Asymmetric Synthesis of Exiguaquinol and Analogs for Biological Testing

用于生物测试的 Exiguaquinol 及其类似物的不对称合成

• 批准号: 8594799
• 负责人: Gregg Schwarzwalder
• 金额: $ 3.53万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8594799
• 关键词: 3-hydroxybutanal; Adverse effects; Alkanesulfonates; Bacteria; Bacterial Infections; Binding Sites; Biological; Biological Factors; Biological Testing; California; Cancer Etiology; Cancer cell line; Cell Wall; Cessation of life; Collaborations; Complex; Crystallography; Data; Development; Docking; Enzymes; Epithelium; Evaluation; Gastric Adenocarcinoma; Gastritis; Goals; Gram-Negative Bacteria; Helicobacter Infections; Helicobacter pylori; Infection; Inorganic Sulfates; Lead; Learning; Ligands; Malignant Neoplasms; Marines; Methods; Modification; Molecular Models; Pharmaceutical Preparations; Porifera; Prevention; Proteins; Reaction; Reporting; Research; Risk; Roentgen Rays; Route; Source; Stomach; Structure; Techniques; Testing; Therapeutic; Universities; Unspecified or Sulfate Ion Sulfates; analog; cancer therapy; cytotoxic; cytotoxicity; experience; inhibitor/antagonist; killings; malignant stomach neoplasm; molecular modeling; novel; pathogenic bacteria; prevent; professor; public health relevance; screening

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.

描述（申请人提供）：Exiguaquinol 首次从海生海绵 Neopetrosia exigua 中分离出来，含有五个稠合环、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 抑制剂筛选中发现，它是第一个报道可抑制该酶的天然产物。幽门螺杆菌是一种已知会导致长期胃炎并急剧增加胃癌风险的病原菌，而 MurI 酶对于细胞壁生物合成至关重要。1,2 因此，我们相信 exiguaquinol 是细菌治疗幽门螺杆菌感染且不破坏有益肠道细菌的绝佳主要靶点。然而，由于从偏远天然来源分离出的材料稀缺，对exiguaquinol进行的研究有限，合成是获得大量exiguaquinol进行测试的最佳方法。通过我在加州大学欧文分校Vanderwal实验室的研究，我们完成了天然产物核心的合成，目标是完成第一个exiguaquinol的全合成。我们提出的合成（参见研究策略）是直接的、不对称的和模块化的，并且允许通过策略修改来合成非自然类似物。一旦完成，将筛选 exiguaquinol 及其合成类似物的 MurI 抑制作用，并分析细胞毒性和抗癌活性。