SYNTHESIS OF ANTIBIOTICS

描述(由申请人提供)：竞争性更新提案描述了一项针对天然产生的抗生素和设计的抗菌剂的全合成的研究计划。这项拟议的工作代表了我们由美国国立卫生研究院资助的(AI55475)研究活动的继续，并将具体涉及硫链菌素(1)、诺卡硫菌素I(2)、马里诺霉素A(3)和深霉素C(4c)及其类似物的分子设计和合成工作。在硫链菌素项目中，我们计划优化一种具有生物活性的先导化合物，该化合物代表我们在成功地全合成这种抗生素过程中发现的分子的二脱氢哌啶结构域。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，实现天然产物的全合成，并将该技术应用于构建用于SAR研究目的的设计类似物。滨霉素A的全合成是为了测试钯催化的交叉偶联反应和烯烃歧化反应的范围和局限性。阿比索霉素C的设计全合成依赖于生物合成假说级联，并有望提供这一类别的其他成员，包括设计的用于生物学评估的类似物。总体而言，这项研究计划旨在产生治疗抗感染性疾病的新知识，促进应用于药物设计和开发的化学合成艺术，并可能导致新的潜在抗菌剂的合成。

DESCRIPTION (provided by applicant): 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.