Discovery of N-methylpiperazinyl flavones as a novel class of compounds with therapeutic potential against Alzheimer’s disease : synthesis, binding affinity towards amyloid β oligomers (Aβo) and ability to disrupt Aβo-PrPC interactions
| Autor: | David A. Evans, Benjamin M. Partridge, James H. Grayson, Emma Mead, Claire J. Garwood, Amélia P. Rauter, Teresa Man, Cleide C. Souza, Beining Chen, Imane Ghafir El Idrissi, Ke Ning, Maria Cristina Oliveira, Ana M. Matos, Gary Sharman, Joanna Wolak, Charlotte Dunbar |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences Amyloid β General Chemical Engineering Neurodegeneration General Chemistry medicine.disease Neuroprotection Flavones Oligomer Para position 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Thiomorpholine chemistry Biochemistry Morpholine medicine 030217 neurology & neurosurgery 030304 developmental biology |
| ISSN: | 0033-4545 |
| Popis: | With no currently available disease-modifying drugs, Alzheimer’s disease is the most common type of dementia affecting over 47 million people worldwide. In light of the most recent discoveries placing the cellular prion protein (PrPC) as a key player in amyloid β oligomer (Aβo)-induced neurodegeneration, we investigated whether the neuroprotective potential of nature-inspired flavonoids against Aβ-promoted toxicity would translate into the ability to disrupt PrPC-Aβo interactions. Hence, we synthesized a small library of flavones and studied their binding affinity towards Aβo by STD-NMR. C-glucosyl flavones exhibited improved binding affinity with morpholine, thiomorpholine or N-methylpiperazine rings attached to the flavone skeleton in ring B para position. Moreover, a N-methylpiperazinyl flavone displayed suitable physicochemical properties and optimal water solubility even without the sugar moiety, and a high interaction with Aβo involving the whole flavone core. Its C-glucosyl derivative, was, however, the best compound to inhibit PrPC-Aβo interactions in a dose-dependent manner, with 41 % of inhibition capacity at 10 μM. The potential of C-glucosyl flavones and their aglycones as protein-protein interaction inhibitors able to tackle PrPC-Aβo interactions is here presented for the first time, and supports this class of compounds as new prototypes for further development in the treatment of Alzheimer’s disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|