Peptide-Based Catalysts for the Enantio-, Diastereo-, and Site-Selective Functionalization of Complex Organic Molecules with Reactive Nitrogen Containing Heterocycles

用于含活性氮杂环的复杂有机分子的对映体、非对映体和位点选择性官能化的肽基催化剂

• 批准号: 351831450
• 负责人: Dr. Golo Trutz Benjamin Storch
• 金额: --
• 依托单位: Lehrstuhl für Organische Chemie I
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/351831450?language=en
• 关键词: Peptide; Based; Catalysts; Enantio; Diastereo

A large proportion of approved pharmaceuticals are complex molecules, and both total synthesis and semisynthetic derivatization of natural products grant access to innovative new drug candidates. However, the selective modification of compounds with high complexity is a significant challenge and requires new synthetic transformation strategies. In this regard, enantio-, diastereo-, and site-selectivity play a key role in functionalization, since the simultaneous presence of multiple, and often similar, functional groups results in isomers with potentially different biological activity. Peptide-based catalysts serve as powerful tools in this context, as their selectivity is based on interactions with multiple functional groups of the substrates. Through the association of catalyst and substrate, the catalytically active sites are positioned in proximity to specific reactive sites on the substrates, and thus stereo- and site-selectivity is induced. The group of Prof. Scott J. Miller has pioneered the development of small beta-turn peptides, in which four amino acid residues nucleate secondary structures with highly beneficial properties in enantioselective catalysis. In this research project, peptide-based catalysts for the enantio-, diastereo-, and site-selective aziridination, as well as the nitroso Diels-Alder reaction, of alkene groups within increasingly complex molecules will be developed. This will be realized through systematic screening of beta-turn peptides based on variation of catalytically active side chains - e.g. Brønsted acids, ligands for transition metals or Lewis bases - as well as interaction sites for binding of substrates and reagents. The alkene substrates will later include natural products with intrinsic antitumor or antibiotic activity, such as rapamycin, oligomycin A, and thiostrepton. They are all available in sufficient quantities through biosynthesis. In addition, their mechanism of interaction with biological targets is well studied, which allows the design of derivatization according to structure-activity relationships.The investigation of biological activities of the obtained derivatives will complete the research project, and two potential advantages have to be pointed out in this regard: Aziridine groups are capable of ring opening with nucleophiles - such as DNA - which also represents the key feature of antibiotic and anticancer mitomycinoid alkaloids as well as azinomycin. Additionally, the introduced reactive nitrogen heterocycles allow a multitude of subsequent functionalization possibilities, which may aim for changing polarity, attachment of labels and enhancing or blocking of binding sites.All methods developed in this research project are not limited to application in semisynthesis, but rather represent general toolboxes for the selective functionalization of complex molecules.

大部分批准的药物是复杂的分子，天然产物的全合成和半合成衍生化都可以获得创新的新药候选物。然而，具有高复杂性的化合物的选择性修饰是一个重大挑战，需要新的合成转化策略。在这方面，对映体、非对映体和位点选择性在官能化中发挥着关键作用，因为同时存在多个且通常相似的官能团会导致具有潜在不同生物活性的异构体。基于肽的催化剂在这种情况下充当强有力的工具，因为它们的选择性是基于与底物的多个官能团的相互作用。通过催化剂和基材的结合，催化活性位点被定位在基材上的特定反应位点附近，从而诱导立体选择性和位点选择性。Scott J.米勒教授的团队率先开发了小β-转角肽，其中四个氨基酸残基使二级结构成核，在对映选择性催化中具有高度有益的特性。在本研究项目中，将开发用于对映体，非对映体和位点选择性氮丙啶化以及亚硝基Diels-Alder反应的肽基催化剂，这些反应是在日益复杂的分子中进行的。这将通过基于催化活性侧链的变化（例如，布朗斯台德酸、过渡金属或刘易斯碱的配体）以及用于结合底物和试剂的相互作用位点对β-转角肽进行系统筛选来实现。烯烃底物随后将包括具有内在抗肿瘤或抗生素活性的天然产物，例如雷帕霉素、寡霉素A和硫链丝菌素。它们都可以通过生物合成获得足够的数量。此外，它们与生物靶点的相互作用机制已被充分研究，这使得可以根据构效关系设计衍生化。对所获得衍生物的生物活性的研究将完成研究项目，在这方面必须指出两个潜在的优势：氮丙啶基团能够与亲核试剂（如DNA）开环，这也代表了抗生素和抗癌丝裂霉素生物碱以及azinomycin的关键特征。此外，引入的活性氮杂环允许多种后续功能化的可能性，这可能旨在改变极性，标签的连接和增强或阻断bindingsites.All方法开发在本研究项目中不限于应用于半合成，而是代表了一般的工具箱复杂分子的选择性功能化。