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

Magnus Walter¹  AnaM. de Matos²  Alice Martins²  AméliaP. Rauter²  MariaConceição Oliveira³  JoséG. Fernandez-Bolaños⁴  Óscar López⁴  David Evans⁵  Teresa Man⁵  Beat Ernst⁶  Philipp Dätwyler⁶  NicolaA. Colabufo⁷  Marialessandra Contino⁷  M.Paula Macedo⁸ 

[1] Abbvie Germany, Knollstr. 51, 67061 Ludwigshafen, Germany;Center of Chemistry and Biochemistry, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, Campo Grande, 1749-016 Lisboa, Portugal;Centro de Química Estrutural, Instiuto Superior Técnico, Ulisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal;Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Sevilla, Spain;Department of Chemistry, Erl Wood Manor, Eli Lilly, Windlesham, Surrey GU20 6PH, UK;Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland;Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari/Biofordrug, Via Edoardo Orabona, 4-70125 Bari, Italy;MEDIR: Metabolic Disorders, CEDOC Chronic Diseases, Nova Medical School, Campus Sant’Ana, Rua Câmara Pestana, 6, Lab 3.8, 1150-082 Lisboa, Portugal;

关键词: Alzheimer’s disease;    Aβ_1-42;    cholinesterase inhibitors;    flavones;    chromen-4-ones;    C-glucosyl flavonoids;    PAMPA;   

DOI  :  10.3390/ph12020098

来源: DOAJ

【 摘 要 】

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 Aβ_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 μM, as a new lead structure for further development against AD.

【 授权许可】

Unknown