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Synthesis and Inhibition of Aβ Aggregation and Neurotoxicity of Benzofuran Neolignan Derivatives

Author: YuLiHong
Tutor: ZhangChao
School: Guangzhou Medical College
Course: Pharmacology
Keywords: Benzofuran New lignin Suppression  Gather Neurotoxicity
CLC: R749.16
Type: Master's thesis
Year: 2010
Downloads: 48
Quote: 0
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Abstract


Objective: Alzheimer's disease (Alzheimer's disease, AD) is a primary neurodegenerative diseases; With the rising incidence, the incidence of long duration and the high costs of treating AD seriously troubled public health . The specific AD pathogenesis is not clear, but the evidence confirmed amyloid fibrosis is an important cause of the AD. Inhibition of misfolding and aggregation and inhibition of Aβ neurotoxicity new target for the design and development of AD drugs. Aβ aggregation process research in recent years against Aβ drug research focus. Lignans are a class of natural phenolic compounds with weak estrogenic and anti-estrogenic properties of phenolic phytoestrogens. Fruits, vegetables and beverages contain large amounts of lignans. The study found that lignans have a variety of biological activity, including anti-oxidation, anti-tumor, anti-microbial, anti-inflammatory and immunomodulatory. With further research, benzofuran compounds found to inhibit the aggregation of Aβ and inhibit Aβ neurotoxicity showed good biological activity. Therefore, design synthesis of a series of new benzofuran lignin, and determination, and compare them on the Aβ 1-40 aggregation and Aβ 1-42 SH-SY5Y cells induced neurotoxicity. Methods: 4 - hydroxybenzaldehyde and 3 - methoxy -4 - hydroxybenzaldehyde as raw materials, preparing propylene-ether derivative, the latter by a series of reactions to the preparation of a quaternary phosphonium salt, and then 2 - hydroxyphenyl formaldehyde 2 - hydroxy -3 - methoxybenzaldehyde and 2 - hydroxy-4 - methoxybenzaldehyde of DBU catalyst made into witting reaction to form a series of o-vinylphenol, after the K 2 CO 3 and under the conditions of the iodine catalyzed oxidation cyclization reaction became a series of benzofuran derivatives (1) (17). Preliminary selected benzo the furan the new lignans derivative 11,12,14 and 15, and determination of compounds 11,12,14 and 15 pairs of Aβ 1-42 in vitro aggregation and Aβ 1 -42 -induced neurotoxicity in SH-SY5Y cells protective effect. Determination of compounds 11, 12 and 15 at 0.01 1 the 00μM the six concentration gradient of with 50μM Aβ 1-42 , the use of in vitro at 37 ℃ for determination of Thioflavin T France different concentrations and different times the fluorescence intensity of each sample value. From the cellular level test compounds 11,12,14 and 15 protection Aβ1-42 oligomer-induced cytotoxicity: the use of MTT assay compounds 11,12,14 and 15 0.01 1 00μM of seven concentration gradient 50μM Aβ1-42 oligomer-induced inhibition of SH-SY5Y cells neurotoxicity. Results: 1. Synthesis of new lignin derivatives of benzofuran 17 and after NMR, 13C NMR and mass spectrometry to confirm that they are correct structure. Thioflavin T fluorescence method experimental results show that the compounds 11,12,14, and 15 pairs of Aβ1-42 in vitro aggregation in a concentration by patience and time in accordance with patience; compounds 11, 12 and 15 and Aβ1-42 were incubated for 3 days The compounds the Aβ 1-42 aggregation in vitro IC 50 : 18.2,15.2,18.3 and 21.7μM. The MTT method results show that the compounds 11, 12 and 15 can be inhibition of Aβ 1-42 the oligomers induced SH-SY5Y cells neurotoxic has a protective effect, IC 50 : 41.8,38.1,34.2 and 46.5μM.

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CLC: > Medicine, health > Neurology and psychiatry > Psychiatry > Cerebral organic mental disorder > Elderly as early as possible the old disorder
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