Synthesis and Applications of Biologically Active Carbohydrate Derivatives and Related Compounds

生物活性碳水化合物衍生物及相关化合物的合成及应用

• 批准号: 9912-2012
• 负责人: Grindley, Bruce
• 金额: $ 2.55万
• 依托单位: Dalhousie University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=568687
• 关键词: Synthesis; Applications; Biologically; Active; Carbohydrate

This proposal contains three separate sections. The first section proposes improvement of the anti-adhesion strategy against urinary tract infections (UTI), the second most diagnosed disease. Anti-adhesion drugs interfere with the binding of bacterial proteins to carbohydrates on tissue surfaces and thereby prevent bacterial colonization. Persistant UTI are initiated by binding of a protein, FimH, at the end of threadlike projections from the surfaces of certain strains of E. coli, to mannose attached to one of the proteins, uroplakin Ia, at the surface of the urinary tract. Binding changes the shape of the molecules making up the surface that allows bacterial entry and colonization. The proposal is to synthesize compounds that match what is known about the structures of the best binding mannose derivatives, then attach as many as possible to polyester dendrimers or to dendritic nanoparticles or to dendritic polymers, so as to bind as many as possible of the 200-500 pili on each bacterium, to eliminate the shielded bacterial colonies. A second section is to develop a vaccine against Lyme disease, a disease that is expanding northward around the world. Initially, improved syntheses of the two known small molecule antigens of Lyme disease would be developed. Then, methods for attachment of these compounds to polyester dendrimers would be sought that retained their antigenicity. The antigen-covered polyester dendrimers would be tested as vaccines. It is hoped that dendrimers covered with both antigens would produce vaccines that are both potent and active against all strains of the bacteria causing Lyme disease. In connection with the above areas, we have a long-standing interest in methods for the regioselective substitution of carbohydrates, needed to make biologically active molecules. Tin-containing compounds act as synthetic intermediates that give regioselective substitution. The third section proposes to investigate these reactions by both experimental and computational means and to improve the reaction by making it catalytic in tin. It also proposes to investigate alternative reactions.

该提案包括三个单独的部分。第一部分提出了针对尿路感染（UTI）的抗粘连策略的改进，尿路感染是第二大诊断疾病。 抗粘连药物干扰细菌蛋白与组织表面上的碳水化合物的结合，从而防止细菌定植。 持续性UTI是由某些大肠杆菌表面线状突起末端的FimH蛋白结合引发的。大肠杆菌，甘露糖连接到蛋白质之一，尿斑蛋白Ia，在泌尿道表面。 结合改变了构成表面的分子的形状，从而允许细菌进入和定植。 该建议是合成与已知的最佳结合甘露糖衍生物的结构相匹配的化合物，然后将尽可能多的化合物附着到聚酯树枝状聚合物或树枝状纳米颗粒或树枝状聚合物上，以便尽可能多地结合每个细菌上的200-500个皮利，以消除被屏蔽的细菌菌落。 第二部分是开发一种针对莱姆病的疫苗，这种疾病正在向北扩展到世界各地。最初，将开发两种已知的莱姆病小分子抗原的改进合成。 然后，将寻求将这些化合物附着到聚酯树枝状聚合物上的方法，以保留它们的抗原性。 抗原覆盖的聚酯树枝状聚合物将作为疫苗进行测试。 人们希望覆盖有这两种抗原的树枝状聚合物将产生对导致莱姆病的所有细菌菌株都有效和活跃的疫苗。 与上述领域相关，我们对制备生物活性分子所需的碳水化合物的区域选择性取代方法有着长期的兴趣。 含锡化合物作为合成中间体，提供区域选择性取代。 第三部分提出通过实验和计算手段来研究这些反应，并通过使其在锡中催化来改善反应。 它还建议研究替代反应。