Synthesis And Inhibition Of Aβ Aggregation And Neurotoxicity Of Benzofuran Neolignan Derivatives

Objective:Alzheimer's disease (AD) is a primary neurodegenerative condition which has become a major public health problem because of its increasing prevalence, long duration and high cost of care. Although the precise pathogenesis of Alzheimer's disease is not fully established, Substantial evidence suggests that deposition of aggregates of amyloid-βprotein (Aβ) which is caused by amyloid precursor protein (APP) overexpression and faulty processing plays a seminal role in the aetiology of AD. So, inhibition of Aβmisfolding and aggregation is therefore viewed as one possible method to halt the progression of AD.Lignans are naturally occurring phenol compounds, which are one of major classes of phytoestrogens with estrogenic or antiestrogenic activity and abundant micronutrients in fruits, greenstuff and beverage. Evidence for their several biologically activity in the prevention of antioxidation, antitumor, antimicrobial, antiinflammatory, immune regu- lation. Rencently crude and antificial benzofuran compounds, which could inhibition of Aβoligomerization or fibrillation and neuroprotection against Aβ–induced toxicity, have received much attention as potential protectors against AD. Herein, a series of new benzofuran neoligans were synthesized, then their inhibition the self–aggregative polymerization ofβ–amyloid peptide and protective Aβ-induced cytotoxicty were studied.Methods4 - hydroxybenzaldehyde and 3 - methoxy -4 - hydroxybenzaldehyde was used to prepare the propylene ether derivatives and their quaternary phosphonium salts were synthesisd by a series of reactions. Then it was produced a series of o-vinylphenol derivatives via Witting Reaction catalyzed by DBU with the reactant of phosphonium salts and hydroxybenzaldehyde.Finally, a series of benzofuran derivatives were produced via the cyclization of o-vinylphenol derivatives catalyzed by potassium carbonate and iodine.Then, we choose compounds 11,12,14 and 15 and investigate their capabilities in neuroprotective, thioflavin T fluorescence spectroscopy and MTT assy were used. We preincubated Aβ_1-42 and compounds 11,12,14 and 15 at concentrations of 0.01,0.1,1,₅₀and 100μΜat 37℃in vivtro, we determine the fluorescence intensity of those samples at different concentration and time.The MTT (3-[4,5-dimethylth-iazol-2-yl]-2,5-diphenyltetrazolium bromide) assay which has been widely used as a colorimetric approach based on the activity of mitochondrial dehydrogenase enzymes in cells. Preincubated Aβ1–42 oligomers with compounds 11,12,14 and 15 at concentrations of 0.01,0.1,1,10,75and 1₅₀μΜcan reduce Aβ1–42 cytotoxic effects on human neuroblastoma SH-SY5Y cells.ResultsThe results were obtained using thioflavin T fluorescence spectroscopy. We found that four compounds can inhibit Aβ1–42 fibril aggregation in a dose–and time–dependent manner. And the four compounds can inhibite Aβ_1-42 aggregation(IC₅₀: 15 21μM).The results suggest that those compounds can nuroprotect agaist Aβ1–42 oligomers cycotocity, but the results did not satisfied ( IC₅₀: 34 47μM ).