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: 8601711
• 负责人: Corey Stephenson
• 金额: $ 28.75万
• 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/8601711
• 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; public health relevance; 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）：本提案的首要主题是新的光氧化还原催化方法在制备生物活性化合物中的应用。这些方法提供了战略层面的优势，在其各自的合成，由于广泛的官能团相容性和温和的反应条件。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，一种无毒的“试剂”，不产生化学废物，是有吸引力的化学合成策略。由于大多数有机分子不能有效地吸收可见光，光敏催化剂因其物理化学性质而被广泛研究，已成功地用于许多新的化学方法，这些方法将应用于合成具有生物活性的天然化合物。NIH化学基因组学中心（NCGC）的英国实验室将使用其高通量筛选能力评价作为本提案一部分制备的化合物的生物活性。将与NCGC的药物化学组合作，对这些筛选活动产生的线索进行随访。将在BU制备初始靶向文库，并在适当情况下使用主要研究者实验室制备的支架进行后续支架开发，以便在NCGC进行修饰。此外，Liu小组（科罗拉多大学）将评估开发的化合物对细胞周期调节的影响。拟议研究项目的目的是：1）合成了双吲哚生物碱天然产物gliocladin C、deoxyleptosin D、deoxybionectin A和plectosphaeroic acid A，实现了异二聚体双（吡咯并吲哚啉）生物碱Asperdimin和WIN 64745，利用光氧化还原介导的、立体控制的自由基环化到吡咯上来合成一系列中氮茚生物碱，实现光氧化还原催化片段偶联策略合成放线菌酸。2)开发新的方法？-利用光氧化还原催化胺的C-H功能化反应，并将这些方法应用于生物碱类天然产物山楂碱A、去氢骆驼蓬碱、唐古托碱和undulifoline的合成。