, of a new compounds with the chemical and biological properties programmed in their structures.

Third, strongly marked direction of research is stereochemistry of P-chiral nucleotide analogues. We found out the sources of high diastereoselectivity (up to 90% de) observed during internucleotide bond formation by the H-phosphonate approach, and proposed a mechanism that governs stereochemistry of those reactions. Currently are investigated problems associated with the participation of intramolecular nucleophilic catalysis in stereospecific substitution at the phosphorus atom. Although, these studies are curried out on nucleotide derivatives they are relevant to general phosphorus chemistry.

Studies of chemistry of nucleosides and nucleotides are always carried out having in mind their potential practical applications. We are developing new concepts and ideas concerning nucleoside and nucleotide with programmable anti-virus and/or anti-cancer properties. The novel compounds, (usually pronucleosides or pronucleotides) are designed to prevent proliferation of viral infections or to be toxic (preferably selectively) against tumor cells.

 

Current research activity

  • search for new approaches towards synthesis of nucleobases and nucleosides (controlled degradation, rearrangements);
  • synthesis and characterization of nucleoside analogues of potential biological activity, mainly ring analogs of pyrimidine and purine, derivatives of 1,2,3-triazole, acyclonucleosides, 2’-C-alkylribofuranosides, and analogs od dinucleoside monophosphates, in which internucleotide bond has been replaced with triazole moiety;
  • synthesis and biological activity of analogs of dinucleoside monophosphates, in which internucleotide bond has been replaced with 1,2,3-triazole moiety;
  • study on the mechanism and applications of transglycosylation reactions;
  • regioselective modification of the 2’,3’-cis-diol system in ribonucleosides;,
  • study on glycosylation reactions of naturally occurring poliphenolic compounds and biological activity of their sugar conjugates.
  • mechanistic investigation on stereochemistry of ribonucleoside H-phosphonothioates;
  • reactivity of nucleophilic catalysts against H-phosphonates and derivatives of other phosphorus acids;
  • intramolecular catalysis in stereospecific synthesis of P-chiral esters of phosphorus acids;

 

Most important research achievements:

  • synthesis of new nucleoside analogues of antiviral activity against DNA- and RNA-viruses, modified either in the base portion, e.g. derivatives of 1,N2-ethenoguanosine, indazole, 1,2,3-triazole, furano- and pyrrolo[2,3-d]pyrimidine, or in the sugar part, e.g. acyclonucleosides, 2’-C-β-methyl-β-d-ribofuranosides.
  • invention of a simple and efficient method to synthesis of antiviral drugs, acyclovir and ganciclovir, via transglycosylation of guanosine;
  • synthesis of sugar conjugates of naturally occurring poliphenolic compounds (e.g. genistein) of cystostatic activity;
  • reinvestigation of the mechanism of glycosylation and transglycosylation of heterocycles; a new conception of the mechanism of ribosylation reaction of purine bases: adenine and guanine;
  • proving the correlation between tautomerism of heterocycles and regioselectivity of their ribosylation;
  • discovery of a new type of compounds – oxyonium phosphobetaines – that were found to form in reactions of H-phosphonates with N-oxides, and determination of the mechanism of their formation;
  • design and development of synthetic methods for 2’,3’-dideoxy-nucleoside (N-heteroaryl)phosphoroamidates, and determination of their very high anti-HIV activity along with very low cytotoxicity;
  • development of a new method for synthesis of nucleoside phosphoramidates;
  • disclosure of the mechanism of asymmetric induction observed in condensation of ribonucleoside H-phosphonates. It was found that the reaction follows the scenario of dynamic kinetic asymmetric transformation (DYKAT);
  • development of optimal conditions for condensation of ribonucleoside H-phosphonates, with diastereomeric excess up to 90% and yield >99%;
  • development of a new "DP/LP" nomenclature system for P-chiral nucleotide analogues that circumvents some disadvantages of the regular CIP system and facilitates analysis and discussion on stereochemistry, particularly in multi-step processes.

 

Present or Current (Actual) research projects:

  • Nucleoside diphosphates - a new concept of anti-HIV pronucleotides (SIMS) / execution within 2014 - 2017, 36 months/
  • Synthesis, structure and biological activity of nucleic acid components and their analogs (statutory)

 

Selected publications:

A. Krajczyk, K. Kulińska, T. Kuliński, B.L. Hurst, C.W. Day, D.F. Smee, T. Ostrowski, P. Januszczyk, J. Zeidler
Antivirally active ribavirin analogues – 4,5-disubstituted 1,2,3-triazole nucleosides: biological evaluation against certain respiratory viruses and computational modeling.
Antivir. Chem. Chemother. 23, 161-171 (2014)

M.A. Leśniewska, T. Ostrowski, J. Zeidler, I. Muszalska
Ester groups as carriers of antivirally active tricyclicanalogue of acyclovir in prodrugs designing: synthesis, lipophilicity ­comparative statistical study of the chromatographic and theoreticalmethods, validation of the HPLC method.
Comb. Chem. High Throughput Screen. 17, 639-650 (2014)

Z. Jahnz-Wechmann, G. Framski, P. Januszczyk, J. Boryski
Bioactive fused heterocycles: Nucleoside analogs with an additional ring
Eur. J. Med. Chem. 97, 388-396 (2015)

K. Kołodziej, J. Romanowska, J. Stawiński, J. Boryski, A. Dąbrowska, A. Lipniacki, A. Piasek, A. Kraszewski, M. Sobkowski
Aryl H-Phosphonates 18. Synthesis, properties, and biological activity of 2’,3’-dideoxy-nucleoside (N-heteroaryl)phosphoroamidates of increased lipophilicity.
Eur. J. Med. Chem. 100, 77-88 (2015)

J. Zeidler, D. Baraniak, T. Ostrowski
Bioactive nucleoside analogues possessing selected five-membered azaheterocyclic bases.
Eur. J. Med. Chem. 97, 409-418 (2015)

M.A. Leśniewska, P. Dereziński, A. Klupczyńska, Z.J. Kokot, T. Ostrowski, J. Zeidler, I. Muszalska
HPLC and HPLC/MS/MS studies on stress, accelerated and intermediate degradation tests of antivirally active tricyclic analog of acyclovir.
J. AOAC Int. 98, 1240-1247 (2015)

M. Honcharenko, B. Bestas, M. Jeżowska, B.A. Wojtczak, P.M.D. Moreno, J. Romanowska, S.M. Bachle, E. Darzynkiewicz, J. Jemielity, C.I.E. Smith
Synthetic m(3)G-CAP attachment necessitates a minimum trinucleotide constituent to be recognised as a nuclear import signal
RSC Advances, 56, 51367-73 (2015)

M. Sobkowski, A. Kraszewski, J. Stawiński
Recent Advances in H-Phosphonate Chemistry. Part 1. H-Phosphonate Esters: Synthesis and Basic Reactions.
Topics in Current Chemistry 361, 137-177 (2015)

M. Sobkowski, A. Kraszewski, J. Stawiński
Recent Advances in H-Phosphonate Chemistry. Part 2. Synthesis of C-Phosphonate Derivatives.
Topics in Current Chemistry 361, 179-216 (2015)

A. Krajczyk, J. Zeidler, P. Januszczyk, S. Dawadi, H.I. Boshoff, C.E. Barry III, T. Ostrowski, C.C. Aldrich
2-Aryl-8-aza-3-deazaadenosine analogues of 5’-O-[N-(salicyl)sulfamoyl]adenosine: nucleoside antibiotics that block siderophore biosynthesis in Mycobacterium tuberculosis.
Bioorg. Med. Chem. 24, 3133-3143 (2016)

A. Szymańska-Michalak, D. Wawrzyniak, G. Framski, M. Kujda, P. Zgoła, J. Stawiński, J. Boryski, A. Kraszewski
New 3’-O-aromatic acyl-5-fluoro-2’-deoxyuridine derivatives as potential anticancer agents.
Eur. J. Med. Chem. 115, 41-52 (2016)

D. Baraniak, D. Baranowski, P. Ruszkowski, J. Boryski
3’-O- and 5’-O-Propargyl Derivatives of 5-Fluoro-2’-Deoxyuridine: Synthesis, Cytotoxic Evaluation and Conformational Analysis.
Nucleosides, Nucleotides and Nucleic Acids, 35, 178-194 (2016)

Z. Jahnz-Wechmann, G. Framski, P. Januszczyk, J. Boryski
Base-modified nucleosides: etheno derivatives
Frontiers in Chemistry, 4, article No 19 (2016)

M. Szlenkier, K. Kamel, J. Boryski
Regioselective Mitsunobu Reaction of Partially Protected Uridine.
Nucleosides, Nucleotides and Nucleic Acids, 35, 410-425 (2016)

M. Materna, J. Stawiński, A. Kiliszek, W. Rypniewski, M. Sobkowski
Oxyonium phosphobetaines - unusually stable nucleophilic catalyst-phosphate complexes formed from H-phosphonates and N-oxides.
RSC Adv. 6, 14448-14451 (2016)