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

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.

Iterative Synthesis of 2‐Deoxyoligosaccharides Enabled by Stereoselective Visible‐Light‐Promoted Glycosylation

“…As shown in Table 2b, the 2‐deoxyglycosylation modification occurred smoothly under the standard reaction conditions, affording the desired products 21 – 27 in good to excellent yields and with α‐stereoselectivity. Phenolic compounds possess various biological activities, but their clinical use is restricted by their poor water solubility and low oral bioavailability [13] . Glycosylation of phenolic compounds could improve their water solubility.…”

“…The late-stage glycosylation of complex small molecules is a very important approach in modern drug discovery. [13] To this end, we applied our method to the 2-deoxyglycosylation of natural products and drugs. As shown in Table 2b, the 2-deoxyglycosylation modification occurred smoothly…”

Iterative Synthesis of 2‐Deoxyoligosaccharides Enabled by Stereoselective Visible‐Light‐Promoted Glycosylation

“…The late‐stage glycosylation of complex small molecules is a very important approach in modern drug discovery [13] . To this end, we applied our method to the 2‐deoxyglycosylation of natural products and drugs.…”

“…The late-stage glycosylation of complex small molecules is a very important approach in modern drug discovery. [13] To this end, we applied our method to the 2-deoxyglycosylation of natural products and drugs. As shown in Table 2b, the 2-deoxyglycosylation modification occurred smoothly under the standard reaction conditions, affording the desired products 21-27 in good to excellent yields and with αstereoselectivity.…”

“…Phenolic compounds possess various biological activities, but their clinical use is restricted by their poor water solubility and low oral bioavailability. [13] Glycosylation of phenolic compounds could improve their water solubility. It was found that phenolic compounds can be employed as suitable substrates of this transformation, as exemplified by the formation of glycosides 23-26.…”