The long-term objectives of this project are to achieve syntheses of lomaiviticin B and palau'amine. Both molecules are marine natural products that have unprecedented structures and unique biological activities. We will utilize a stereoselective oxidative ketone enolate coupling reaction as the key step in the lomaiviticin B synthesis. Furthermore, a reductive cascade reaction will be used to deliver the lomaiviticin B structure. Palau'amine will be constructed using a complex radical cascade reaction and a potentially biomimetic oxidative cyclization. Both compounds challenge the state-of-the art of organic synthesis. Through the synthesis of lomaiviticin B, we will be able to study the mechanism by which it is activated and cleaves DNA. The palau'amine synthesis will help address the feasibility of steps proposed for its biosynthesis as well as provide material for future biological studies. Lomaiviticin B is a potent antitumor antibiotic that appears to act through a new mechanism. Part of this project is to study that mechanism which may illuminate new ways that small molecules can react with DNA. Palau'amine potently inhibits the proliferation of stimulated lymphocytes and may well provide insight into new mechanisms for immunosuppression. We will be performing Comet tail assays in mammalian cells to determine whether the lomaiviticins cleave DNA. Also, we will be working with mammalian cells and Western blots to determine which cell signaling pathways are perturbed by palau'amine.
|Morris, William J; Shair, Matthew D (2010) Synthesis of the N-(tert-butyloxycarbonyl)-O-triisopropylsilyl-D-pyrrolosamine Glycal of Lomaiviticin A & B via Epimerization of L-Threonine. Tetrahedron Lett 51:4310-4312|
|Lee, Hong Geun; Ahn, Jae Young; Lee, Amy S et al. (2010) Enantioselective synthesis of the lomaiviticin aglycon full carbon skeleton reveals remarkable remote substituent effects during the dimerization event. Chemistry 16:13058-62|
|Morris, William J; Shair, Matthew D (2009) Stereoselective synthesis of 2-deoxy-beta-glycosides using anomeric O-alkylation/arylation. Org Lett 11:9-12|
|Krygowski, Evan S; Murphy-Benenato, Kerry; Shair, Matthew D (2008) Enantioselective synthesis of the central ring system of lomaiviticin A in the form of an unusually stable cyclic hydrate. Angew Chem Int Ed Engl 47:1680-4|