Studies On The Chemical Constituents And Bioactivities Of Aspergillus Terreus

Three chapters were included in the dissertation.In the first chapter,the chemical constituents of Aspergillus terreus were systematic studied.In addition,the biogenetic pathways of two novel meroterpenoids with an unprecedented 1,2,5-trimethyl-4,9-dioxobicyclo[3.3.1]non-2-ene-3-carboxylic acid moiety were discussed.In the second chapter,the biological activity screening of selected secondary metabolites obtained from A.terreus were performed,including BACE1 inhibitory activities.In the third chapter,the chemical constituents from A.terreus for the last 70 years were summarized(1946-2016).A.terreus was one of the most common fungus in earth,which belongs to the genus Aspergillus and widely distributed in the soil,oceans,and animal waste.Lovatatin,which was obtained from A.terreus that could reduce the synthesis of cholesterol and low density lipoprotein cholesterol in body,was one of the most widely used clinical lipid-lowering drug created huge economic effect and social value.In order to find bioactive natural products with novel structure and broad prospects for development,we studied the ethanol extracts of A.terreus isolated from tidal flats of Yangtze river.By means of silica-based normal phase chromatographic columns,Sephadex LH-20,ODS reversed phase column,high performance liquid chromatography,chromatography and spectroscopic evidences,85 compounds with 32 new ones were isolated and identified from A.terreus,including 23 new meroterpenoids and 9 new lignans.Compound 1 is a 3,5-dimethylorsellinic acid-based meroterpenoid containing a unique β-oriented Me-21 with an unprecedented 1,2,5-trimethyl-4,9-dioxobicyclo[3.3.1]non-2-ene-3-carboxylic acid moiety,while compound 2 is a derivative of 1 with A-ring opening by oxidation.In addition,the BACE 1 inhibitory activity,cytotoxic activity,anti-HIV,DPPH scavenging activity,and anti-microbial of some compounds were evaluated.As the results shown:1)Compounds 1 and 2 exhibited promising inhibitory activities against BACE1 with IC50 values of 78.8 and 59.1 nM,respectively.The positive control,LY2811376,one of the most potent clinical BACEI inhibitors,showed an IC50 of 260 nM.Compound 1 also exhibited similar activity as LY2811376 against Alzheimer’s disease(AD)in 3xTg AD mice.2)Compound 39 shown moderate cytotoxic activities against HCC1806,HepG2,and SW1990 with IC50 values of 12.28 μM,5.67μM and 8.62 μM,respectively;48 exhibited IC50 values of 13.71 μM,17.32 μM and 6.51 μM,respectively,while compound 49 shown moderate cytotoxic activities against HCC.1806 and HepG2 with IC50 values of 15.93 μM and 11.31 μM,respectively.3)DPPH radical scavenging assays disclosed that 28 and 51 showed scavenging rates of 78.903%and 76.982%,respectively,at the concentration of 50μg/mL.The phytochemical investigation of A.terreus lead to the isolation of a large number of meroterpenoids and lignans,which greatly enriched the structural diversity of meroterpenoids and promoted the research level of this field.In addition,compound 1,which contains a novel carbon skeleton,is the first terpenoid to exhibit effective BACE1 inhibitory activity.Compound 1 is a potential lead compound and a versatile scaffold for the development of drugs for the treatment of Alzheimer’s Disease.