This program of target-driven discovery is broadly directed to investigate advances of methodologies and strategies for the synthesis of biologically significant natural products. Part I. Marine Antitumor Macrolides: Peloruside A. A plan for the convergent, enantiocontrolled synthesis of peloruside A will be executed. Peloruside A induces apoptosis in the G2-M phase of the cell cyclic with microtubule-stabilizing activity. The macrolide is more than 300 X less susceptible than paclitaxel to multi-drug resistance due to the over-expression of the P-glycoprotein efflux pump. Additionally, peloruside A is more readily administered, and appears to bind to a different site on tubulin compared to paclitaxel. Peloruside A studies offer significant chemical advancements, which will supply natural product and important derivatives for probing biological investigations. Part II. Zoanthamines. Investigations of this novel class of marine alkaloids describe challenging issues of chemical synthesis toward densely functionalized, polycyclic systems. Members of this class have exhibited important antitumor and anti-inflammatory activities, and norzoanthamine is considered to be a promising osteoporetic candidate. Recently, zoanthenol has demonstrated specific inhibition of collagen-induced platelet aggregation. Part III (a). Australifungin. Australifungin is a potent antifungal which is the first nonspingosine-based inhibitor of sphingolipid biosynthesis. It functions as a selective inhibitor of sphinganine N-acyl transferase, and may have an important role in lipid signal transduction, cell differentiation, and apoptosis. Part III (b). Daphnicyclidin A. This recent discovery has revealed a new molecular architecture which exhibits significant antitumor activity. Our research will investigate strategies for chemical synthesis of these complex polycyclic systems. ? ? ?
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