title: Highly efficient biocompatible neuroprotectants with dual activity as antioxidants and P2Y receptor agonists.
abstract: Currently, there is a need for novel, biocompatible, and effective neuroprotectants for the treatment of neurodegenerative diseases and brain injury associated with oxidative damage. Here, we developed nucleotide-based neuroprotectants acting dually as antioxidants and P2Y-R agonists. To improve the potency, selectivity, and metabolic stability of ATP/ADP, we substituted adenine C2-position by Cl and Pα/Pβ position by borano group, 6-9. Nucleotides 6-9 inhibited oxidation in cell-free systems (Fe(II)-H2O2), as detected by ESR (IC50 up to 175 μM), and ABTS assay (IC50 up to 40 μM). They also inhibited FeSO4-induced oxidative stress in PC12 cells (IC50 of 80-200 nM). 2-Cl-ADP(α-BH3), 7a, was found to be the most potent P2Y1-R agonist currently known (EC50 7 nM) and protected primary cortical neurons from FeSO4 insult (EC50 170 nM). In addition, it proved to be metabolically stable in human blood serum (t(1/2) 7 vs 1.5 h for ADP). Hence, we propose 7a as a highly promising neuroprotectant.
authors.affiliation: Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Sagit
authors.initials: S
authors.lastname: Azran
authors.forename: Daniel
authors.initials: D
authors.lastname: Förster
authors.forename: Ortal
authors.initials: O
authors.lastname: Danino
authors.forename: Yael
authors.initials: Y
authors.lastname: Nadel
authors.forename: Georg
authors.initials: G
authors.lastname: Reiser
authors.forename: Bilha
authors.initials: B
authors.lastname: Fischer
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D009711:Nucleotides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D016716:PC12 Cells; D011487:Protein Conformation; D058912:Purinergic P2Y Receptor Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D058470:Receptors, Purinergic P2Y / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D001672:Biocompatible Materials; D018696:Neuroprotective Agents; D009711:Nucleotides; D058912:Purinergic P2Y Receptor Agonists; D017382:Reactive Oxygen Species; D058470:Receptors, Purinergic P2Y