Primary Amines as Versatile Precursors for the Synthesis of Bioactive Molecules and Macromolecular Drug Carriers

项目总结/摘要 新疗法的发明是一项多学科的奋进，其中化学起着至关重要的作用。 作用在发现一种疾病的靶点（通常是蛋白质）后，化学家们的任务是 提供小分子抑制剂或激动剂，其将选择性地结合靶受体并诱导免疫应答。 负责改善患者状况的分子事件级联。候选药物的鉴别 结合效力、功效、低毒性和期望的药代动力学需要强烈的综合努力 在此期间，通过生物活性支架的多样化产生数千个分子。为了支持 在这些药物发现活动中，不断需要发明新的方法，以允许选择性地 复杂分子的修饰，包括肽、碳水化合物和其他天然产物。一次 候选药物被提名，化学家需要设计一个可扩展的工艺路线，满足成本，安全性， FDA的要求，这是化学创新的另一个机会。有些药物可能 差的物理性质和/或稳定性，这可能需要开发聚合物药物递送 系统，充分发挥其潜力。这些复杂的大分子代表了另一种类型的合成 挑战，因为它们被设计成在外部刺激时释放它们的货物，例如，通过微妙的 pH或温度变化。这项研究计划旨在提供广泛关注的新方法， 通过描述具有挑战性的小分子化合物的有效合成来说明它们与药物研究的相关性。 分子和刺激响应聚合物。 该提案的首要主题是初级胺的转化，这是最重要的 天然和合成分子中普遍存在的基团-转化为各种连接，包括C-C，C-H，C-F和 通过C-N活化形成C-B键。在第一部分中，将开发一个点击反应来转换原色 胺转化为磺酰胺。这些相当奇特的基团将作为聚合物中的氢键供体进行研究。 和生物活性分子，以及C-N活化平台的前体。此外，作为点击链接器， 磺酰胺将用于选择性地官能化肽和氨基糖苷类。合作也将是 启动开发此反应作为肽大环化的工具。第二部分探讨了 潜在的磺酰胺作为祖先的自由基对，其随后的重组将提供一系列的 脂肪族C-C键形成。最后一节假设磺酰胺也可以通过 过渡金属催化，这将打开（杂）芳基化，取代，和硼基化反应的大门， 还有其他的这些机理上不同的C-N活化过程将被应用于官能化 用于药物输送的生物活性分子和聚合物结构。

Project Summary/Abstract The invention of new therapeutics is a multidisciplinary endeavor in which chemistry plays a crucial role. Following the discovery of a target responsible for a disease—generally a protein—chemists are tasked to provide small-molecule inhibitors or agonists that will selectively bind to the target receptor and induce a cascade of molecular events responsible for improving the patient’s condition. Identification of a drug candidate combining potency, efficacy, low toxicity, and desirable pharmacokinetics requires an intense synthetic effort during which thousands of molecules are created by diversification of a bioactive scaffold. In order to support these drug discovery campaigns, there is a constant need to invent new methods allowing for selective modifications of complex molecules including peptides, carbohydrates, and other natural products. Once a drug candidate is nominated, chemists need to devise a scalable process route that meets cost, safety, and FDA requirements, which is another opportunity for chemical innovation. Some pharmaceuticals might have poor physical properties and/or stability, which might necessitate the development of polymeric drug-delivery systems to fully achieve their potential. These intricate macromolecules represent another type of synthetic challenge since they are designed to release their cargo upon external stimulation, for example, via a subtle pH or temperature change. This research program seeks to deliver new methods of widespread interest and to illustrate their relevance to pharmaceutical research by delineating efficient syntheses of challenging small molecules and stimuli-responsive polymers. The overarching theme of this proposal is the transformation of primary amines—one of the most ubiquitous groups in natural and synthetic molecules—into a variety of linkages including C–C, C–H, C–F, and C–B bonds via C–N activation. In the first section, a click reaction will be developed to transform primary amines into sulfamides. These rather exotic groups will be investigated as hydrogen-bond donors in polymeric and bioactive molecules, as well as precursors for a C–N activation platform. Furthermore, as a click linker, sulfamides will serve to selectively functionalize peptides and aminoglycosides. A collaboration will also be launched to develop this reaction as a tool for peptide macrocyclization. The second section explores the potential of sulfamides as progenitors of radical pairs, whose subsequent recombination will afford an array of aliphatic C–C bond formations. The last section hypothesizes that sulfamides can also be transformed via transition-metal catalysis, which would open the door to (hetero)arylation, fluorination, and borylation reactions, among others. These mechanistically distinct C–N activation processes will be applied to the functionalization of bioactive molecules and polymeric architectures for drug delivery.