SYNTHESIS OF ANTIBIOTICS

竞争性续签提案描述了一项针对总 合成天然抗生素和设计的抗菌剂。这个 拟议的工作代表着我们由NIH资助的(AI55475)研究活动的继续 并将具体涉及硫链菌素的分子设计和合成工作 (1)、诺卡硫菌素I(2)、马林霉素A(3)和深渊霉素C(4c)及其类似物。在……里面 在硫链菌素项目中，我们计划优化一种生物活性的铅化合物 表示我们已经发现的分子的二脱氢哌啶结构域 在我们成功地合成了这种抗生素的过程中。在诺卡硫菌素I项目中我们 将遵循我们最近开发的W-羟基吲哚合成方法来 实现天然产物的全合成，并将该技术应用于 为合成孔径雷达研究目的而设计的类似物的构造。全合成 滨霉素A的设计目的是测试钯催化的 交叉偶联反应和烯烃歧化反应。所设计的全合成 阿比索霉素C依赖于生物合成假说级联，预计将提供 班上的其他成员，包括为生物评估设计的类比。 总体而言，这项研究计划旨在为抗心力衰竭的治疗产生新的知识。 感染性疾病，推动化学合成艺术应用于药物设计和 开发，并可能导致合成新的潜在抗菌剂。

The competitive renewal proposal describes a research program directed at the total synthesis of naturally occurring antibiotics and designed antibacterial agents. The proposed work represents continuation of our NIH-funded (AI55475) research activities and will specifically involve molecular design and synthetic work toward thiostrepton (1), nocathiacin I (2), marinomycin A (3) and abyssomycin C (4c) and their analogs. In the thiostrepton project, we plan to optimize a biologically active lead compound representing the didehydropiperidine domain of the molecule that we have discovered during our successful total synthesis of this antibiotic. In the nocathiacin I project we will follow our recently developed methodology for W-hydroxyindole synthesis to achieve a total synthesis of the natural product and apply the technology to the construction of designed analogs for the purposes of SAR studies. The total synthesis of marinomycin A is designed to test the scope and limitations of the palladium-catalyzed cross-coupling and olefin metathesis reactions. The designed total synthesis of abysommycin C relies on a biosynthetic hypothesis cascade and is expected to deliver other members of the class, including designed analogs for biological evaluation. Overall, this research program aims to generate new knowledge for the treatment of anti- infective diseases, advance the art of chemical synthesis as applied to drug design and development, and, possibly, result in the synthesis of new potential antibacterial agents.