Peptide-Conjugated Palladium Oxidative Addition Complexes for Site-Selective Arylation Chemistry

项目摘要/摘要 蛋白质和生物活性小分子等生物分子的定点化学修饰 分子目前被认为是化学生物学中一个重要而又未被满足的挑战。当当前 事实证明，蛋白质化学修饰的策略高度支持与以下相关的各种应用 机械生物学和生物材料和药物的生产，选址方法很少见 而且很有价值。这项提案的第一个目标详细说明了访问定义明确的站点的策略-选择性地标记 蛋白质结合物在化学生物学中的各种应用。这项提案的核心是 布赫瓦尔德和潘特鲁特已经证明的钯氧化加成络合物的使用 实验室在温和的生理条件下有效地使蛋白质靶标参与C-杂原子芳基化反应。 这些基于钯的试剂与结合蛋白的多肽序列的共价衍生化 提出了将Interest作为一种策略来实现蛋白质半胱氨酸的位置选择性芳基化 分子间环境。这些技术预计将支持无数应用程序，包括 形成位点选择性修饰的抗体-药物偶联物和选择性蛋白质降解平台。在一个 努力显著简化药物结构-活性-关系研究，并为 机械生物学，这一建议的第二个目的是扩展多肽-共轭钯芳基化化学 到生物活性小分子的区域选择性修饰。虽然目前对现场的方法- 选择性小分子衍生化通常在很小范围的底物类别和缺乏 一般而言，这项建议旨在提供一个通用的和高度模块化的方法，以位置选择性芳基化 复杂的多元醇和多胺靶标，依赖于多肽结合的明确的二级结构 介绍帕金森病的活跃部位。总体而言，建议的位置选择性生物结合方法详述于 该提案将有可能对化学生物学产生极大的影响，因为它将使强大的发现成为可能 用于机械生物学和制药应用的平台。这项提议的目标直接是 与促进人类健康有关，与美国国立卫生研究院的目标非常一致。 布赫瓦尔德大学的最终目标是在一所主要的研究型大学获得学术职位 麻省理工学院的潘特鲁特实验室是一个理想的环境， 进行有机金属生物结合的博士后培训。布赫瓦尔德实验室在金属方面的专业知识- 催化交叉偶联及其在碳杂原子键形成过程和潘特鲁特实验室中的应用 重点放在化学生物学和多肽合成方面，将有助于执行拟议的 研究。在我的培训期间，我将获得化学生物学和有机金属化学方面的关键技能，这将 称赞我在对映体选择性有机催化方面的背景，并为我在教员职位上的出色表现做好准备。

PROJECT SUMMARY/ABSTRACT The site-selective chemical modification of biomolecules including proteins and biologically active small molecules is currently recognized as an important and unmet challenge in chemical biology. While current strategies for chemical protein modification have proven highly enabling for a variety of applications related to mechanistic biology and the production of biomaterials and pharmaceuticals, site-selective approaches are rare and highly valued. The first Aim of this proposal details a strategy to access well-defined site-selectively labeled protein conjugates for varied applications across chemical biology. Central to the thesis of this proposal is the use of palladium oxidative addition complexes that have been previously shown by the Buchwald and Pentelute labs to efficiently engage protein targets in C–heteroatom arylation reactions under mild physiological conditions. The covalent derivatization of these palladium-based reagents with peptide sequences that bind a protein of interest is proposed as a strategy to achieve site-selective protein cysteine arylation in both intra- and intermolecular contexts. These technologies are expected to enable a myriad of applications including the formation of site-selectively modified antibody-drug-conjugates and selective protein degrading platforms. In an effort to significantly simplify drug structure-activity-relationship studies and produce valuable probes for mechanistic biology, the second Aim of this proposal extends peptide-conjugated palladium arylation chemistry to the regioselective modification of biologically-active small molecules. While current approaches to site- selective small molecule derivatization generally operate on a narrow range of substrate classes and lack generality, this proposal aims to deliver a general and highly modular approach to site-selective arylation of complex polyol and polyamine targets, reliant on the well-defined secondary structure that peptide conjugates impart about the Pd active site. Overall, the proposed the site-selective bioconjugation approach detailed in this proposal will have the potential to be highly impactful for chemical biology by enabling powerful discovery platforms for mechanistic biology and pharmaceutical applications. The objectives of this proposal are directly related to the advancement of human health, are well aligned with the aims of the NIH. With the ultimate goal of securing an academic position at a major research university, the Buchwald and Pentelute laboratories at the Massachusetts Institute of Technology represent an ideal setting in which to conduct my postdoctoral training in organometallic bioconjugation. The Buchwald lab’s expertise in metal- catalyzed cross-coupling and its application to C–heteroatom bond forming processes and the Pentelute lab’s focus within chemical biology and peptide synthesis will be instrumental in the execution of the proposed research. During my training, I will gain crucial skills in chemical biology and organometallic chemistry that will compliment my background in enantioselective organocatalysis, and prepare me to excel in a faculty position.