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Divergent synthesis of biflavonoids yields novel inhibitors of the aggregation of amyloid β (1-42).

Accepted version
Peer-reviewed

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Type

Article

Change log

Authors

Sum, Tze Han 
Sum, Tze Jing 
Collins, Súil 
Galloway, Warren RJD 
Twigg, David G 

Abstract

Biflavonoids are associated with a variety of biologically useful properties. However, synthetic biflavonoids are poorly explored within drug discovery. There is considerable structural diversity possible within this compound class and large regions of potentially biologically relevant biflavonoid chemical space remain untapped or underexplored. Herein, we report the development of a modular and divergent strategy towards biflavonoid derivatives which enabled the step-economical preparation of a structurally diverse collection of novel unnatural biflavonoids. Preliminary studies established that the strategy could also be successfully extended to the preparation of very rare triflavonoids, which are also expected to be useful tools for biological intervention. Prompted by previous inhibitory studies with flavonoid libraries, amyloid anti-aggregation screening was performed, which led to the identification of several structurally novel inhibitors of the aggregation of the amyloid β peptide (Aβ42). Aggregated Aβ42 is a pathological hallmark of Alzheimer's disease and the use of small molecules to inhibit the aggregation process has been identified as a potentially valuable therapeutic strategy for disease treatment. Methylated biaurones were associated with highest levels of potency (the most active compound had an IC50 value of 16 μM), establishing this scaffold as a starting point for inhibitor development.

Description

Keywords

Amyloid beta-Peptides, Biflavonoids, Chemistry Techniques, Synthetic, Peptide Fragments, Protein Aggregates

Journal Title

Org Biomol Chem

Conference Name

Journal ISSN

1477-0520
1477-0539

Volume Title

15

Publisher

Royal Society of Chemistry (RSC)
Sponsorship
Engineering and Physical Sciences Research Council (EP/K039520/1)
European Research Council (279337)
European Research Council (665631)
We thank the Cambridge Commonwealth Trust and Cambridge Home and European Scholarship Scheme for the awards of scholarships to T. H. S., T. J. S and S. C. The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreements no. [279337/DOS and 695669 & 665631/FH]. The authors also thank AstraZeneca, the European Union (EU), the Engineering and Physical Sciences Research Council (EPSRC), the Biotechnology and Biological Sciences Research Council (BBSRC), the Medical Research Council (MRC), and the Wellcome Trust for funding.