Photoredox Catalysis Applications to Bioactive Compounds

光氧化还原催化在生物活性化合物中的应用

• 批准号: 8750909
• 负责人: Corey Stephenson
• 金额: $ 18.72万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8750909
• 关键词: Acids; Alcohols; Alkaloids; Amines; Ammonium; Biological; Biological Factors; Carboxypeptidase U; Cardiovascular Diseases; Catalysis; Cations; Cell Cycle Regulation; Chemicals; Collaborations; Colorado; Conscious; Coupling; Cyclization; DNA Sequence Rearrangement; Development; Electrons; Genomics; Infection; Ions; Laboratories; Libraries; Malignant Neoplasms; Mediating; Methodology; Methods; Modification; Pharmaceutical Chemistry; Preparation; Principal Investigator; Process; Property; Pyrroles; Reaction; Reagent; Research Project Grants; Series; Tryptophan; United States National Institutes of Health; Universities; Visible Radiation; analog; base; catalyst; chemical reaction; chemical synthesis; follow-up; functional group; high throughput screening; inhibitor/antagonist; nitroalkane; professor; scaffold; screening; wasting

DESCRIPTION (provided by applicant): The overarching theme of this proposal is the application of new photoredox catalysis methods to the preparation of biologically active compounds. These methodologies provide strategy-level advantages in their respective syntheses due to broad functional group compatibility and mild reaction conditions. Importantly they will also enable syntheses in an environmentally conscious fashion. New methods using visible light, a non-toxic 'reagent' that does not generate chemical waste, are attractive strategies for chemical synthesis. Since most organic molecules do not productively absorb visible light, photosensitive catalysts, widely studied for their photophysical properties, have been successfully employed for numerous new chemical methods which will be applied in the synthesis of biologically active natural compounds. The compounds prepared as part of this proposal will be evaluated for their biological activity by the Inglese Laboratory at the NIH Chemical Genomics Center (NCGC) using their high throughput screening capabilities. Leads which arise from these screening activities will be followed up in collaboration with the medicinal chemistry group at NCGC. The initial targeted libraries will be prepared at BU, with follow-up scaffold development, where appropriate, using scaffolds prepared in the Principal Investigator's lab for modification at NCGC. In addition, the Liu Group (University of Colorado) will evaluate the effect of the developed compounds on cell-cycle regulation. The aims of the proposed research projects are to: 1) Synthesize the bisindole alkaloid natural products gliocladin C, deoxyleptosin D, deoxybionectin A and plectosphaeroic acid A, achieve the synthesis of heterodimeric bis(pyrroloindoline) alkaloids asperdimin and WIN 64745, undertake the syntheses of a series of indolizidine alkaloids using photoredox- mediated, stereocontrolled radical cyclization onto pyrroles, and achieve the synthesis of actinophyllic acid using a photoredox-catalyzed fragment coupling strategy. 2) Develop new methods for the ?-C-H functionalization of amines using photoredox catalysis and appyl these methods to the syntheses of the alkaloid natural products crispine A, harmicine, tangutorine and undulifoline.

描述（由申请人提供）：该提案的总体主题是将新的Photoredox催化方法应用于生物活性化合物的制备。由于广泛的功能组兼容性和轻度的反应条件，这些方法在各自的合成中提供了策略级别的优势。重要的是，它们还将以环保的方式实现合成。使用可见光的新方法，一种不会产生化学废物的无毒的“试剂”，是化学合成的有吸引力的策略。由于大多数有机分子没有有效地吸收可见光，因此已成功地用于用于多种新化学方法的光敏催化剂，已广泛研究其光物理特性，这些方法将用于合成生物活性天然化合物。作为该提案的一部分制备的化合物将使用其高吞吐量筛查能力评估Inglese实验室在NIH化学基因组中心（NCGC）的生物学活性。这些筛查活动引起的潜在客户将与NCGC的药物化学组合作进行跟踪。最初的目标库将在BU上准备，并在适当的情况下，使用在首席研究员实验室中准备的脚手架进行后续脚手架开发，以在NCGC进行修改。此外，刘集团（科罗拉多大学）将评估开发化合物对细胞周期调节的影响。拟议的研究项目的目的是：1）合成双吲哚生物碱天然产物胶质素C，脱氧脂蛋白D，脱氧辅维蛋白A和plectosposposyac A，达到杂型二聚体Bis（吡咯并丁烷）ALKALOID AS -predimins anse syake anse syake a -6444445的合成。使用光毒素介导的立体控制的自由基环化到吡咯并使用Photoredox催化的片段偶联策略实现肌发脂的合成。 2）开发了使用Photoredox催化和将这些方法与生物碱天然产物Crispine A，Harmicine，Congutorine，Congutorine和Udulifoline一起使用的新方法，并使用Photoredox催化和将这些方法与这些方法相关。