New Bioactive Metabolites Of Fungi From Special Habitats

This dissertation reports the structure and bioactivity of secondary metabolites produced by two symbiotic microbes including one fungal endophyte Guignardia mangiferae obtained from a normal leaf of Ilex cornuta,and marine fungus Curvularia sp.isolated from the gut of Argyrosomus argentatus.A total of forty-seven compounds were isolated from the fermentation broth by a combination of chromatographies over silica gel and ODS reverse column,gel filtration overSephadex LH-20,and semipreparative HPLC.The structures of the new compounds consisting of thirty two indolizidine alkaloids and three meroterpens were elucidated by spectroscopic analyses(HR-ESI-MS,EIMS,IR,1H-NMR,13C-NMR,HMQC,1H-1H COSY,HMBC,NOESY,ROESY,CD)and X-ray diffractions.Furthermore,these isolated compounds were assayed in vitro for antimicrobial and TLR3 regulating activities.The endophytic fungus Guignardia mangiferae isolated from Ilex cornuta leaves has been shown to produce a family of TLR3 regulating meroterpenes(1-3),of which 2-4 possess new structures.The absolute stereochemistry of these compounds was assigned unequivocally through a combination of NMR experiments,chemical derivation,CD spectra and single-crystal X-ray diffraction analyses(CuKa).Meroterpenes 1-3 and 5-8 selectively up-regulate,but 4 and 9 down-regulate,poly-inosinic acid-cytidylic acid[poly(I:C)]-induced TLR3 expression in mouse dendritic cells.The relationship between the absolute structure and TLR3 regulation of these meroterpenes was clarified,and precursor labelled cultivation suggests that these meroterpenes are most likely assembled in the fungus through terpenoid-shikimate pathways.The findings are of values for the discovery of new TLR3 regulating therapeutic agents,and for the metabolomic manipulation aiming at the optimal production of the promising fungal meroterpenes.Repeated column chromatographies of the extract from the culture of the marine-derived fungus Curvularia sp.IFB-Z10 in the gut of Argyrosomus argentatus led to the isolation of thirty-six indolizidine alkaloids,of which thirty possessed novel carbon skeletons.The biosynthetic polyketide pathway of these alkaloids was investigated by precursor labelled sodium acetate and alanine,along with the inhibitory experiment of ?-oxoamine synthase(AOS).Furthermore,some of these alkaloids were subjected to the anti-microbial assay and the results showed that part of these compounds were activity against the clinical oral pathogens,such as Veillonella parvula,Streptococcus sp.,Bacteroides vulgatus and Peptostreptococcus sp.with the MIC ranging from 0.37-9.57 ?M,some of which was demonstrated to be better than the positive control tinidazle.Finally,recent advances concerning the marine-derived fungus were reviewed in the thesis.