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2-Deoxyglycosylation towards more effective and bioavailable neuroprotective molecules inspired by nature
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Orientador(es)
Resumo(s)
The neuroprotective role of natural polyphenols is well established but phenolics poor water solubility affects their bioavailability and bioactivity. Aiming to overcome this issue, we were encouraged to investigate the 2-deoxyglycosylation of natural or nature inspired neuroprotective molecules, using glycals as easily accessed glycosyl donors. This robust methodology allowed the generation of a set of new resveratrol and caffeic acid ester glycosides, envisioning more effective and bioavailable compounds. Resveratrol 2-deoxyglycosides were more effective at protecting the neuronal cells from peroxide-induced cytotoxicity than resveratrol itself, while the caffeic acid ester glycoside also showed extraordinary neuroprotection activity. Coefficient partition measurements demonstrated the moderate lipophilicity of resveratrol glycosides, which Log D values are typical of a central nervous system (CNS) drug and ideal for blood-brain barrier (BBB) penetration. Passive permeation assessed by the parallel artificial membrane permeability assay (PAMPA) revealed that 2,6-dideoxy-l-arabino-hexopyranosides were more effective than 2-deoxy-d-arabino-hexopyranosides. The lack of toxicity of the neuroprotective glycosides and their promising physicochemical properties revealed the usefulness of sugar coupling towards the modulation of natural product properties and bioactivity.
Descrição
Funding: The European Union is gratefully acknowledged for the support of the project “Diagnostic and Drug Discovery Initiative for Alzheimer’s Disease” (D3i4AD), FP7-PEOPLE-2013-IAPP, GA 612347. Fundação para a Ciência e a Tecnologia is also acknowledged for the support of project UID/Multi/0612/2019, Funder Id: http://dx.doi.org/10.13039/501100001871, and for the Ph.D. grant co-sponsored by CIPAN SFRH/ BDE/51998/2012 (CD), Funder Id: http://dx.doi.org/10.13039/501100001871.
Palavras-chave
bioactive molecules biomolecular chemistry caffeic acid ester cytotoxicity deoxy glycoside ICS-29 lipophilicity medicinal chemistry neuroprotection organic synthesis resveratrol General Chemistry General Chemical Engineering