New Molecules, Methods, and Platforms at the Interface of Organic Chemistry and Chemical Biology

这项建议支持有机化学的多学科培训；我们的长期愿景是设计新的合成方法和合成新分子，以回答化学和生物中的重要问题和解决问题。研究是基础，并解决方法学、合成、分子识别和催化方面的重大挑战，应用于精细化学合成、成像、药物化学以及设计由DNA制成的下一代“智能药物”和传感器。我们的初步数据和正在进行的工作以及最近的出版物预示着在这些目标方面取得成功。具体地说，我们将通过追求非其他赠款资助的五个长期目标来促进知识的发展。1.基于新型改性吲哚的生物活性天然产物和多肽的合成：我们将合成具有挑战性的化合物，其特点是在改性吲哚(一种天然杂环)方面做了新的工作。这些为关键的生物目标带来了新的合成技术和新的探测器。2.开发晚期荧光异吲哚结合多肽大环：在我们发现的荧光异吲哚多肽结合的基础上，我们将开发一个强大的化学平台来发现高亲和力的荧光多肽，为基于细胞的筛选和共聚焦研究提供工具。3.合成新的RBF_3异构体用于生物学应用：有机三氟硼酸盐(RBF_3)是一种在生物学上模拟羧酸盐的阴离子。令人兴奋的是，RBF3支持便捷的PET成像，这是我们发明的一种应用程序。我们提出了合成新的RBF3的新方法，这些方法将在生化分析中进行研究。4.使用有机氟硼化合物形成C-F键：含氟化合物在农用化学品、医药和材料中非常受重视，但很难制备。我们对RBF3的兴趣使我们发现了一种新的应用，在这种应用中，RBF3可以用作廉价的试剂来氟化碳。提出了新的方法来利用这一点。5.扩大DNAzyme和适配子的化学功能，用于传感、成像和治疗线索：DNA是一个令人兴奋的技术平台，用于选择能够用作“智能药物”和传感器的催化剂和配体。在这里，我们将结合化学合成和分子生物学来进化新型的杂化DNA催化剂，这种催化剂包含类似蛋白质的功能，以增强特异性和活性。这些项目代表着新的、有风险的想法，具有很高的突破潜力，可以由机构和行业提供额外资金，这些机构和行业将根据更成熟的成果为高度应用的项目提供资金。就广度和深度而言，这项拟议研究的多学科性质及其提供的培训在加拿大是无与伦比的。凭借在上述五个主题方面的出版和培训记录，以及利用和商业化以前由NSERC资助的工作的记录，我们是唯一有资格执行这些目标的机构。

This proposal supports multidisciplinary training in organic chemistry; Our long-term vision is to devise new synthetic methods and synthesize new molecules to answer important questions and solve problems in chemistry and biology. Research is fundamental and addresses significant challenges in methodology, synthesis, molecular recognition, and catalysis with applications in fine-chemical synthesis, imaging, medicinal chemistry and the design of the next generation of "smart drugs" and sensors made of DNA. Our preliminary data and ongoing work and recent publications augur for success in these goals. Specifically, we will advance knowledge through the pursuit of five long-term goals not funded by other grants. 1.Synthesize bioactive natural products and peptides based on novel modified indoles: We will synthesize challenging compounds featuring new work on modified indoles (a natural heterocycle). These bring new synthetic know-how and new probes for key biological targets. 2.Develop late-stage fluorescent isoindole stapled peptide macrocycles: Based on our discovery of fluorescent isoindole peptide stapling, we will develop a powerful chemical platform to discover high-affinity peptides with emergent fluorescence to provide tools for cell-based screens and confocal studies. 3.Synthesize new RBF3s as isosteres for applications in biology: Organotrifluoroborates (RBF3s) are anions that mimic carboxylates in biology. Excitingly, RBF3s enable facile PET imaging, an application that we invented. We propose new methods for synthesizing new RBF3s that will be studied in biochemical assays. 4.Use Organofluoroborates for C-F Bond Formation: Fluorinated compounds are highly prized in agrichemicals, pharmaceuticals and materials but are difficult to prepare. Our interest in RBF3s led us to discover a new application where RBF3s can be used as cheap reagents to fluorinate carbon. Novel methods are proposed to exploit this. 5.Expand chemical functionality in DNAzymes & aptamers for sensing, imaging, and therapeutic leads: DNA is an exciting technological platform for selecting catalysts and ligands capable serving as "smart drugs" and sensors. Here we will merge chemical synthesis and molecular biology to evolve novel hybrid DNA catalysts that contain protein-like functionalities for enhanced specificity and activity. These projects represent new and risky ideas that have the high potential for breakthroughs that can be spun out for additional funding by agencies and industries that will fund highly applied projects based on more mature results. The multidisciplinary nature of this proposed research and the training it provides is unparalleled in Canada in terms of the breadth and depth. With a track record of publishing and training in these five above subjects, along with a record of leveraging and commercializing previous NSERC-funded work, we are uniquely qualified to execute on these goals.