Nucleoside 5′-phosphorothioate derivatives are highly effective neuroprotectants

Identification of Highly Promising Antioxidants/Neuroprotectants Based on Nucleoside 5′-Phosphorothioate Scaffold. Synthesis, Activity, and Mechanisms of Action

“…Previously we found that 3 was a potent antioxidant inhibiting OH radical production in the Fe­(II)–H 2 O 2 system . In addition, we found that 3 is a highly promising neuroprotectant rescuing primary neurons from insults such as FeSO 4 and Aβ 42 . These findings have encouraged us to further explore the potential of adenosine 5′-phosphorothioate analogues as antioxidants and neuroprotectants.…”

“…We found that certain natural and synthetic adenine nucleotides at submillimolar concentrations prevented OH radical production from H 2 O 2 in the presence of Cu­(I)/Fe­(II) ions better than standard antioxidants. , Specifically, 3 proved to be a 100 and 20 times more active antioxidant at Fe­(II)/H 2 O 2 system than 1 and the potent antioxidant Trolox, respectively. Furthermore, we identified 3 as a highly promising antioxidant and neuroprotective agent in PC12 cells and primary neurons exposed to oxidative stress, which was significantly more potent than 5 and GDP-β-S. Yet a major limitation of 3 is its enzymatic instability.…”

“…16,17 Specifically, 3 proved to be a 100 and 20 times more active antioxidant at Fe(II)/H 2 O 2 system than 1 and the potent antioxidant Trolox, 16 respectively. Furthermore, we identified 3 as a highly promising antioxidant and neuroprotective agent in PC12 cells and primary neurons exposed to oxidative stress, 19 which was significantly more potent than 5 and GDP-β-S. Yet a major limitation of 3 is its enzymatic instability.…”

DNA Backbone Sulfur-Modification Expands Microbial Growth Range under Multiple Stresses by its anti-oxidation function

“…The finding that PT modified DNA is highly efficient at removing ROS warrants further examination in the context of its application in biological engineering and therapeutic applications: Redox reactions have significant commercial utility, as they play a key role in the synthesis of industrially relevant compounds. Nucleoside PT derivatives have already been shown to be highly effective neuroprotectants in the treatment of Alzheimer’s disease 37, 38 . Further understanding the mechanism underlying PT modification could help to cure diseases related to ROS accumulation, such as cancer and neurodegenerative diseases.…”

A review on the chemical synthesis of pyrophosphate bonds in bioactive nucleoside diphosphate analogs

“…20 Recently, an a-P-borano-2-Cl-ADP isomer, a promising neuroprotectant, was found to be a potent P2Y 1 -receptor agonist (EC 50 7 nM), 21 while ADPbS and GDPbS were reported to be much better neuroprotectants than the corresponding parent nucleoside phosphorothioates against oxidative stress. 22 Diphosphate bond chemical synthesis can be accessed via the condensation of two pentavalent monophosphates {P(V)-P(V)}, a pentavalent monophosphate with a trivalent phosphite {P(V)-P(III)}, or two phosphites {P(III)-P(III)}. In early years, nucleoside pyrophosphate bond formation was mainly through P(V)-P(V) approaches, including a protected nucleoside benzyl phosphorochloridate condensation with a second monophosphate ester; direct condensation of two unprotected phosphomonoesters in the presence of trifluoroacetic anhydride or coupling reagents like dicyclohexylcarbodiimide (DCC) and PPh 3 /(PyS) 2 /N-methylimidazole; and the attack of a monophosphate analog on an activated nucleoside monophosphate (activated NMP).…”