This project will investigate fundamental aspects of polyketide biosynthesis and evolution through a multidisciplinary collaboration. A synergistic synthetic effort, between the Richard Taylor group (University of Notre Dame) and the group of Professor Markus Kalesse (Leibniz Universitat Hannover), is directed at the putative intermediates in the biosynthesis of the marine polyketide, tedanolide. Putative biosynthetic intermediates, such as the targets of the current proposal, are a valuable new source of chemical diversity with the potential for discovery of novel biological targets and potentially new modes of action. In addition, the synthesis of iso-tedanolide will provide a unique opportunity to explore the feasibility of a 1,5-acyl migration, a key step in a proposed biogenic pathway to the tedanolides. Biological analyses will be carried out under the direction of Dr. Florenz Sasse at the Helmholtz Zentrum fuer Infektionsforschung (HZI Braunschweig).
With this award, the Organic and Macromolecular Chemistry Program and the Office of International Science and Engineering are supporting the research of Professor Richard Taylor of the Department of Chemistry & Biochemistry at the University of Notre Dame. This award coordinates with a collaborative award funded by Deutsche Forschungsgemeinschaft (DFG) for Dr. Markus Kalesse, Leibniz Universitat Hannover and Dr. Florenz Sasse, Helmholtzzentrum für Infektionsforschung GmbH. Their research program involves the development of synthetic and biosynthetic methods for identification of new biologically active chemical entities inspired by the evolution of natural products and their producing organism. Successful preparation of these highly complex targets such as those proposed within this project will be enabled by the development of novel synthetic methods and strategies while providing a training platform for graduate and undergraduate student coworkers. Moreover, complementary biological studies of the prepared derivatives will probe the evolutionary role of post-polyketide synthase modifications in polyketide biosynthesis thus provide new information of fundamental significance.
This "International Collaborations in Chemistry" project is supported by the both the National Science Foundation (NSF) and the Deutsche Forschungsgemeinschaft (DFG). Through this award we successfully completed a study of the microbial metabolite, gephyronic acid. Gephyronic acid is a natural product with potential activity against cancer. Utilizing state-of-the-art analytical techniques we corrected the published assignment of its gross chemical structure and determined important details regarding its stereochemical configuration. With this information in hand, we were able to design and execute a complete total chemical synthesis of the compound from commercially available material. The strategy used provided a new appreciation for the complexities associated with classic fragment coupling strategies. In addition, the route provided increased availability of material as well as structural analogues for biological analysis in collaboration with researchers at the Helmholtz Zentrum fuer Infektionsforschung (HZI Braunschweig). Through these biological experiments researchers were able to determine the mode of action of gephyronic acid’s anti-cancer properties. In addition, we identified and characterized the gene cluster responsible for the production of gephyronic acid in the producing organism, Cystobacter violaceus. The biosynthetic pathway was found to contain a number of unique features. Finally, a collaborative effort made progress towards the production of a biosynthetic intermediate in the pathway for the natural production of tedanolide, a complex, marine-derived toxin, related to gephyronic acid. This study addressed unanswered questions of natural product chemistry, leading to an understanding of how microbial organisms produce such complex molecules and may pave the way to the discovery of new pharmaceutical agents. In addition to the intellectual merit clearly articulated in our publication record and summarized above, the broader impacts of the program were significant. The grant supported several graduate and undergraduate student coworkers with concentrations in chemistry, biochemistry, and biology. All of students were provided significant training and broad experience in interdisciplinary research that required skills in synthetic, medicinal and biological chemistry as well as purely biological studies. Several graduate students participated in the international collaboration through externships at the University of Stuttgart, Saarland University, the University of Hannover, and the Helmholtz Center, Braunschweig. These opportunities provide students valuable experience for their development into mature, independent scientists and valuable contributors to the economic workforce.
