Division of Bioorganic Chemistry
The long term interest of this Department is focused upon the design of new strategies and methodologies aiming the synthesis of biomolecules and their congeners to be used for investigation of processes of molecular recognition and stereoselection in biological systems. For that purpose, oligonucleotides and their phosphorothioate, phosphorodithioate, or methanephosphonate analogs as well as dinucleotide polyphosphates, are the most frequently used constructs.
The major distinction of scientific programme is the stereocontrolled synthesis of P-chiral congeners of biophosphates, including isotopomeric phosphates, phosphorothioates, phosphoramidates, and methanephosphonates. Initiated 20 years ago, pioneering research on enantiospecific synthesis of P-chiral anticancer drugs, which formulated the basis for chirotechnology, is nowadays expressed by developed in-house novel method of solid phase stereocontrolled synthesis of P-chiral oligo(nucleoside phosphorothioate)s. Stereodefined P-chiral oligo(nucleoside phosphorothioate)s and oligo(nucleoside phosphoroselenoate)s were found to possess unique ability to form extremely stable parallel duplexes and triplexes with RNA templates. This very interesting feature opened a new way for arresting of viral RNA or cellular mRNA to combat viral or genetic diseases.
The development of a new strategy for phosphorothioylation of polyfunctional compounds such as poliols, diamines and hydroxyacids allowed us to synthesize new analogs of diadenosinepolyphosphates, which occurred to be inhibitors of hydrolytic activity of Fhit protein and inhibitors of ADP-dependent blood platelet aggregation. Synthesized non-hydrolysable analogs of Ap4A are used to explain Fhit protein induced apoptosis mechanism.
Studies are carried on the design, synthesis, and biological evaluation of novel antiviral and anticancer prodrugs (so-called pronucleotides). This new prodrug chemistry is expected to improve the efficacy of current prodrugs by utilizing different unmasking strategies. The first set of N-acyl phosphoramidate derivatives of gemcitabine to be valuable prodrugs active in the selected cancer cells.
Studies on synthetic methodologies are accompanied by efforts in the designing of constructs aiming at RNAi gene silencing complementary to antisense-, DNAzyme- and ribozyme-approaches, targeting genes related to the Alzheimer disease. Interactions of modified oligonucleotides with DNA, RNA and proteins are studied by spectrometric, biochemical, and cytological methods, with emphasis on the influence of P-chirality on the nature of interaction.
In collaboration with Medical University of Lodz, we run the studies on genetic and environmental factors related to gastric cancer, including the H. pylori infection. Within this project, the level of expression of the selected tumor suppressor genes (especially for HIT superfamily proteins) in non-cancer patients is measured and analyzed. Next project is aimed at elucidation of molecular mechanisms for cancer cell invasiveness. We are particularly interested in metalloproteinases expression and activation in cancer cells that differ in migratory phenotype. We also look for new protein substrates of metalloproteinases, particularly receptor proteins.
Recently, we have focused our attention on the stability of the sulfur-modified transfer RNA (tRNA) in oxidative stress, and the consequences of desulfuration of these biomolecules on the codon-anticodon interactions and cellular processes in which tRNA is engaged.
In another project realized in collaboration with Medical University of Lodz and the Copernicus Memorial Hospital, the influence of hypoxia on cancer immunosuppression was investigated (project completed)
In our Department, a screening laboratory has been set up (headed by Dr. Marcin Cieślak), which serves for testing of cytotoxic properties of different compounds. Several tumor cell lines as well as primary cells are used in those studies. The compounds showing the highest cytotoxicity are further tested for their ability to trigger apoptosis or necrosis. Another new laboratory is a facility for crystallography of proteins, nucleic acids and their complexes, headed by Dr. Rafał Dolot. Over 3 years of functioning, several high resolution structures have already been deposited in PDB and at least 3 papers have been published in this field.
- A. Rowley, A. H. Kachroo, Ch.Hui Ma, A. D. Maciaszek, P. Guga, M. Jayaram: Stereospeciﬁc suppression of active site mutants by Methylphosphonate substituted substrates reveals the stereochemical course of site-speciﬁc DNA recombination. Nucleic Acids Res. 2015, 43: 6023-6037 (IF 8.808)
- A.Tomaszewska-Antczak, P. Guga, B. Nawrot, G. Pratviel: Guanosine in a Single Stranded Region of Anticodon Stem–Loop tRNA Models is Prone to Oxidatively Generated Damage Resulting in Dehydroguanidinohydantoin and Spiroiminodihydantoin Lesions. Chem. Eur. J. 2015, 21: 6381-6385 (IF 5.696)
- A. P. Dabkowska, A. Michanek, L. Jaeger, M. Rabe, A. Chworos, F. Höök, T. Nylandera, E. Sparr: Assembly of RNA nanostructures on supported lipid bilayers.Nanoscale 2015, 7: 583-596 (IF 6.739)
- E. Sochacka, R. H. Szczepanowski, M. Cypryk, M. Sobczak, M. Janicka, K. Kraszewska, P. Bartos, A. Chwialkowska, B. Nawrot: 2-Thiouracil deprived of thiocarbonyl function preferentially base pairs with guanine rather than adenine in RNA and DNA duplexes. Nucleic Acids Res. 2015, 43: 2499-2512 (IF 8.808)
- M. Krawiecka, B. Kuran, J. Kossakowski, M. Cieślak, J. Kazmierczak-Barańska, K. Królewska, B. Nawrot: Synthesis and Cytotoxic Properties of Halogen and Aryl-/Heteroarylpiperazinyl Derivatives of Benzofurans. Anti-Cancer Agents in Medicinal Chemistry 2015, 15: 115-121 (IF 2.939)
- J. Kaźmierczak-Barańska, Ł. Pęczek, P. Przygodzka, M. J. Cieślak: Downregulation of striatin leads to hyperphosphorylation of MAP2, induces depolymerization of microtubules and inhibits proliferation of HEK293T cells. FEBS Let. 2015, 589: 222–230 (IF 3.341)
- A. P. Dabkowska, A. Michanek, L. Jaeger, M. Rabe, A. Chworos, F. Höök, T. Nylandera, E. Sparr: Assembly of RNA nanostructures on supported lipid bilayers. Nanoscale 2015, 7: 583-596 (IF 6.739)
- A.Maciaszek, A. Krakowiak, M. Janicka, A. Tomaszewska, M. Sobczak, B. Mikołajczyk, P. Guga: LNA Units Present in (2’-OMe)-RNA Strand Stabilize Parallel Duplexes (2’-OMe)-RNA/[All-RP-PS]-DNA and Parallel Triplexes (2’-OMe)-RNA/[All-RP-PS]-DNA/RNA. An Improved Tool for Inhibition of Reverse Transcription.
Org. & Biomol. Chem. 2015, 13: 2375-2384 (IF 3.487)
- A. Krakowiak, R. Pawłowska, B. Kocoń-Rębowska, R. Dolot, W. J. Stec: Interactions of cellular Histidine triad nucleotide binding protein 1 with nucleosides 5′-O-monophosphorothioate and their derivatives – implication for desulfuration process in the cell. Biochim. Biophys. Acta 2014, 1840: 3357–3366 (IF 3.829)
- S. Y. Wu, X. Yang, K. M. Gharpure, H. Hatakeyama, M. Egli, M. H. McGuire, A. S. Nagaraja, T. M. Miyake, R. Rupaimoole, C. V. Pecot, M. Taylor, S. Pradeep, M. Sierant, C. Rodriguez-Aguayo, H. J. Choi, R. A. Previs, G. N. Armaiz-Pena, Li Huang, C. Martinez, T. Hassell, C. Ivan, V. Sehgal, R. Singhania, H.-D. Han, C. Su, Ji Hoon Kim, H. J. Dalton, C. Kovvali, K. Keyomarsi, N. A. J. McMillan, W.illem W. Overwijk, Jinsong Liu, Ju-Seog Lee, Keith A. Baggerly, Gabriel Lopez-Berestein, Prahlad T. Ram, Barbara Nawrot, Anil K. Sood: 2’-OMe-phosphorodithioate-modiﬁed siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity. Nature Comm. 2014, 5: 3459 (IF 10.742)
- J. Baraniak, A. Pietkiewicz, R. Kaczmarek, E. Radzikowska, K. Kulik, K. Krolewska, M. Cieslak, A. Krakowiak, B. Nawrot: N-Acyl-phosphoramidates as potential novel form of gemcitabine prodrugs. Bioorg. Med. Chem. 2014, 22: 2133–2140 (IF 3.829)
- R. Chollakup, W. Smitthipong, A. Chworos: DNA-functionalized polystyrene particles and their controlled self-assembly. RSC Adv. 2014, 4: 30648–30653 (IF 3.708)
- R. Kaczmarek, E. Radzikowska, J. Baraniak: Efficient Synthesis of Gemcitabine 5′-O -Triphosphate Using Gemcitabine 5′-O -Phosphoramidate as an Intermediate. Synlett 2014, 25: 1851–1854 (IF 2.463)
- P. Bartos, A. Maciaszek, A. Rosinska, E. Sochacka, B. Nawrot: Transformation of a wobble 2-thiouridine to 2-selenouridine through S-geranyl-2-thiouridine as a likely pathway in the cell. Bioorg. Chem. 2014, 56: 49-53 (IF 2.141)
- P. S. Pallan, Xianbin Yang, M. Sierant, N. D. Abeydeera, T. Hassell, C. Martinez, M. Janicka, B. Nawrot, M. Egli: Crystal structure, stability and Ago2 aﬃnity of phosphorodithioate-modiﬁed RNAs. RSC Adv. 2014, 4: 64901-64904 (IF 3.708)
- M. Szubert, J. Suzin, M. Duechler, A. Szużawska , M. Czyż, K. Kowalczyk-Amico: Evaluation of selected angiogenic and inflammatory markers in endometriosis before and after danazol treatment. Reprod. Fertil. Dev. 2014: 26: 414-420 (IF 2.577)
- E. Sochacka, P. Bartos, K. Kraszewska, B. Nawrot: Desulfuration of 2-thiouridine with hydrogen peroxide in the physiological pH range 6.6-7.6 is pH-dependent and results in two distinct products. Bioorg Med Chem Lett. 2013, 23: 5803-5805 (IF 3.829)
- A. Kwiatkowska, M. Sobczak, B. Mikolajczyk, S. Janczak, A. B. Olejniczak, M. Sochacki, Z. J. Lesnikowski, B. Nawrot: siRNAs modified with boron cluster and their physicochemical and biological characterization. Bioconjugate Chem. 2013, 24: 1017-1026 (IF 4.821)
- X.Yang, M. Sierant, M. Janicka, L. Peczek, C. Martinez, T. Hassell, N. Li, X. Li, T. Wang, B. Nawrot: Gene silencing activity of siRNA molecules containing phosphorodithioate substitutions. ACS Chem. Biol. 2012, 7: 1214-1220 (IF 5.356)
- A.Tomaszewska, S. Mourgues, P. Guga, B. Nawrot, G. A. Pratviel: Single nuclease-resistant linkage in DNA as a versatile method for the characterization of DNA lesions: application to the guanine oxidative lesion “G+34” generated by metalloporphyrin/KHSO5 reagent. Chem. Res. Toxicol. 2012, 25: 2505-2512 (IF 4.190)
- K Żuk, ł. Pęczek, K. Stec-Michalska, M. Medrek, B. Nawrot: Family history of gastric cancer correlates with decreased expression of HINT-1 tumor suppressor gene in gastric mucosa of dyspeptic patients. Oncology Lett. 2012, 3: 219-223 (IF 0.987)
- B. Nawrot, E. Sochacka, M. Düchler: tRNA Structural and functional changes induced by oxidative stress. Cell. Mol. Life Sci. 2011, 68: 4023-4032 (IF 5.86)
- R. Dolot, M. Ozga, A. Krakowiak, B. Nawrot, W. J. Stec: High-resolution X-ray crystal structure of rabbit histidine triad nucleotide-binding protein 1 (rHINT1) – adenosine complex at 1.10 A resolution. Acta Crystal. Section D: Biol. Crystal. (Acta Cryst. D) 2011, 67: 601-607 (IF 7.232)
- A. Krakowiak, R. Pęcherzewska, R. Kaczmarek, A. Tomaszewska, B. Nawrot, W. J. Stec: Evaluation of influence of Ap(4)A analogues on Fhit-positive HEK293T cells; cytotoxicity and ability to induce apoptosis. Bioorg. Med. Chem. 2011, 19: 5053-5060 (IF 2.951)
- E. Sochacka, K. Kraszewska, M. Sochacki, M. Sobczak, M. Janicka, B. Nawrot: The 2-thiouridine unit in the RNA strand is desulfured predominantly to 4-pyrimidinone nucleoside under in vitro oxidative stress conditions. Chem. Commun. 2011, 47: 4914–4916 (IF 6.718)
- R. Hubmann, M. Düchler, S. Schnabl, M. Hilgarth, D. Demirtas, D. Mitteregger, A. Hölbl, K. Vanura, T. Le, T. Look, J. D. Schwarzmeier, P. Valent, U. Jäger, M. Shehata: NOTCH2 links protein kinase C delta to the expression of CD23 in chronic lymphocytic leukaemia (CLL) cells. British Journal of Haematology 2010, 148: 868-878 (IF 4.94)
- M. Ozga, R. Dolot, M. Janicka, R. Kaczmarek, A. Krakowiak: Histidine triad nucleotide-binding protein 1 (Hint-1) phosphoramidase transforms nucleoside 5′-O-phosphorothioates to nucleoside 5′-O-phosphates. J. Biol. Chem. 2010, 285: 40809-40818 (IF 4.600)
- D. Błaziak, P. Guga, A. Jagiełło, D. Korczyński, A. Maciaszek, A. Nowicka, A. Pietkiewicz, W. J. Stec: Stereoselective formation of a P-P bond in the reaction of 2-alkoxy-2-thio-1,3,2-oxathiaphospholanes with O,O-dialkyl H-phosphonates and H-thiophosphonates. Org. Biomol. Chem. 2010, 8: 5505-5510 (IF 3.487)
- P. A. Rowley, H. A. Kachroo, Ma Chien-Hui, A. D. Maciaszek, P. Guga, J. Makkuni: Electrostatic suppression allows tyrosine site-specific recombination in the absence of a conserved catalytic arginine. J. Biol. Chem. 2010, 285: 22976–22985 (IF 4.600)
- M. Sierant, M. Sobczak, M. Janicka, A. Paduszynska, D. Piotrzkowska: Biological and physicochemical characterization of siRNAs modified with 2′,2′-difluoro-2′-deoxycytidine. New J. Chem. 2010, 34: 918-924 (IF 3.159)
- K. Stec-Michalska, Ł. Peczek, B. Michalski, M. Wisniewska-Jarosinska, A. Krakowiak, B. Nawrot: Helicobacter pylori infection and family history of gastric cancer decrease expression of FHIT tumor suppressor gene in gastric mucosa of dyspeptic patients. Helicobacter 2009, 14: 126-134 (IF 2.993)
- Sierant, K. Kubiak, J. Kazmierczak-Baranska, M. Warashina, T. Kuwabara, B. Nawrot: Evaluation of BACE1 silencing in cellular models. Int. J. Alzheimer’s Dis. 2009, ID 257403B. Nawrot, K. Widera, M. Sobczak, M. Wojcik, W. J. Stec: Effect of RP- and SP-phosphorothioate substitution at the scissile site on the cleavage activity of deoxyribozyme 10-23. Curr. Org. Chem. 2008, 12: 1004-1009 (IF 2.537)B. Nawrot, K. Widera, M. Wójcik, B. Rębowska, G. Nowak, W. J. Stec: Mapping of the functional phosphate groups in the catalytic core of deoxyribozyme 10–23. FEBS J. 2007, 274: 1062–1072 (IF 3.986)P. Guga, M. Janicka, A. Maciaszek, B. Rębowska, G. Nowak: Hoogsteen paired homopurine [RP-PS]-DNA and homopyrimidine RNA strands form a thermally stable parallel duplex. Biophys. J. 2007, 93: 3567-3574 (IF 3.832)K. Sipa, E. Sochacka, J. Kaźmierczak-Barańska, M. Maszewska, M. Janicka, G. Nowak, B. Nawrot: Effect of base modifications on structure, thermodynamic stability and gene silencing activity of short interfering RNA. RNA 2007, 13: 1301-1316 (IF 5.377)B. Nawrot, E. Gaggelli: Understanding the chemical mechanisms of life. Nat. Chem. Biol. 2007, 3: 745-749 (IF 13.217)