Multifunctional enzyme-like catalysts for organic synthesis

用于有机合成的多功能类酶催化剂

• 批准号: 9813085
• 负责人: DAVID JOHN MICHAELIS
• 金额: $ 43.65万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813085
• 关键词: Acids; Affect; Alder plant; Alkenes; Alkylation; Area; Binding; Binding Sites; Biological; Biology; Catalysis; Catalytic Domain; Chemical Structure; Chemicals; Complement; Complex; Computer Simulation; Coupling; Data; Development; Drug Kinetics; Enzymes; Fermentation; Goals; Health; Human; Improve Access; Indoles; Interdisciplinary Study; Kinetics; Laboratories; Length; Mediating; Medicine; Mission; Modernization; Modification; Natural Products; Nature; Organic Synthesis; Organism; Outcome; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Process; Production; Property; Public Health; Publishing; Reaction; Resources; Side; Site; Source; Specificity; Structure; Synthesis Chemistry; System; Thiourea; Time; Transition Elements; United States National Institutes of Health; Work; base; catalyst; chemical synthesis; cost; cost effective; design; drug candidate; drug discovery; improved; innovation; novel; novel therapeutics; scaffold; small molecule; tool

Project Summary/Abstract Natural products and derivatives are a significant potential source of new drug candidates due to their high complexity and biological activity. However, chemical synthesis is often too time and resource-intensive to enable timely development of natural product derivatives as drugs. In contrast, nature has an incredible proficiency for the synthesis of complex chemical structures. Many organisms have evolved powerful enzymes that have been used by chemists to produce natural products cost-effectively and in large quantities via fermentation. However, it remains a significant challenge to modify the structure of natural products to improve pharmacokinetic properties and increase efficacy. This proposal seeks to develop multifunctional catalysts that mimic the synthetic efficiency of enzymes and benefit from the versatility of chemical synthesis. To accomplish this, we will use structurally well-defined helical peptides to scaffold multiple catalysts (e.g. organocatalysts, transition metals, Lewis acids) in close proximity to enable enzyme-like catalysis. Preliminary data from our laboratory confirm that helical peptides can preorganize multiple catalysts in such a way to facilitate proximity- accelerated reactivity and selectivity based on the binding of multiple substrates. In this proposal, we will first optimize the efficiency of our enzyme-like catalysts to maximize the enhanced reactivity and selectivity already observed to levels that approach the efficiency of natural enzymes. These efforts will be guided by predictive computational models developed in our group. We will then capitalize on these proximity effects to rationally design multifunctional catalysts and multi-catalyst systems that achieve unprecedented reactivity and enable bond constructions that cannot be performed with traditional catalysts. We will also develop multifunctional catalysts that overcome inherent reaction selectivity by preorganizing reacting partners to achieve novel selectivity (regioselectivity, enantioselectivity). These efforts will enable new reactions that streamline the synthetic process, improve access to complex molecules for drug discovery, and enable cost-effective development of new medicines. The use of helix-templated catalysts will enable new synthetic strategies based on the ability of the catalysts to bind and activate intermediates in close proximity, leading to lower step counts in synthesis. By doing so, this project has the potential to greatly affect overall human health by advancing drug discovery and enabling cost-effective production of new pharmaceuticals. The interdisciplinary research proposed herein will enable significant innovation in synthetic chemistry, de novo enzyme design, and drug discovery, and when successful, will have a broad impact in the areas of catalysis, synthetic design, and medicine.

项目概要/摘要 天然产物和衍生物是新药候选物的重要潜在来源，因为它们具有以下特点： 高复杂性和生物活性。然而，化学合成往往过于耗时和资源密集，无法实现。 能够及时开发作为药物的天然产物衍生物。相比之下，大自然有着令人难以置信的 熟练合成复杂的化学结构。许多生物体已经进化出强大的酶 化学家已使用它们来经济有效地大量生产天然产品 发酵。然而，改变天然产物的结构以改善天然产物的性能仍然是一个重大挑战。 药代动力学特性并提高疗效。该提案旨在开发多功能催化剂 模仿酶的合成效率并受益于化学合成的多功能性。为了完成 为此，我们将使用结构明确的螺旋肽来支撑多种催化剂（例如有机催化剂、 过渡金属、路易斯酸）非常接近，以实现类似酶的催化作用。我们的初步数据 实验室证实，螺旋肽可以预先组织多个催化剂，以促进接近- 基于多种底物的结合加速反应性和选择性。在这个提案中，我们首先 优化我们的类酶催化剂的效率，以最大限度地提高反应活性和选择性 观察到接近天然酶效率的水平。这些努力将以预测为指导 我们小组开发的计算模型。然后我们将利用这些邻近效应来理性地 设计多功能催化剂和多催化剂系统，实现前所未有的反应活性并实现 传统催化剂无法实现的键结构。我们还将开发多功能 通过预组织反应伙伴克服固有反应选择性以实现新颖的催化剂 选择性（区域选择性、对映选择性）。这些努力将促成新的反应，从而简化 合成过程，改善药物发现中复杂分子的获取，并实现成本效益 新药的开发。螺旋模板催化剂的使用将使新的合成策略成为可能 催化剂结合并激活附近中间体的能力，从而减少步数 在合成中。通过这样做，该项目有可能通过推进药物的发展来极大地影响人类的整体健康 发现并实现新药物的经济高效生产。跨学科研究 本文提出的方案将实现合成化学、从头酶设计和药物方面的重大创新 发现一旦成功，将在催化、合成设计和 药品。