Investigation of the potential of marine natural products as inhibitors of HIV integrase.

摘要

Marine organisms produce an abundance of secondary metabolites exhibiting a broad range of biological activities. These marine natural products have been the focus of biomedical research and provided intriguing targets for synthetic chemists. Over the last four decades, many of the major metabolites from marine organisms have been identified. Novel bioassays are being employed to coax the minor metabolites with biological activity from complex mixtures found in crude extracts. The human immunodeficiency virus (HIV) integrase inhibition assay was used to aid in the identification of novel marine-derived natural products.; HIV integrase is an essential viral enzyme for replication and is a promising drug target in the development of anti-AIDS drugs. Current drug therapy consists of reverse transcriptase and protease inhibitors. However, the emergence of drug resistant strains of the virus has driven the search for novel therapeutics. In order to identify marine natural products that inhibit HIV integrase, thousands of crude extracts from marine organisms were screened for their potential as HIV integrase inhibitors.; The research presented in this dissertation focuses on the biomedical potential of marine natural products in the context of their prospect as HIV integrase inhibitors. In Chapter I, I will provide an overview of marine natural products chemistry, focusing on recent advances in drug development and the potential of these bioactive metabolites as probes in cellular systems. Chapters II and III provide an overview of the structure and function of HIV integrase, and the potential of marine natural products as inhibitors.; The HIV integrase assay has been a useful tool in the discovery of novel marine natural products. With the use of this assay, two marine sponges were identified that contained new metabolites, and I described two classes of novel compounds. The unusual polyoxgenated sterols in Chapter IV, featuring the unique 14α-methyl group suggesting a unique biosynthetic pathway from typical sterols. As well as, the first report of brominated polyacetyleneic diols from a new sponge species from a previously unreported genus Diplastrella described in Chapter V. In addition, novel analogues of cyclodidemniserinol trisulfate were isolated from an ascidian Didemnum guttatum from Palau presented in chapter VI.