Asymmetric Synthesis of Exiguaquinol and Analogs for Biological Testing

描述(申请人提供)：甜菜酚首先是从海绵Neopetrosia exigua中分离出来的，它含有五个融合环，四个连续的立体中心，一个芳基硫酸盐和一个烷基磺酸盐。1在幽门螺杆菌MURI抑制剂的筛选中发现，它是第一个报道抑制这种酶的天然产物。幽门螺杆菌是一种已知的病原菌，可导致长期胃炎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，我们认为外标喹醇是细菌治疗幽门螺杆菌感染的良好先导靶点，而不破坏有益的肠道细菌。然而，由于从遥远的自然来源分离出的材料稀少，对外瓜喹酚进行的研究有限，合成是获得更大数量的外瓜喹酚进行测试的最佳途径。通过我在加州大学欧文分校Vanderwal实验室的研究，我们已经完成了天然产品核心的合成，目标是完成第一个外瓜喹醇的全合成。我们建议的合成(参见研究战略)是直接的、不对称的和模块化的，并允许合成具有策略修改的非自然类似物。一旦完成，将对外瓜喹醇及其合成类似物进行Muri抑制筛选，并分析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.