2-Deoxyglycosylation towards more effective and bioavailable neuroprotective molecules inspired by nature

Catarina Dias, Ana M. Matos, Maria T. Blásquez-Sanchez, Patrícia Calado, Alice Martins, Philipp Dätwyler, Beat Ernst, M. Paula Macedo, Nicola Colabufo, Amélia P. Rauter

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalPure and Applied Chemistry
DOIs
Publication statusPublished - 1 Jan 2019

Fingerprint

Resveratrol
Glycosides
Molecules
Bioactivity
Esters
Central Nervous System Agents
Acids
Peroxides
Neurology
Polyphenols
Cytotoxicity
Biological Products
Permeation
Sugars
Toxicity
Assays
Solubility
Modulation
Membranes
resveratrol

Keywords

  • bioactive molecules
  • biomolecular chemistry
  • caffeic acid ester
  • cytotoxicity
  • deoxy glycoside
  • ICS-29
  • lipophilicity
  • medicinal chemistry
  • neuroprotection
  • organic synthesis
  • resveratrol

Cite this

Dias, Catarina ; Matos, Ana M. ; Blásquez-Sanchez, Maria T. ; Calado, Patrícia ; Martins, Alice ; Dätwyler, Philipp ; Ernst, Beat ; Macedo, M. Paula ; Colabufo, Nicola ; Rauter, Amélia P. / 2-Deoxyglycosylation towards more effective and bioavailable neuroprotective molecules inspired by nature. In: Pure and Applied Chemistry. 2019.
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2-Deoxyglycosylation towards more effective and bioavailable neuroprotective molecules inspired by nature. / Dias, Catarina; Matos, Ana M.; Blásquez-Sanchez, Maria T.; Calado, Patrícia; Martins, Alice; Dätwyler, Philipp; Ernst, Beat; Macedo, M. Paula; Colabufo, Nicola; Rauter, Amélia P.

In: Pure and Applied Chemistry, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 2-Deoxyglycosylation towards more effective and bioavailable neuroprotective molecules inspired by nature

AU - Dias, Catarina

AU - Matos, Ana M.

AU - Blásquez-Sanchez, Maria T.

AU - Calado, Patrícia

AU - Martins, Alice

AU - Dätwyler, Philipp

AU - Ernst, Beat

AU - Macedo, M. Paula

AU - Colabufo, Nicola

AU - Rauter, Amélia P.

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Y1 - 2019/1/1

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AB - 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.

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KW - biomolecular chemistry

KW - caffeic acid ester

KW - cytotoxicity

KW - deoxy glycoside

KW - ICS-29

KW - lipophilicity

KW - medicinal chemistry

KW - neuroprotection

KW - organic synthesis

KW - resveratrol

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M3 - Article

JO - Pure and Applied Chemistry

JF - Pure and Applied Chemistry

SN - 0033-4545

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