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，并将这些进展应用于生物甚至医学进口问题。在化学层面，我们选择新颖和具有挑战性的小分子天然产物结构，这将有助于激发和举例说明新策略和新反应方法的价值。在我们“小分子”工作的这一方面，我们特别强调方法的简洁性、收敛性和立体控制。与此同时，我们有一个程序，以化学合成复杂的低聚糖，在多肽或蛋白质的结合物的背景下。在这项工作中，我们特别强调新的糖基化方案，并寻求特殊的反合成断开和保护策略，使合成努力的简洁性。在这个程序中，我们寻求扩大我们的能力，建立复杂的低聚糖到大量的多肽甚至蛋白质设置的背景下。对于AI-16943-25-29拨款期，我们已经确定了8个项目进行探索：(1)迁移抑素——顾名思义，这种化合物被报道可以阻止肿瘤细胞迁移。因此，它可能为血管生成的重要候选药物提供基础；(2)免疫抑制剂brasilicardin；(3) garsubellin——这种化合物是一系列具有神经生长因子活性的非肽小分子的典型代表；(4)tashironin -这种化合物实质上不同于garsubellin。它还具有非肽性NGF活性；(5) NG0187 -该化合物是一种多氧类固醇样系统，也具有非肽性神经生长因子活性；(6)模拟前列腺特异性抗原（PSA）关键结构特征的天冬酰胺连接糖共肽构建；(7)模拟GP120关键特征的构建体的合成。除了化学挑战之外，这一目标的隐含意义是希望诱导抗体反应，这可能对艾滋病的演变进程有价值；(8)复合糖缀合物计划的长期目标是功能性促红细胞生成素（EPO）的总合成。

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).