Synthesis And Evaluation Of A Series Of Phenylethanoid Thioglycoside As O-GlcNAcase Inhibitors

Alzheimer disease（AD）is a neurodegenerative disease.The major pathological hallmarks of AD are considered to be amyloid beta plaques outside of neuron cell and neurofibrillary tangles generated by Tau phosphorylation inside the cell.Inhibition of Tau hyperphosphorylation is a possible way to treat Alzheimer disease.Human O-GlcNAcase（h OGA）is a member of family 84 glycosyl hydralyases（GH84）,which is the key enzyme to regulate the modification of protein oxygen linked acetylglucosamine（O-GlcNAcylation）.The phosphorylation level of Tau protein can be reduced indirectly by regulating O-GlcNAcylation level of Tau protein,so as to delay the progression of Alzheimer disease.Phenylethanoid glycosides widely exist in a variety of medicinal plants.Most of them have biological activities,such as antibacterial,antitumor,glycosidase inhibitory activity and so on.In this paper,an efficient epoxy ring-opening method was designed and developed to synthesize phenylethanol thioglycosides,and the inhibitory activity of these compounds was explored on human O-Glc Nacase（OGA）,in order to develop new human OGA inhibitors and provide theoretical reference for the treatment of Alzheimer disease.In this paper,monosaccharides（glucose,galactose,rhamnose,mannose,acetylglucosamine and acetylgalactosamine）were reacted with pyridine and acetic anhydride to obtain fully acetylated monosaccharide derivatives.Then,1-bromosaccharide was obtained in hydrogen bromide solution in acetic acid.Afterwards,1-bromosaccharide reacted with thiourea to obtain stereoselective S-glycosylisothiourea salt.S-glycosylisothiourea salt was used to produce glycosylthiols in the presence of sodium bisulfite.1,2 trans glycosylthiols were obtained by silica gel column chromatography.Then,the epoxide ring-opening conditions of glycosylthiols with（S）/（R）-Styrene oxide under alkaline conditions were explored.The reaction conditions were optimized from the aspects of solvent,temperature,basic reagent and feed ratio,12 new and stereoselective phenylethanoid thioglycosides derivatives were synthesized.The yields of all the products were above 69%.All the compounds were confirmed by ¹H-NMR that the original configuration of epoxy was remained.The natural product analogue phenylethanoid thioglycosides were obtained by removing the acetyl group with CH₃OH/CH₃ONa.Finally,the inhibitory activity of these compounds against O-Glc Nacase（OGA）was evaluated.and it was found that the inhibitory activity against OGA is linked to the configuration of phenylethanoid glycosides.（R）-Phenylethanoid thioglycosides have better activity than the compound with（S）configuration.Among them,（R）-acetylglucosamine derivative(11a,IC₅₀=0.99 mmol·L^-1)has the best inhibitory effect.This compound can be used as a lead compound for the design and synthesis of novel efficient inhibitors of OGA.