Asymmetric Synthesis of Exiguaquinol and Analogs for Biological Testing

描述（由申请人提供）：阿瓜喹酚首次从海绵Neopetrosia exigua中分离出来，含有5个稠合环、4个相邻的立体中心、1个芳基硫酸酯和1个烷基磺酸酯。1在幽门螺杆菌MurI抑制剂筛选中发现，是第一个报道抑制该酶的天然产物。H.幽门螺杆菌是一种致病细菌，已知可导致胃炎延长和胃癌风险急剧增加，而MurI酶对细胞壁生物合成至关重要。1，2因此，我们认为依西呱喹酚是细菌治疗幽门螺杆菌的一个极好的主要靶标。pylori感染而不破坏胃肠道细菌。然而，由于从遥远的自然来源分离出的材料很少，对依西喹酚进行的研究有限，合成是获得大量依西喹酚进行测试的最佳途径。通过我在加州大学欧文分校的Vanderwal实验室的研究，我们已经完成了天然产物的核心合成，目标是完成exiguaquinol的第一个全合成。我们提出的合成（见研究策略）是直接的，不对称的和模块化的，并允许与战略修改的非天然类似物的合成。一旦完成，将筛选依西喹酚及其合成类似物的MurI抑制作用，并分析其细胞毒性和抗癌活性。

DESCRIPTION (provided by applicant): 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.