title: Phosphorothioate analogs of P1,P3-di(nucleosid-5'-yl) triphosphates: Synthesis, assignment of the absolute configuration at P-atoms and P-stereodependent recognition by Fhit hydrolase.
abstract: Di(nucleosid-5'-yl) polyphosphates (NPnN) are involved in various biological processes, and constitute signaling molecules in the intermolecular purinergic systems. They exert tumor suppression function and are substrates for specific hydrolases (e.g., HIT proteins). Their structural analogs may serve as molecular probes and potential therapeutic agents. Three P1,P3-bis-thio-analogs of symmetrical di(nucleosid-5'-yl) triphosphates (NP3N) bearing adenosine, guanosine or ribavirin residues (6, 7 and 8, respectively), were obtained by direct condensation of corresponding base-protected nucleoside-5'-O-(2-thio-1,3,2-oxathiaphospholane) with anhydrous phosphoric acid in the presence of DBU. Deprotected products 6 and 8 were separated into individual P-diastereoisomers, whereas 7 was partially separated to yield diastereomerically enriched fractions. The absolute configuration at P-stereogenic centers in the separated diastereoisomers was assigned by RP-HPLC analysis of the products of enzymatic digestion with snake venom phosphodiesterase. The Fhit-assisted hydrolysis rates for 6 and 7 are by 2-3 orders of magnitude lower than that for the reference AP3A, and depend on the configuration of the stereogenic phosphorus atoms, while 8 occurred to be resistant to this cleavage.
authors: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland. Electronic address: renata@cbmm.lodz.pl.
authors: Renata
authors: R
authors: Kaczmarek
authors: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland. Electronic address: akrakow@cbmm.lodz.pl.
authors: Agnieszka
authors: A
authors: Krakowiak
authors: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland.
authors: Dariusz
authors: D
authors: Korczyński
authors: Institute of Chemistry and Environmental Protection and Biotechnology, Jan Dlugosz University, Armii Krajowej 13/15, 42-200 Czestochowa, Poland.
authors: Janina
authors: J
authors: Baraniak
authors: Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland.
authors: Barbara
authors: B
authors: Nawrot
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D011122:Polyphosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D011122:Polyphosphates; D000099170:Bis(5'-adenosyl)triphosphatase; C005692:triphosphoric acid
keywords: A(P3)A; Absolute configuration; Fhit; Oxathiaphospholane methodology; P-chirality; Polyphosphate