Highly Reactive Hydrazone Chemistry: Orthogonal Modification in Cellular Contexts
高反应性腙化学:细胞环境中的正交修饰
基本信息
- 批准号:9197650
- 负责人:
- 金额:$ 30.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-03-01 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAldehydesAlkynesAnilineBiologicalCatalysisCellsChemicalsChemistryClinicalDevelopmentDyesFormaldehydeFormalinGeometryGoalsHydrazinesHydrazonesImageKineticsLabelLeadMethodsModernizationModificationMolecularNucleic AcidsOximesPerformancePermeabilityPropertyProteinsProtonsRNAReactionReagentRecoveryResearchSpecimenSpeedTestingTissuesToxic effectWorkadductanthranilatebasebiomedical scientistcatalystcrosslinkcycloadditiondesignexperimental studyfallshuman diseaseimaging studyimprovedinnovationinterestnovelnovel strategiesphosphonateprogramspublic health relevancereaction raterepairedsmall moleculetool
项目摘要
DESCRIPTION (provided by applicant): Our proposed research is aimed at developing a venerable but useful bioorthogonal reaction - hydrazone and oxime formation - into a modern, efficient, and highly versatile tool for biological functionalization. We will overcome some of the
important limitations of this reaction in the past, including slow rates at biological pH and low stability, and add to it new functional properties and capabilities that current orthogonal reactions do not have. In our preliminary work we have developed multiple new organocatalysts that are by far the best catalysts in existence for hydrazone and oxime formation, speeding the reaction by orders of magnitude. Importantly, we have shown that such catalysts can speed the reversal of formaldehyde adducts of RNA bases, such as those found in formalin-fixed tissue. In addition, we have identified important structural features in aldehyde and hydrazines that lead to especially high reaction rates, surpassing even those of strained alkyne cycloadditions. Further, we have demonstrated proof of principle for a new class of fluorogenic ("DarkZone") labeling agents. Our proposed project will specifically address a goal of developing new, highly reactive self-catalyzing aldehydes and hydrazines to accelerate reaction rates by orders of magnitude, making them even more efficient than modern orthogonal cycloadditions. In addition, we will establish novel preformed hydrazones as exchange reagents for labeling both aldehydes or hydrazines on biomolecules of interest. Further, we will develop exceptionally efficient, low-toxicity, cell-permeable catalysts to enable rapid intracellular bioconjugations. Finally, our catalysts will be used to reverse crosslinks in formalin-fixed tissues, unlocking clinically important RNA and protein-based information. This work tests novel mechanistic hypotheses for accelerating reactivity in hydrazone/oxime formation. It will introduce several new chemical design concepts, including self-catalyzing "ultrafast" reactants, "DarkZone" fluorogenic reagents, and hydrazone labels for superresolution imaging. The work is important because it takes a widely used, biomedically important reaction and makes it much more efficient and useful. Our experiments will develop the fastest hydrazine and oxime reactants in existence, and will develop catalysts that are more efficient than any known to date. If successful, the research will enable cellular experiments that could not be done before, and will facilitate the recovery of clinically important molecular information from millions of stored tissue specimens.
描述(由申请人提供):我们提出的研究旨在开发一种古老但有用的生物正交反应-腙和肟形成-成为一种现代,高效和高度通用的生物功能化工具。我们将克服一些
该反应克服了过去该反应的重要局限性,包括在生物pH下的缓慢速率和低稳定性,并为其添加了当前正交反应所不具有的新的功能性质和能力。在我们的初步工作中,我们已经开发了多种新的有机催化剂,这些催化剂是目前存在的用于腙和肟形成的最佳催化剂,将反应速度提高了几个数量级。重要的是,我们已经证明,这种催化剂可以加速RNA碱基的甲醛加合物的逆转,例如在福尔马林固定的组织中发现的那些。此外,我们已经确定了醛和肼的重要结构特征,导致特别高的反应速率,甚至超过那些紧张的炔环加成。此外,我们已经证明了一类新的荧光(“暗区”)标记剂的原理证明。我们提出的项目将专门解决开发新的,高反应性的自催化醛和肼的目标,以加快反应速率的数量级,使它们甚至比现代正交环加成更有效。此外,我们将建立新的预先形成的腙作为交换试剂,用于标记感兴趣的生物分子上的醛或肼。此外,我们将开发非常有效,低毒性,细胞可渗透的催化剂,以实现快速的细胞内生物缀合。最后,我们的催化剂将用于逆转福尔马林固定组织中的交联,解锁临床上重要的RNA和基于蛋白质的信息。这项工作测试新的机制假设,加快反应性的腙/肟形成。它将介绍几种新的化学设计概念,包括自催化“超快”反应物,“DarkZone”荧光试剂和用于超分辨率成像的腙标记。这项工作很重要,因为它需要一个广泛使用的,生物医学上重要的反应,并使其更有效和有用。我们的实验将开发出现存最快的肼和肟反应物,并将开发出比迄今为止任何已知的催化剂都更有效的催化剂。如果成功,这项研究将使以前无法完成的细胞实验成为可能,并将促进从数百万存储的组织标本中恢复临床重要的分子信息。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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ERIC T. KOOL其他文献
ERIC T. KOOL的其他文献
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