New Synthetic Chemistries Enabled by Oxyallyl and 2-Aminoallyl Cations

由氧烯丙基和 2-氨基烯丙基阳离子实现的新合成化学

• 批准号: 9757809
• 负责人: Rendy Gregory Kartika
• 金额: $ 28.15万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757809
• 关键词: Applications Grants; Architecture; Attention; Biological; Biomedical Research; Biotechnology; Carbon; Cations; Chemicals; Chemistry; Collection; Complex; Cyclization; Development; Disease; Evaluation; Exhibits; Foundations; Future; Goals; Health; Human; Imides; Interleukin-17; Ketones; Knowledge; Lead; Libraries; Methods; Mission; Modernization; Molecular; Organic Synthesis; Pharmacologic Substance; Positioning Attribute; Process; Production; Proteins; Reaction; Research; Structure; Synthesis Chemistry; Technology; Therapeutic; Therapeutic Agents; United States National Institutes of Health; Work; cycloaddition; drug discovery; high throughput screening; improved; interest; novel; open innovation; programs; scaffold; small molecule; small molecule libraries; stereochemistry

PROJECT SUMMARY/ABSTRACT This grant application describes our proposed research in the production of value-added compounds of synthetic and biological interests, using novel chemistries that are centralized in the intermediacy of unsymmetrical oxyallyl and 2- aminoallyl cations. Oxyallyl and 2-aminoallyl cations are structurally unique reactive species. These intermediates have been utilized extensively in the Nazarov-type cyclization as well as cycloaddition reactions to assemble various complex molecular architectures. Despite these well-known reactivity, synthetic methods that harness the nucleophilic capture of unsymmetrical oxyallyl and 2-aminoallyl cations in a regioselective manner remain underexplored. This lack of studies consequently limit the full synthetic utilities of these versatile intermediates particularly in the arena of drug discovery. The long-term goal of our research program is to investigate the synthetic applicability of unsymmetrical oxyallyl and 2-aminoallyl cation technology in generating a library of novel small molecules in the chemical space that are suitable for high throughput screening in drug discovery. These studies could lead to protecting and improving human health, which is the ultimate goal of the NIH. The objective of the proposed research is to demonstrate that unsymmetrical oxyallyl and 2-aminoallyl cations are highly versatile reactive intermediates that could be readily harnessed to produce diverse molecular scaffolds of biological and pharmaceutical relevance. Our hypothesis is that unsymmetrical oxyallyl and 2- aminoallyl cations could be generated under mild catalytic conditions and captured by a broad spectrum of nucleophiles at the α-carbon in a regioselective manner by introducing appropriate “protecting” groups in their respective heteroatom centers. We have conducted extensive preliminary studies to support this hypothesis. We expect that completion of the proposed research will enable the rapid production of structurally novel small molecules with diverse stereochemistry and functionalities, which can be then evaluated for their therapeutic applications. To screen their biological activities, we have participated in the Open Innovation Drug Discovery (OIDD) at Eli Lilly. In fact, submission of synthetic products generated during our preliminary studies to this program has yielded interesting results. For instance, several of our compounds were found to exhibit inhibitory activities against IL-17A and PCSK9 proteins. Overall, our research will lay the foundation for detailed synthetic applications of oxyallyl and 2-aminoallyl cations, enabling future studies of the resulting structurally unique small molecules as potential therapeutic agents.

项目摘要/摘要 该赠款应用程序描述了我们在生产合成和合成化合物的拟议研究中 生物学利益，使用集中在不对称的氧和2-的中间体中的新型化学物质 氨基阳离子。含氧和2-氨基甲阳离子是结构独特的反应性物种。这些中间体有 在纳扎罗夫型环化以及环加成反应中广泛使用以组装各种复合物 分子体系结构。尽管有这些众所周知的反应性，但可以利用核整体捕获的合成方法 不对称的含氧和2-氨基甲基阳离子以调节方式保持不足。缺乏研究 因此，这些多功能中间体的完整合成实用性尤其是在药物发现领域。 我们的研究计划的长期目标是研究不对称的含氧和 在化学空间中生成一个新型小分子库的2-氨基利亚阳离子技术适合 药物发现中的高吞吐量筛查。这些研究可能导致保护和改善人类健康，这 是NIH的最终目标。拟议的研究的目的是证明含氧和含氧和 2-氨基利亚阳离子是高度用途的反应性中间体，可以很容易地利用生产潜水员 生物学和药物相关性的分子支架。我们的假设是，含氧和2-- 可以在轻度催化条件下产生氨基阳离子，并通过广泛的核pholips捕获 通过在各自的杂原子中引入适当的“保护”组，以调节方式以调节方式进行α-碳 中心。我们已经进行了广泛的初步研究，以支持这一假设。 我们预计拟议的研究的完成将使结构新颖的小型生产能够快速生产 具有潜水员立体化学和功能的分子，然后可以评估其治疗应用。 为了筛选他们的生物学活动，我们参加了Eli Lilly的开放创新药物发现（OIDD）。在 事实，在我们的初步研究中生成的合成产品提交该计划引起了兴趣 结果。例如，发现我们的几种化合物表现出对IL-17A和PCSK9的抑制作用 蛋白质。总体而言，我们的研究将奠定基础，以详细的含氧化合物和2-氨基甲素的合成应用为基础 阳离子，使未来的研究在结构上独特的小分子作为潜在的治疗剂。