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Structure-activity relationships for flavone interactions with amyloid beta reveal a novel anti-aggregatory and neuroprotective effect of 2 ',3 ',4 '-trihydroxyflavone (2-D08)

Artikel i vetenskaplig tidskrift
Författare D. T. Marsh
S. Das
Jessica Ridell
S. D. Smid
Publicerad i Bioorganic & Medicinal Chemistry
Volym 25
Nummer/häfte 14
Sidor 3827-3834
ISSN 0968-0896
Publiceringsår 2017
Publicerad vid Institutionen för neurovetenskap och fysiologi
Sidor 3827-3834
Språk en
Länkar doi.org/10.1016/j.bmc.2017.05.041
Ämnesord Amyloid beta, 2 ',3 ',4 '-Trihydroxyflavone, 2-D08, Jaceosidin, Nobiletin, Quercetin, Transilitin, catechol-type flavonoids, alzheimers-disease, fibril formation, alpha-synuclein, protein, inhibitor, quercetin, nobiletin, docking, binding, Biochemistry & Molecular Biology, Pharmacology & Pharmacy, Chemistry
Ämneskategorier Neurologi

Sammanfattning

Naturally-occurring flavonoids have well documented anti-aggregatory and neuroprotective properties against the hallmark toxic protein in Alzheimer's disease, amyloid beta (A beta). However the extensive diversity of flavonoids has limited the insight into the precise structure-activity relationships that confer such bioactive properties against the A beta protein. In the present study we have characterised the A beta binding properties, anti-aggregatory and neuroprotective effects of a discreet set of flavones, including the recently described novel protein sumoylation inhibitor 2',3',4'-trihydroxyflavone (2-D08). Quercetin, transilitin, jaceosidin, nobiletin and 2-D08 were incubated with human A beta(1-42) for 48 h in vitro and effects on AB fibrillisation kinetics and morphology measured using Thioflavin T (ThT) and electron microscopy respectively, in addition to effects on neuronal PC12 cell viability. Of the flavones studied, only quercetin, transilitin and 2-D08 significantly inhibited A beta(1-42) aggregation and toxicity in PC12 cells. Of those, 2-D08 was the most effective inhibitor. The strong anti-amyloid activity of 2-D08 indicates that extensive hydroxylation in the B ring is the most important determinant of activity against beta amyloid within the flavone scaffold. The lack of efficacy of jaceosidin and nobiletin indicate that extension of B ring hydroxylation with methoxyl groups result in an incremental loss of anti-fibrillar and neuroprotective activity, highlighting the constraint to vicinal hydroxyl groups in the B ring for effective inhibition of aggregation. These findings reveal further structural insights into anti-amyloid bioactivity of flavonoids in addition to a novel and efficacious anti-aggregatory and neuroprotective effect of the semi-synthetic flavone and sumoylation inhibitor 2',3',4'-trihydroxyflavone (2-D08). Such modified flavones may facilitate drug development targeting multiple pathways in neurodegenerative disease. Crown Copyright (C) 2017 Published by Elsevier Ltd. All rights reserved.

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