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

项目摘要/摘要 新疗法的发明是一项多学科的努力，化学在其中起着至关重要的作用 角色。在发现了导致疾病的靶点--通常是蛋白质--之后，化学家们的任务是 提供小分子抑制剂或激动剂，它们将选择性地与靶受体结合并诱导 一连串的分子事件负责改善患者的病情。候选药物的识别 将药效、疗效、低毒和理想的药代动力学结合起来需要密集的合成努力。 在此过程中，通过生物活性支架的多样化产生了数千个分子。为了支持 这些药物发现活动，不断需要发明新的方法，允许选择性地 包括多肽、碳水化合物和其他天然产物在内的复杂分子的修饰。一旦成为 候选药物被提名时，化学家需要设计一种可扩展的工艺路线，以满足成本、安全性和 FDA的要求，这是化学创新的另一个机会。一些药物可能会有 较差的物理性能和/或稳定性，这可能需要开发聚合物药物输送 系统以充分发挥其潜力。这些错综复杂的大分子代表了另一种类型的合成 挑战，因为它们的设计是在外部刺激下释放货物，例如通过微妙的 PH值或温度变化。这项研究计划寻求提供广受关注的新方法，并 通过描绘挑战小分子的有效合成来说明它们与药物研究的相关性 分子和刺激反应聚合物。 这项提议的首要主题是伯胺的转化--最重要的 天然和合成分子中普遍存在的基团--包括C-C、C-H、C-F和 C-B键通过C-N活化。在第一部分中，将开发点击反应来转化初级 胺转化为磺胺。这些相当奇怪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， 磺胺类药物将用于选择性功能化多肽和氨基糖苷类药物。合作还将是 推出该反应作为多肽大环化的工具。第二部分探讨了 磺胺类化合物作为自由基对前体的潜力，其随后的重组将提供一系列 脂肪族C-C键的形成。最后一节假设磺胺类药物也可以通过 过渡金属催化，这将打开(杂化)芳基化、氟化和硼化反应的大门， 还有其他的。这些机械上不同的C-N活化过程将被应用于功能化 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.