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.

随着化学催化，化学合成和化学过程化学计划化学计划的资金，内布拉斯加州林肯大学的研究小组正在开发新的反应，以帮助工业和制药部门和学术界的化学家。该项目建立在一种原位酶筛选（ISE）的研究方法基础上，以利用酶为催化记者，以促进反应发现和催化剂优化。该方法实时帮助实验者，实现平行的催化剂筛选，并促进反应发现。在大型工业化学公司，尤其是制药和生物技术公司的过程方面，在工业中，工业化学家和化学家的平行筛查方法都引起了人们的极大兴趣。除技术方面外，该项目还将有助于建立未来的STEM（科学，技术，工程和数学）劳动力，通过在跨学科研究环境中培训一群学生组，其中包括化学合成的要素“荧光素触发。”这项研究遵循该小组概念研究的早期证明，表明α-（2'z-fluoro）乙烯基触发和α-（1'-fluoro）乙烯基触发对基于机制的PLP酶的灭活（MBI）都有很大的希望。每种新型的非天然氨基酸（AAS）也对合成，药物和肽化学群落都有价值。该提案中的三个目标每个都具有（i）合成/催化目标； （ii）筛选目标和（iii）化学生物学目标。该项目的目标1通过TM介导的分子内胺化，靶向母体化合物，L-和D-α-（1'-氟）乙烯基甘氨酸的对映选择性合成。初步研究表明，在新的荧光模式下表明了“磷酸盐”。提出了Ni（Bis-磷酸）催化剂的有希望的结果，并提供高度对映选择性的途径，并具有丰富的过渡金属催化剂。化学生物学研究将探测抑制色氨酸合酶用L-和D-α-（1'-氟）（1'-氟）乙烯基甘氨酸的对映选择性，并检查了这些具有其他高价值酶的对映体MBI候选者。 AIM 2涉及乙烯基触发器（AIM 2A）和α-（1'-氟）乙烯基触发（AIM 2B）的Quaternization。实验性工作表明，使用MNBDH染料指示剂，在此处使用荧光酸酯和酒精氧化酶/过氧化物酶夫妇的荧光iSES互补变体的可能性。此外，初步筛选结果表明，在PD（Siphox） - 催化下，可以在高EE中访问第四纪A-乙烯基AAS。 AIM 3A和3B提案分别将催化化学发展为新的“侧链插入1'-氟环烯基和2'-氟韦烯基AAS”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” 1'-氟环苷是触发谷氨酸脱羧酶灭活的触发因素。该奖项反映了NSF的法定任务，并被认为是通过使用基金会的知识分子和更广泛影响的评估来审查Criteria来通过评估来获得的支持。