title: Identification of Highly Promising Antioxidants/Neuroprotectants Based on Nucleoside 5'-Phosphorothioate Scaffold. Synthesis, Activity, and Mechanisms of Action.
abstract: With a view to identify novel and biocompatible neuroprotectants, we designed nucleoside 5'-thiophosphate analogues, 6-11. We identified 2-SMe-ADP(α-S), 7A, as a most promising neuroprotectant. 7A reduced ROS production in PC12 cells under oxidizing conditions, IC50 of 0.08 vs 21 μM for ADP. Furthermore, 7A rescued primary neurons subjected to oxidation, EC50 of 0.04 vs 19 μM for ADP. 7A is a most potent P2Y1-R agonist, EC50 of 0.0026 μM. Activity of 7A in cells involved P2Y1/12-R as indicated by blocking P2Y12-R or P2Y1-R. Compound 7A inhibited Fenton reaction better than EDTA, IC50 of 37 vs 54 μM, due to radical scavenging, IC50 of 12.5 vs 30 μM for ADP, and Fe(II)-chelation, IC50 of 80 vs >200 μM for ADP (ferrozine assay). In addition, 7A was stable in human blood serum, t1/2 of 15 vs 1.5 h for ADP, and resisted hydrolysis by NPP1/3, 2-fold vs ADP. Hence, we propose 7A as a highly promising neuroprotectant.
authors.affiliation: Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Sagit
authors.initials: S
authors.lastname: Azran
authors.affiliation: Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Ortal
authors.initials: O
authors.lastname: Danino
authors.affiliation: Otto von Guericke University , Leipziger Strasse 44, 39120, Magdeburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Förster
authors.affiliation: Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kenigsberg
authors.affiliation: Otto von Guericke University , Leipziger Strasse 44, 39120, Magdeburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Reiser
authors.affiliation: Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Mudit
authors.initials: M
authors.lastname: Dixit
authors.affiliation: Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Vijay
authors.initials: V
authors.lastname: Singh
authors.affiliation: Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Dan T
authors.initials: DT
authors.lastname: Major
authors.affiliation: Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Bilha
authors.initials: B
authors.lastname: Fischer
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D055808:Drug Discovery; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors; D006868:Hydrolysis; D007501:Iron; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D009711:Nucleotides / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D054735:Phosphorothioate Oligonucleotides / Q000737:chemistry / Q000494:pharmacology*; D058912:Purinergic P2Y Receptor Agonists / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism
chemical_list: D000975:Antioxidants; C045076:Fenton's reagent; D018696:Neuroprotective Agents; D009705:Nucleosides; D009711:Nucleotides; D054735:Phosphorothioate Oligonucleotides; D058912:Purinergic P2Y Receptor Agonists; D017382:Reactive Oxygen Species; D058472:Receptors, Purinergic P2Y1; D006861:Hydrogen Peroxide; D007501:Iron