Publication Type Journal Article
Title Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and A beta(1-42)-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells
Authors Ana M. de Matos Alice Martins Teresa Man David Evans Magnus Walter M. Conceição Oliveira Oscar Lopez Jose G. Fernandez-Bolanos Philipp Datwyler Beat Ernst Maria Paula de Macedo Marialessandra Contino Nicola A. Colabufo Amélia P. Rauter
Groups HC BioMol
Journal PHARMACEUTICALS
Year 2019
Month June
Volume 12
Number 2
Pages
Abstract With the lack of available drugs able to prevent the progression of Alzheimer s disease (AD), the discovery of new neuroprotective treatments able to rescue neurons from cell injury is presently a matter of extreme importance and urgency. Here, we were inspired by the widely reported potential of natural flavonoids to build a library of novel flavones, chromen-4-ones and their C-glucosyl derivatives, and to explore their ability as neuroprotective agents with suitable pharmacokinetic profiles. All compounds were firstly evaluated in a parallel artificial membrane permeability assay (PAMPA) to assess their effective permeability across biological membranes, namely the blood-brain barrier (BBB). With this test, we aimed not only at assessing if our candidates would be well-distributed, but also at rationalizing the influence of the sugar moiety on the physicochemical properties. To complement our analysis, logD(7.4) was determined. From all screened compounds, the p-morpholinyl flavones stood out for their ability to fully rescue SH-SY5Y human neuroblastoma cells against both H2O2- and A beta(1-42)-induced cell death. Cholinesterase inhibition was also evaluated, and modest inhibitory activities were found. This work highlights the potential of C-glucosylflavones as neuroprotective agents, and presents the p-morpholinyl C-glucosylflavone 37, which did not show any cytotoxicity towards HepG2 and Caco-2 cells at 100 mu M, as a new lead structure for further development against AD.
DOI http://dx.doi.org/10.3390/ph12020098
ISBN
Publisher MDPI
Book Title
ISSN
EISSN 1424-8247
Conference Name
Bibtex ID ISI:000477028700052
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