There is a renewed realization of the utility of natural products as sources for new drug leads. The practical limits on synthesis in terms of size and complexity often preclude promising natural products from consideration as drugs. The research that I propose addresses this problem in the context of three natural products. Madindoline B is derived from Streptomyces and is a selective interleukin 6 (IL-6) inhibitor. In tumor cells IL-6 stimulates cell proliferation and is also associated with cachexia. Selective inhibition of IL-6 could offer a new treatment for cancer. The original source for the madindolines no longer produces these compounds, therefore material can only be secured through synthesis. Merrilactone A, isolated from Illicium merrillianum, has potent neurotrophic activity (0.1 mol/L in fetal rat cortical neurons), and is of interest as a treatment for neurodegenerative diseases such as Parkinson's and Alzheimer's, Since it constitutes only 0.004% of the dry weight of the pericarps, the supply problem can only be solved through synthesis. Terpestacin is a fungal metabolite that inhibits the formation of syncytia, large multinucleated cells that are associated with HIV infection (ID50 0.46 ug/mL) and is therefore of great interest in the treatment of AIDS. Anti angiogenic activity has been associated with terpestacin, making it interesting as an anticancer lead. All three natural products are structurally unique, therefore they may exert their respective activities through novel mechanisms. Progress in this area occurs at two levels, by discovering improved methodologies and by using them to develop new strategies for total synthesis. In parallel with the total syntheses I will continue to improve and expand the scope of the methodology. Each of the natural product total syntheses referred to above uses a cyclization reaction in the key step that my research group developed.

R01GM057873

1998-08-01

2013-01-31