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.

A promising drug candidate for the treatment of glaucoma based on a P2Y6-receptor agonist

“…7). This is in agreement with our earlier docking studies of P2Y1-R [38]. Based on the hP2Y6-R model and docking results, we propose that the phosphate chain of the endogenous hP2Y6-R agonist, UDP, 2, is tightly held by the three cationic residues (Arg103, Arg284, and Lys25) and a tyrosine residue (Tyr262) (Fig.…”

Polypharmacology of conformationally locked methanocarba nucleosides

“…In some cases, a secondary activity, such as antioxidant, can be engineered into the nucleoside or nucleotide [59]. In other cases, the nucleobase alone displays a spectrum of activities (e.g., adenine derivatives that hit multiple targets).…”

Development of Novel N-hydroxypyridone Derivatives as Potential Anti-Ischemic Stroke Agents

“…Among these 31 compounds, some compounds showed lower neuroprotective effects at 10 μM than that at 1 μM. To evaluate whether these compounds have a toxic effect on normal cells at higher concentration, we tested the influence of the compounds (1,2,3,4,5,6,10,11,12,15,16,17,18,20,21,22,23,28,29, and CPX) on the cell viability of SH-SY5Y cells without OGD insult. The results indicated that CPX, 10, 11, and 29 reduce the viability at a concentration of 10 μM (Table S7), which might be related with their lower neuroprotective activity at a concentration of 10 μM.…”

“…ORAC (Trolox Equivalents) and Permeability Results (P e × 10 −6 cm s −1 ) from the PAMPA-BBB Assay forCompounds 4,6,10,11, 21,22,and 29 …”