Thioflavones as novel neuroprotective agents.
Oxidative stress is associated with the pathology of neurodegenerative diseases. Identification of small molecules capable of protecting against oxidative stress is therefore of significant importance. In this context, a library of 76 hydroxy flavones, methoxy flavones and their 4-thio analogues has been evaluated for neuroprotection against H2O2-induced oxidative stress. This revealed the synthetic 7,8-dihydroxy 4-thioflavones as neuroprotective compounds, with 14d and 18d showing highest neuroprotective effects at lower concentrations (0.3μM). Neuroprotection was found to be mediated via activation of the anti-apoptotic cell survival proteins of the ERK1/2 and PI3K/Akt pathways. Structure-activity relationship analysis revealed the B-ring phenyl group as essential for greater neuroprotection. Replacing the 4-CO moiety with a 4-CS moiety also generally enhanced neuroprotection.
School of Pharmacy, University of Reading, Whiteknights, RG6 6AD Berkshire, UK.
Divyashree
D
Ravishankar
Molecular Nutrition Group, Department of Food and Nutritional Sciences, School of Chemistry, Food and Pharmacy, University of Reading, RG6 6AP Reading, UK.
Giulia
G
Corona
School of Pharmacy, University of Reading, Whiteknights, RG6 6AD Berkshire, UK.
Stephanie M
SM
Hogan
Molecular Nutrition Group, Department of Food and Nutritional Sciences, School of Chemistry, Food and Pharmacy, University of Reading, RG6 6AP Reading, UK.
Jeremy P E
JPE
Spencer
School of Pharmacy, University of Reading, Whiteknights, RG6 6AD Berkshire, UK. Electronic address: f.greco@reading.ac.uk.
Francesca
F
Greco
School of Pharmacy, University of Reading, Whiteknights, RG6 6AD Berkshire, UK. Electronic address: h.m.i.osborn@reading.ac.uk.
Helen M I
HMI
Osborn
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D047309:Flavones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D013329:Structure-Activity Relationship
D047309:Flavones; D018696:Neuroprotective Agents; C571255:thioflavone; D006861:Hydrogen Peroxide
Flavones; Neuroprotection; Oxidative stress; Structure–activity relationship