Natural products from some filamentous fungi and other sources
thesisposted on 27.03.2022, 21:50 by Nirmal Kumar Chaudhary
Natural products remain a major source for new drugs and drug leads owing to their unparalleled structural and chemical diversity and "drug-likeness" because of their evolutionary optimization to interact with living systems, unlike synthetic libraries. However, a combination of tedious isolation, repetitive isolation of known compounds, poor yields (supply) and structural complexities hindering total synthesis are some major bottlenecks in the process of drug discovery and development from natural products. Microorganisms offer a relatively unexplored source of new natural products by virtue of their vast biodiversity that can address the supply issue through fermentation. Moreover, microorganisms are amenable to selection and genetic manipulation for overproduction of the desired metabolite(s). The primary aim of this thesis is the isolation, characterization and biological screening of the secondary metabolites of some filamentous fungal species. Secondary metabolites of three filamentous fungi - Aspergillus banksianus, Aspergillus luteorubrus and Talaromyces stipitatus were characterized and screened. A total of 15 polyketide derived natural products were isolated from A. banksianus of which 10 were new metabolites. Among these, were the first isochromanone-orsellinic acid conjugates, isochromanone-anthraquininone conjugateand sulphur containing isochromanones including a rare sulfoxide metabolite. Chemical investigation of A. luteorubrus resulted in six metabolites including two new molecules, one was known but is a new natural product. Talaromyces stipitatus led to the isolation of 21molecules among which nine were new molecules. Among the new metabolites of T.stipitatus were 5 natural talauxins, which are condensation products of duclauxin with various L-amino acids. The semi-synthesis of new analogues of talauxins derived from D- and L-amino acids (except proline) and duclauxin is described. In addition, four new molecules from an Australian rainforest tree Galbulimima baccata were isolated and characterized. The structures of the isolated compounds were established by 2D NMR spectroscopy. Absolute stereochemistry of the isolated compounds was determined based on optical rotations, ECD, NMR, molecular modelling and TDDFT calculations. Plausible biogenetic pathway leading to these secondary metabolites are proposed wherever possible which can help in the design of biomimetic synthesis of these compounds.