Thioflavones as novel neuroprotective agents

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• 作者：Divyashree Ravishankar^a ; Giulia Corona^b ; ^&dagger ; ; Stephanie M. Hogan^a ; Jeremy P.E. Spencer^b ; Francesca Greco^a ; ^{f.greco@reading.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Helen M.I. Osborn^a ; ^{h.m.i.osborn@reading.ac.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：MTT ; 3-(4 ; 5-dimethylthiazol-2-yl)-2 ; 5-diphenyltetrazolium bromide ; DPPH ; 2 ; 2-diphenyl-1-picrylhydrazyl ; EDTA ; ethylenediaminetetraacetic acid ; ERK1/2 ; extracellular signal-regulated kinase ; mTOR ; mammalian target of rapamycin ; AMPKα ; 5&prime ; adenosine monophosphate-activated protein kinase ; GSK-3β ; glycogen synthase kinase-3β ; Bad ; Bcl-2-associated death promoter ; PRAS40 ; proline-rich Akt substrate of 40  ; kDa ; PI3K ; phosphatidylinositol-4 ; 5-bisphosphate-3-kinase ; BDNF ; brain-derived neurotr
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：24
• 期：21
• 页码：5513-5520
• 全文大小：2216 K

文摘

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 (0.3 μM). 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.