New Approaches to Catalyst Screening and Development

催化剂筛选和开发的新方法

• 批准号: 2400333
• 负责人: David Hage
• 金额: $ 79.83万
• 依托单位: University of Nebraska-Lincoln
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2400333&HistoricalAwards=false
• 关键词: New; Approaches; Catalyst; Screening; Development

With funding from the Chemical Catalysis, Chemical Synthesis, and Chemistry of Life Processes programs of the Division of Chemistry, the research team at the University of Nebraska-Lincoln is developing new reactions to help chemists in the industrial and pharmaceutical sectors and in academia. The project builds on a research approach termed In Situ Enzymatic Screening (ISES) to exploit enzymes as catalytic reporters to facilitate reaction discovery and catalyst optimization. The approach assists experimentalists in real time, enables parallel catalyst screening, and facilitates reaction discovery. Parallel screening methods are of great interest to both academic chemists and chemists in industry, in both the large industrial chemical companies and particularly on the process side in pharmaceutical and biotech companies. Beyond the technical aspects, the project will help to build the future STEM (science, technology, engineering, and mathematics) workforce by training a diverse group of students in an interdisciplinary research environment that includes elements of chemical synthesis, analytical chemistry, and chemical biology.The targeted platform reactions for each of the three aims of this proposal build on the strong foundation established by the investigator's group in developing unnatural amino acids (AAs) bearing “fluorovinyl triggers.” This research follows earlier proof of concept studies from the group, demonstrating that both the alpha-(2’Z-fluoro)vinyl trigger and the alpha-(1’-fluoro)vinyl trigger have great promise for the mechanism-based inactivation (MBI) of PLP enzymes. Each of the classes of novel unnatural amino acids (AAs) will be of value to the synthetic, medicinal and peptide chemistry communities, as well. The three aims in this proposal each have a (i) synthetic/catalytic goal; (ii) a screening goal and (iii) a chemical biology goal. Aim 1 of this project targets the enantioselective synthesis of the parent compound, L- and D- alpha-(1’-fluoro)vinylglycine via TM-mediated intramolecular amination. Preliminary studies demonstrate ‘phosphate-ISES’ in a new fluorescence mode. Promising results with Ni(bis-phosphine) catalysts are presented, offering a highly enantioselective route with an earth abundant transition metal catalyst. Chemical biology studies will probe the enantioselectivity of the inhibition of tryptophan synthase with L- and D- alpha-(1’-fluoro)vinylglycine, as well as examining these enantiomeric MBI candidates with other high value enzymes. Aim 2 involves the quaternization of both the vinyl trigger (Aim 2A) and of the alpha-(1’-fluoro)vinyl trigger (Aim 2B). Experimental work points to the possibility of using a complementary variant of fluorescence ISES here with carbonate leaving groups and alcohol oxidase/peroxidase couple using the MNBDH dye indicator. Moreover, preliminary screening results suggest that quaternary a-vinyl AAs can be accessed in high ee under Pd(SiPhox)-catalysis. Aim 3A and 3B propose to develop catalytic chemistry into new classes of ‘side chain-embedded’ 1’-fluorovinyl and 2’-fluorovinyl AAs, respectively. On the chemical biology side, an exciting preliminary result shows that the ‘embedded’ 1’-fluorovinyl is a trigger for glutamate decarboxylase inactivation.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学部化学催化，化学合成和生命过程化学项目的资助下，内布拉斯加大学林肯分校的研究团队正在开发新的反应，以帮助工业和制药部门以及学术界的化学家。该项目基于一种称为原位酶筛选（ISES）的研究方法，利用酶作为催化报告分子，以促进反应发现和催化剂优化。该方法可以帮助实验者在真实的时间，使并行催化剂筛选，并促进反应发现。 平行筛选方法对学术化学家和工业化学家都非常感兴趣，在大型工业化学公司，特别是在制药和生物技术公司的工艺方面。除了技术方面，该项目将有助于建立未来的STEM（科学，技术，工程和数学）的劳动力，通过培训一个跨学科的研究环境，包括化学合成，分析化学，和化学生物学。本提案的三个目标中的每一个的靶向平台反应都建立在研究者的研究所建立的坚实基础之上。一个研究小组正在开发带有“氟乙烯基触发剂”的非天然氨基酸（AA）。这项研究遵循了该小组早期的概念验证研究，证明了α-（2 'Z-氟）乙烯基触发剂和α-（1'-氟）乙烯基触发剂对于PLP酶的基于机制的失活（MBI）具有很大的前景。每一类新的非天然氨基酸（AAs）也将对合成，医药和肽化学社区具有价值。本提案中的三个目标各有一个（i）合成/催化目标;（ii）筛选目标和（iii）化学生物学目标。本项目的目标1是通过TM介导的分子内胺化反应对映选择性地合成母体化合物L-和D-α-（1 '-氟）乙烯基甘氨酸。初步研究表明，磷酸盐ISES '在一个新的荧光模式。镍（双膦）催化剂的前景看好的结果，提供了一个高对映选择性的路线与地球丰富的过渡金属催化剂。化学生物学研究将探测用L-和D-α-（1 '-氟）乙烯基甘氨酸抑制色氨酸合酶的对映体选择性，以及用其他高价值酶检查这些对映体MBI候选物。目的2涉及乙烯基引发剂（目的2A）和α-（1 ′-氟）乙烯基引发剂（目的2B）的季铵化。实验工作点的可能性，使用互补的变体的荧光ISES在这里与碳酸酯离去基团和醇氧化酶/过氧化物酶对使用MNBDH染料指示剂。此外，初步的筛选结果表明，季α-乙烯基AA可以在Pd（SiPhox）催化下以高ee获得。 目的3A和3B分别提出将催化化学发展到“侧链嵌入的”1 '-氟乙烯基和2'-氟乙烯基AA的新类别。在化学生物学方面，一个令人兴奋的初步结果表明，“嵌入的”1 '-氟乙烯基是谷氨酸脱羧酶失活的触发器。该奖项反映了NSF的法定使命，并已被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。