Exiguaquinol was first isolated from the marine sponge, Neopetrosia exigua, and contains five fused rings, four contiguous stereogenic centers, an aryl sulfate and an alkyl sulfonate.1 Discovered in a screen for inhibitors of Helicobacter pylori MurI, it is the first natural product reported to inhibit this enzyme. H. pylori is a pathognic bacterium known to cause prolonged gastritis and sharply increased risks for gastric cancer and the MurI enzyme is critical to cell wall biosynthesis.1,2 Therefore, we believe exiguaquinol is an excellent lead target for bacterial treatment of H. pylori infection without disruption of beneficil gut bacteria. However, due to the scarcity of material isolated from remote natural sources, limited studies have been performed on exiguaquinol and synthesis is the best way to access larger quantities of exiguaquinol for testing. Through my research in the Vanderwal lab at University of California, Irvine, we have completed a synthesis of the core of the natural product and aim to complete the first total synthesis of exiguaquinol. Our proposed synthesis (see Research Strategy) is direct, asymmetric and modular and allows for the synthesis of unnatural analogs with strategic modifications. Once completed, exiguaquinol and its synthetic analogs will be screened for MurI inhibition and also analyzed for cytotoxicity and anti- cancer activity.
Gastric adenocarcinoma is the second leading cause of cancer-related death worldwide.2 Infection by a pathogenic bacterium called Helicobacter pylori is known to sharply increase the risk of developing gastric cancer and unfortunately, it is the most common bacterial infection in the world.2 Selective eradication of H. pylori could lead to breakthrough therapeutics for the prevention of gastric cancer and treatment of gastritis in many patients.3 Our research plan focuses on the total synthesis of a natural product called exiguaquinol, which was found to inhibit the H. pylori MurI enzyme and is likely to kill the bacteria selectively.1 We will learn more about this mode of action through X-ray protein crystallography, analog synthesis and biological evaluation.
| Schwarzwalder, Gregg M; Vanderwal, Christopher D (2017) Strategies for the Synthesis of the Halenaquinol and Xestoquinol Families of Natural Products. European J Org Chem 2017:1567-1577 |
| Schwarzwalder, Gregg M; Scott, David R; Vanderwal, Christopher D (2016) A Synthesis of Exiguaquinol Dessulfate. Chemistry 22:17953-17957 |
| Schwarzwalder, Gregg M; Steinhardt, Sarah E; Pham, Hung V et al. (2013) Synthesis of the tetracyclic core of exiguaquinol. Org Lett 15:6014-7 |
