UC San Diego

The oceans are a unique resource that has contributed greatly to the field of natural products chemistry. Secondary metabolites from natural sources still play an important role in drug discovery and development by providing pharmaceutical candidates with novel structures that are valuable for synthetic modification. Of the marine organisms described to date, the vast majority of marine natural products derive from invertebrates such as sponges, ascidians, bryozoans, and tunicates. Recently, marine microbes have also come to the forefront of natural products research since they are now being recognized as a significant new source of diverse and unique chemical compounds. With the existence of various diseases which pose a dangerous threat to human health, many bioassays have been developed in an attempt to find suitable agents as cures to those symptoms. Among recognizable infectious diseases, fungal infection is one of the significant causes of mortality and morbidity. As there are only few numbers of antifungal drugs available for therapeutic treatment, searching for new classes of active compounds proves to be crucial. This thesis discusses different methods for screening extracts of marine organisms in search of novel antifungal agents that possess relevant clinical value, with emphasis on the isolation and characterization of these compounds. Chapter I introduces the concept of the main thesis research that is described in subsequent chapters. Chapter II provides details of the discovery of new secondary metabolites from marine invertebrates, including sponges and ascidians, through a bioassay-guided screening process. The new compounds that were isolated include the merotriterpenoid adociasulfate, steroidal sulfates, and a pyridoacridine alkaloid. This chapter also describes antifungal bioassays that were performed and the results of the screening. Chapter III describes the isolation of new secondary metabolites from marine actinomycete strains selected based upon the results of a liquid antifungal assay. In this latter chapter, the problem regarding the screening of marine microbes using the liquid antifungal assay, and the subsequent adjustment by assay modification are described. The isolation and identification of new quinoline alkaloids, a bacterial sesterterpenoid and a novel cytotoxic macrolide are also discussed in detail, with respect to structural elucidation and biological activity