Studies On The Secondary Metabolites Of Endophytic Fungi And Preliminary Application Of Chemical Epigenetics

Fungus living in a special habitat,such as endophyte fungus and marine fungus,evolves a unique metabolism and defense system in the process of adapting to the environment.These fungi have been considered as rich sources of novel and bioactive secondary metabolites.Recent study show that chemical epigenetic modification of the fungus by reagents such as histone deacetylase(HDAC)inhibitors and/or DNA methyltransferase inhibitors could activate certain silent genes,which would lead to the production of a varity of new secondary metabolites.Employ these strategy,we have systematically investigated the natural products from the endophyte fungi Phomopsis sp.xz-18 and a halotolerant endogenic fungal Aspergillus sp.F00785 via chemical epigenetic manipulation.In this thesis,we have isolated and elucidated 48 compounds from both strains,where 17 compounds are new chemical entities.Thirty-six compounds were isolated and elucidated from the extrcats of endophyte fungi Phomopsis sp.xz-18,including eighteen cytochalasins,four xanthones,three azaphilones,and eleven other types of compounds.Among them,seventeen compound,accounting for 47.2%of all obtained compounds,were novel structure.There're ninenew cytochalasins,and more interestingly three of them were the first time to be reported with unique chemo-type.Twelve compounds were isolated and elucidated from seaweed halotolerant symbiotic niger Aspergillus sp.F00785 via chemical epigenetic manipulationincluding four benzaldehyde derivative,four asperentins derivatives,a known naphthol derivatives and three known anthraquinone derivatives(G8-E,H1-C1,G8-D1).It needs to be pointed out that these three anthaquinons were only observed under chemical epigenetic manipulation conditions,but not for untreated conditions.These natural products were further evaluated using a panel of bioactivity assays including antimicrobial,antitumor,antioxidant,antityrosinase and anti-acetylcholinesterase tests.Compound A8-G31a showed moderate antimicrobial activity against Bacillus pumilus(B.p),Candida albicans(C.a);A8-G31b showed moderate inhibition against B.p and Bacillus subtilis(B.s);A8-G33c showed weak antimicrobial activity against Aspergillus niger;B7-A3b showed weak antimicrobial activity against B.s and C.a;A5-C11 exhibited weak activity against C.a and Staphlococcus aureus(S.a);B9-D1 a exhibited relative strong activity against B.p,S.a and Escherichia coli.A5-C11,A5-D41,A3-Alla showed relatively strong anti-free scavenging activity of DPPH.In summary,our results of 17 new compounds out of 36 compounds in total obtained from endophyte fungi Phomopsis sp.xz-18 highlights the notion that fungus in special ecotope such as endophyte fungi is a rich sourse to discover novel and bioactive second metabolites.Epigenetic manipulation to a marine fungi activates silent gene clusters to give three anthaquinons which were not observed under untreated conditions,suggests its potential use in fully exploiting new natural products from known fungus.