Natural Product Drug Discovery against Tropical Diseases

• Main Author: Ma, Wai Sheung
• Format: Doctoral or Postdoctoral Thesis
• Language: unknown
• Published: Digital Commons @ University of South Florida 2011
• Subjects: Norselic acids; cytochalasins; dicerandrols; malaria; leishmania; chemical investigation; American Studies; Arts and Humanities; Chemistry; Antarctic; Antarc*; Antarctica
• Online Access: https://digitalcommons.usf.edu/etd/3224; https://digitalcommons.usf.edu/context/etd/article/4419/viewcontent/Ma_usf_0206D_10223.pdf

This dissertation describes the isolation of secondary metabolites from natural origins through a series of chromatographic techniques and spectrometric characterization in the effort of drug discovery. The isolated compounds obtained were used as drug leads against tropical diseases, namely malaria and leishmaniasis. While first chapter offers an introduction on the use of a natural product by itself as an effective therapeutic and its role on inspiring the discovery of new drugs, the later chapters will concentrate on isolation and characterization of bioactive natural products from an Antarctic sponge and mangrove endophytic fungi during the dissertation work. The second chapter describes the attempt to develop a new method of solving the absolute configuration of tertiary alcohol using lanthanide chiral shift reagent and 13C NMR spectroscopy. The third chapter describes the isolation of five new steroids, norselic acids A-E, from Crella sp. collected in Antarctica. The structures of the norselic acids were established by NMR and MS techniques. The absolute stereochemistry of norselic acid A was elucidated by SXRD. The antimicrobial and anti-leishmania activities of norselic acid A have been studied. Norselic acid A displays antimicrobial activities against methicillin-resistant S. aureus (MRSA), S. aureus, E. faecium, and C. albicans. Norselic acids B-E exhibit mild antimicrobial activities. All norselic acids exhibit strong cytotoxicity against leishmania. The fourth and fifth chapters describe a Medicine for Malaria Venture (MMV) funded malaria bioassay-guided screening program. The chemical investigation of the crude endophytic fungal extracts has led to the isolations of a series of known cytochalasins along with the discovery of a few new compounds, including a new simple carboxylic acid, and several known and novel compounds belonging to the dimeric xanthone family. Majority of the cytochalasins display mild cytotoxicity and outstanding inhibition to chloroquine-resistant reference strain Plasmodium ...