Studies On The Chemical Constituents And Bioactivities Of Chaetomium Globosum And Aspergillus Flavipes

Three chapters were included in the dissertation. In the first and second chapters, the secondary metabolites of two fungi, Chaetomium globosum and Aspergillus flavipes, were systematic studied. The fungus C. globosum, derived from a traditional Chinese medicine Armadillidium vulgare, was found to be a rich source of cytochalasans and from which, two cytochalasans with5/6/7/5and5/6/12ring system were isolated. The fungus A. flavipes was also found to produce a series of novel cytochalasans. The bioactivities and plausible biogenetic pathways of these isolates were discussed. The last chapter is a review of natural cytochalasan reported from1966to2014.Cytochalasans are characterized by a highly substituted perhydro-isoindolone moiety to which typically a macrocyclic ring-either a carbocycle, a lactone, or a cyclic carbonate-is fused, which comprise a diverse group of fungal polyketide-amino acid hybrid metabolites with a wide range of distinctive biological functions. The origin of their name is derived from the Greek terms kytos, meaning cell, and chalasis, meaning relaxation, pointing to the best known property of cytochalasans, the capping of actin filaments. Since the first cytochalasans were described in1966(cytochalasins A and B, from Phoma strain S298, and Hel-minthosporium dematioideum, respectively), more than200structurally intriguing cytochalasans have been isolated from various sources and characterized. Depending on the amino acid incorporated into the polyketide backbone, cytochalasans could be classified into five subgroups, which bear a benzyl group (cytochalasins), a p-methoxybenzyl group (pyrichalasins), an (indol-3-yl)methyl group (chaetoglobosins). a2-methylpropyl group (aspochalasins) or a methyl group (alachalasins), respectively. The different core structures together with the variations of the size and the substitution pattern of the macrocycle further increase the chemical diversity of cytochalasans.Armadillidium vulgare, the pill-bug, pill woodlouse, belongs to the genus Armadillidium of the family Oniscidae. As a traditional Chinese medicine, it was used to treat chronic bronchitis, postoperative pain, toothache, stomatitis, thrush, sore throats, urination, and amenorrhoea.Symbiotic fungi are important source of structurally intriguing and biologically active secondary metabolites, due to their special and complex host-guest relationships. The symbiotic fungus, C. globosum was phytochemically investigated, which lead to the isolation and characterization of75compounds, including33new ones. Most of these isolates were cytochalasans, and also some other compounds such as azaphilones. Their structures were elucidated by extensive spectroscopic analyses, ECD calculation, and single-crystal X-ray diffraction analysis. It is notable that armochaeglobines A (1) and B (2) represent the first examples of cytochalasans with a10-and a12-membered carbocyclic rings, which differed greatly from those known cytochalasans with9-,11-, and13-membered carbocyclic rings or10-,12-, and14-ether rings or lactonic rings. Five19,20-seco chaetoglobosins were also obtained, which confirmed the biogenetic pathways of1and2. Selected compounds were tested for their cytotoxic activities against five human cancer cell lines (HL-60, SMMC-7721, A-549, and MCF-7) and most of them showed moderate activities. These pyrrole-based cytochalasans were evaluated for anti-HIV activity using a cytopathic effect (CPE) assay and a p24assay, all of them showed significant activities.A. flavipes was derived from the intertidal zone of Changjiang river, which was phytochemically investigated and led to the isolation and characterization of30compounds, including22new ones. Asperchalasin A (1) represents the first example of dimeric cytochalasan alkaloid, which features an unprecedented13-oxatetracyclo [7.2.1.12.5O1.6]tridec-8,12-dione formed by the polymerization of two molecular of cytochalasans to an epicoccine and possesses a complex decacyclic5/6/11/5/5/6/5/11/6/5ring system with20chiral centers. Compounds2-8present to be unique aspochalasin adducts with a hybrid feature by incorporating the motifs of aspochalasin and epicoccine. Compounds9-12present to be unique aspochalasin adducts with two molecular of epicoccines.The phytochemical investigations of C. globosurn and A. flavipes lead to the isolation of a large number of cytochalasans, which greatly enriched the structural diversity of cytochalasans and promoted the research level of this field.