Synthesis of Antiinfective Agents

描述(由申请人提供)：我们实验室的长期目标包括在化学合成能力方面取得进展，并将这些进步应用于生物甚至医药进口问题。在化学水平上，我们选择新颖和具有挑战性的小分子天然产物结构，这将有助于激发和例证新策略和新反应方法的价值。在我们的“小分子”工作的这一方面，我们特别强调方法的简洁性、收敛和立体控制。同时，我们还有一个项目是针对多肽或蛋白质类结合物的复杂低聚糖的化学合成。在这项工作中，我们特别强调新的糖基化方案，并寻找特定的合成后断开和保护策略，使合成努力能够简明扼要。在这个项目中，我们寻求扩大我们的能力，将复杂的低聚糖构建到大量多肽甚至蛋白质环境中。在这一AI-16943-25-29授权期内，我们已经确定了八(8)个可供探索的计划：(1)米非司汀--顾名思义，这种化合物据报道可防止肿瘤细胞迁移。因此，它可能为一种重要的血管生成候选药物提供基础；(2)Brasilardin--一种免疫抑制剂；(3)garsubellin--这种化合物是一系列迷人的非肽类小分子的典范，显示出神经生长因子的活性；(4)tashirin--这种化合物与garsubellin有很大的不同。它还显示了非肽类NGF活性；(5)NG0187--该化合物是一种多氧类固醇系统，也具有非肽类神经生长因子活性；(6)天冬酰胺连接的糖多肽构建体，它模拟PSA(前列腺特异性抗原)的关键结构特征；(7)模拟GP120关键结构特征的构建体的合成。除了化学挑战之外，这个目标中隐含的是希望诱导一种抗体反应，这可能对艾滋病的发展有价值；(8)复杂糖共轭计划的长期目标是完全合成一种功能性促红细胞生成素(EPO)。

DESCRIPTION (provided by applicant): The long term goals of our laboratory involve the achievement of advances in the capabilities in chemical synthesis and the applications of these advances to problems of biological and even medicinal import. At the chemistry level, we select novel and challenging small molecule natural products structures, which will serve to stimulate and exemplify the value of new strategies and new reaction methodologies. In this facet of our "small molecule" work, we place particular emphasis on conciseness of approach, convergence, and stereocontrol. In parallel we have a program addressed to the chemical synthesis of complex oligosaccharides, in the context of polypeptide or protein like conjugates. In this effort, we place particular emphasis on novel glycosylation protocols and, seek out particular retrosynthetic disconnections and protection strategies which enable conciseness of the synthetic effort. In this program we seek to enlarge upon our capacity to build complex oligosaccharides into the context of substantial polypeptide or even protein settings. For this AI-16943-25-29 grant period, we have identified eight (8) programs for exploration: (1) migrastatin - as its name implies, this compound is reported to prevent tumor cell migration. As such, it might provide the basis for a significant drug candidate in angiogenesis; (2) brasilicardin - an immunosuppressive agent; (3) garsubellin - this compound is exemplary of a fascinating series of non-peptidal small molecules which exhibit neuronal growth factor activity; (4)tashironin - this compound is substantially dissimilar to garsubellin. It also exhibits non-peptidal NGF activity; (5) NG0187 - this compound is a polyoxygenated steroid-like system which also exhibits non-peptidal nerve growth factor activity; (6) Asparagine linked glycopolypeptide constructs which simulate the key structural features of PSA (prostate specific antigen); (7) the synthesis of constructs which simulate the key features of GP120. Aside from the chemical challenge, implicit in this goal is the hope to induce an antibody response which could be of value in progression of the evolution of AIDS disease; (8) A long term goal of the complex glycoconjugate program is the total synthesis of a functional erythropoietin (EPO).