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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

基本信息

批准号：
8879071
负责人：
Gregg Schwarzwalder
金额：
$ 2.1万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-12-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8879071
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 Health 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 screening

项目摘要

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（由申请人提供）：艾瓜喹啉首先从海绵Neopetrosia exigua中分离出来，含有5个熔融环，4个连续的立体中心，一个芳基硫酸盐和一个烷基磺酸盐在筛选幽门螺杆菌MurI抑制剂时发现，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致病菌，可引起长期胃炎，并急剧增加胃癌的风险，MurI酶对细胞壁生物合成至关重要1,2因此，我们认为艾瓜喹啉是幽门螺杆菌感染细菌治疗的一个很好的先导靶点，而不会破坏有益的肠道细菌。然而，由于从遥远的自然来源中分离的材料稀缺，对逸瓜喹啉的研究有限，合成是获得大量逸瓜喹啉用于测试的最佳途径。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物核心的合成，目标是完成第一个全合成的exiguaquinol。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，并允许合成具有战略修饰的非自然类似物。一旦完成，exiguaquinol及其合成类似物将进行MurI抑制筛选，并分析细胞毒性和抗癌活性。