SYNTHESIS OF INHIBITORS OF RHAMNOSE AND GALACTOSE METABOLISM

耐多药结核病的出现，以及 艾滋病毒感染者感染过程迅速，预后不良 与结核病合并感染，强调需要更有效地利用 临床上可用的抗结核药物以及新的、更具选择性的 针对分枝杆菌特异性生化靶标的试剂。 细胞壁生物合成的抑制剂已经成为现代生物合成的支柱。 抗结核化学疗法的公认机制证明， 临床有效药物异烟肼、乙胺丁醇和 乙硫异烟酰胺 分枝杆菌鉴定的最新进展 细胞壁导致了大量的高度独特的 生化目标，可能导致新的，有效的，选择性的， 抗结核药。 为了开发这种新型药物， 该项目将侧重于设计和合成新的抑制剂， 两种分枝杆菌细胞壁蛋白的生物发生和利用 在人类中发现的D-呋喃半乳糖（galf）和L-吡喃鼠李糖（rhap）。 具体来说，我们建议合成胸苷二磷酸类似物， RHAP以及含有特定RHAP的二糖和三糖衍生物 作为鼠李糖代谢和掺入的抑制剂。 我们亦建议 合成尿苷二磷酸-Galf和含有二-和 作为半乳糖呋喃糖代谢抑制剂的曲马多。 目标 化合物将提供给Dr. Leonid Heidens（主要研究者） 和项目负责人1）进行体外试验。 选择的活性化合物作为 将在鼠中进行体内测试 项目2中的模型（项目负责人Michael Cynamon博士）。 所有化合物 也将在项目4（Dr. Michael McNeil，项目负责人）。 项目1、2和 4将指导现在的化合物设计，以提高药物活性， 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.