Dariusz Korczynski

Diadenylated polyols as new non-isopolar analogues of diadenosine tri- and tetraphosphates

Abstract A series of diadenosine polyphosphate-mimics were prepared based upon phosphorothioylation of the hydroxyl functions of polyols 1 and 1,3,2-oxathiaphospholane ring-opening condensation methodology.

Tetra-Thymidine Phosphorofluoridates via Tetra-Thymidine Phosphoro-selenoates: Synthesis and Stability

Abstract Tetra-thymidine phosphoroselenoates obtained via phosphoramidite methodology with bis(di-O,O-isopropyl phosphinothioyl)diselenide as oxidising reagent, under treatment with iodine and triethylamine tris(hydrofluoride) (TAF) provide a diastereomeric mixture of tetra-thymidine phosphorofluoridates whose hydrotytic stability was studied by HPLC.

NEW APPROACH TO THE SOLID PHASE SYNTHESIS OF N3'P5' PHOSPHORAMIDATE OLIGONUCLEOTIDES

Abstract LCA-CPG-nucleoside 5′-O-(O-β-cyanoethyl-H-phosphonates) react with 3′-amino-2′,3′-dideoxynucleoside in the presence of iodine giving in a high yield N3′→P5′ phosphoramidate oligonucleotides.

The α-thio and/or β-γ-hypophosphate analogs of ATP as cofactors of T4 DNA ligase.

T4 DNA ligase is one of the most commonly used enzymes for in vitro molecular research and a useful model for testing the ligation mechanism of ATP-dependent DNA ligation. To better understand the influence of phosphate group modifications in the ligation process, a series of ATP analogs were tested as cofactors. P-diastereomers of newly developed β,γ-hypo-ATPαS (thio) and β,γ-hypo-ATP (oxo) were synthesized and their activity was compared to ATPαS and their natural precursors. The evaluation of presented ATP analogs revealed the importance of the α-phosphate stereogenic center in ATPαS for the T4 DNA ligase activity and sheds new light on the interaction between ATP-dependent DNA ligases and cofactors.

Stereochemical analysis of diastereomeric 1,3-bis(adenosine-5'-O-phosphorothioyl)glycerols.

We have published recently that 1,3-bis(adenosine-50-phosphorothioyl)glycerol (1), prepared according to the oxathiaphospholane methodology possesses stronger inhibitory activity towards FHIT protein, as compared with all known inhibitors. Fhit protein is the Ap3A hydrolase which binds and cleaves diadenosine polyphosphates and acts as a tumor suppressor. Loss of Fhit protein is among the earliest known events in the development of a variety of the most common and lethal human malignancies. Function of Fhit in tumor suppression does not require diadenosine polyphosphates cleavage but correlates with the ability to form enzyme-substrate complexes. If Fhit-substrate complexes promote tumor suppression by stimulating a pro-apoptotic effector, then Fhit inhibitors, that resemble natural substrates, may promote or antagonize Fhit function, depending on their features, in Fhit þ cells. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS Vol. 22, Nos. 5–8, pp. 797–799, 2003

Organometallic Nucleosides: Synthesis and Biological Evaluation of Substituted Dicobalt Hexacarbonyl 2′-Deoxy-5-oxopropynyluridines

Abstract Reactions of dicobalt octacarbonyl [Co2(CO)8] with 2′‐deoxy‐5‐oxopropynyluridines and related compounds gave dicobalt hexacarbonyl nucleoside complexes (83–31 %). The synthetic outcomes were confirmed by X‐ray structure determination of dicobalt hexacarbonyl 2′‐deoxy‐5‐(4‐hydroxybut‐1‐yn‐1‐yl)uridine, which exhibits intermolecular hydrogen bonding between a modified base and ribose. The electronic structure of this compound was characterized by the DFT calculations. The growth inhibition of HeLa and K562 cancer cell lines by organometallic nucleosides was examined and compared to that by alkynyl nucleoside precursors. Coordination of the dicobalt carbonyl moiety to the 2′‐deoxy‐5‐alkynyluridines led to a significant increase in the cytotoxic potency. The cobalt compounds displayed antiproliferative activities with median inhibitory values (IC50) in the range of 20 to 80 μm for the HeLa cell line and 18 to 30 μm for the K562 cell line. Coordination of an acetyl‐substituted cobalt nucleoside was expanded by using the 1,1‐bis(diphenylphosphino)methane (dppm) ligand, which exhibited cytotoxicity at comparable levels. The formation of reactive oxygen species in the presence of cobalt compounds was determined in K562 cells. The results indicate that the mechanism of action for most antiproliferative cobalt compounds may be related to the induction of oxidative stress.