SYNTHESIS OF INHIBITORS OF RHAMNOSE AND GALACTOSE METABOLISM

耐多药结核病(TB)的出现以及 HIV感染者感染速度快、预后差 与结核病合并感染，强调了更有效地利用 临床上可用的抗结核药物以及更具选择性的新药物 针对分枝杆菌特定生化靶标的药物。 细胞壁生物合成的抑制剂一直是现代生物合成的支柱 抗结核化疗的公认机制证明 临床有效药物异烟肼、乙胺丁醇和乙胺丁醇的作用 乙硫酰胺。分枝杆菌的特性研究进展 细胞壁导致了大量高度独特的 可能导致新的、有效的和选择性的生化目标 抗结核药物。以开发这样的新代理为目标，这 该项目将专注于设计和合成新型的血管紧张素转换酶抑制剂。 两种分枝杆菌细胞壁糖NOT的生物发生与利用 发现于人类的D-半乳呋喃糖(GALF)和L-鼠李糖(RHAP)。 具体地说，我们建议合成胸苷-二磷酸的类似物- RHAP以及含有二糖和三糖衍生物的特定RHAP 作为鼠李糖代谢和掺入的抑制剂。我们还建议 尿苷-二磷酸-GALF及含二和的GALF类似物的合成 作为半乳呋喃糖代谢抑制剂的三糖。目标 化合物将提供给Leonid Heifets博士(首席调查员 和项目1的领导者)，用于体外检测。精选活性化合物作为 从体外测试中确定的结果将在小鼠体内进行测试 项目2中的模特(Michael Cynamon博士，项目负责人)。所有化合物 也将在项目4提供的无细胞分析中进行测试(Dr。 项目负责人Michael McNeil)。来自项目1、2和2的生物数据 4现在将指导化合物设计，以增强药物活性和 生物利用度。

The emergence of multidrug resistant forms of tuberculosis (TB), as well as the rapid course of infection and poor prognosis for HIV patients coinfected with TB, underscores the need for more effective utilization of clinically available antitubercular agents as well as new, more selective agents directed against biochemical targets specific to the mycobacterium. Inhibitors of cell wall biosynthesis have been a mainstay of modern antitubercular chemotherapy as evidenced by the accepted mechanisms of action of the clinically effective agents isoniazid, ethambutol and ethionamide. Recent advances in the characterization of the mycobacterial cell wall have led to the identification of a vast array of highly unique biochemical targets that could lead to new, potent, and selective antitubercular agents. With the goal of developing such new agents, this project will focus on design and synthesis of novel inhibitors of the biogenesis and utilization of two mycobacterial cell wall saccharides not found in humans, D-galactofuranose (galf) and L-rhamnopyranose (rhap). Specifically, we propose to synthesize analogs of thymidine-diphosphate- rhap as well as specific rhap containing di- and trisaccharide derivatives as inhibitors of rhamnose metabolism and incorporation. We also propose to synthesize analogs of uridine-diphosphate-galf and galf containing di- and trisaccharides as inhibitors of galactofuranose metabolism. Target compounds will be supplied to Dr. Leonid Heifets (Principal Investigator and Leader of Project 1) for in vitro assays. Selected active compounds as determined from the in vitro assays will be tested in vivo in the murine model in Project 2 (Dr. Michael Cynamon, Project Leader). All compounds will be tested as well in the cell free assays available in Project 4 (Dr. Michael McNeil, Project Leader). Biological data from Projects 1, 2, and 4 will direct now compound design in order to enhance drug activity and bioavailability.