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Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and Aβ1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells

1
Center of Chemistry and Biochemistry, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, Campo Grande, 1749-016 Lisboa, Portugal
2
Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, Campo Grande, 1749-016 Lisboa, Portugal
3
MEDIR: Metabolic Disorders, CEDOC Chronic Diseases, Nova Medical School, Campus Sant’Ana, Rua Câmara Pestana, 6, Lab 3.8, 1150-082 Lisboa, Portugal
4
Department of Chemistry, Erl Wood Manor, Eli Lilly, Windlesham, Surrey GU20 6PH, UK
5
Abbvie Germany, Knollstr. 51, 67061 Ludwigshafen, Germany
6
Centro de Química Estrutural, Instiuto Superior Técnico, Ulisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
7
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Sevilla, Spain
8
Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland
9
Department of Medical Sciences, IBIMED, Universidade de Aveiro, 3810-193 Aveiro, Portugal
10
APDP-ERC, APDP-Diabetes Portugal, Rua do Salitre, Nº 118-120, 1250-203 Lisboa, Portugal
11
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari/Biofordrug, Via Edoardo Orabona, 4-70125 Bari, Italy
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2019, 12(2), 98; https://doi.org/10.3390/ph12020098
Received: 9 April 2019 / Revised: 5 June 2019 / Accepted: 6 June 2019 / Published: 21 June 2019
(This article belongs to the Special Issue Carbohydrates 2018)
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PDF [1278 KB, uploaded 21 June 2019]
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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, logD7.4 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 Aβ1-42-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 μM, as a new lead structure for further development against AD. View Full-Text
Keywords: Alzheimer’s disease; Aβ1-42; cholinesterase inhibitors; flavones; chromen-4-ones; C-glucosyl flavonoids; PAMPA Alzheimer’s disease; 1-42; cholinesterase inhibitors; flavones; chromen-4-ones; C-glucosyl flavonoids; PAMPA
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de Matos, A.M.; Martins, A.; Man, T.; Evans, D.; Walter, M.; Oliveira, M.C.; López, Ó.; Fernandez-Bolaños, J.G.; Dätwyler, P.; Ernst, B.; Macedo, M.P.; Contino, M.; Colabufo, N.A.; Rauter, A.P. Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and Aβ1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells. Pharmaceuticals 2019, 12, 98.

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