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）：该提案的首要主题是应用新的光氧化还原催化方法来制备生物活性化合物。由于广泛的官能团兼容性和温和的反应条件，这些方法在各自的合成中提供了策略级优势。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是一种不产生化学废物的无毒“试剂”，对于化学合成来说是有吸引力的策略。由于大多数有机分子不能有效地吸收可见光，光敏催化剂因其光物理性质而被广泛研究，已成功用于许多新的化学方法，这些方法将应用于生物活性天然化合物的合成。作为该提案的一部分制备的化合物将由 NIH 化学基因组中心 (NCGC) 的 Inglese 实验室利用其高通量筛选能力评估其生物活性。这些筛选活动中产生的线索将与 NCGC 的药物化学小组合作进行跟踪。最初的目标文库将在 BU 准备，并在适当情况下使用首席研究员实验室准备的支架进行后续支架开发，以便在 NCGC 进行修改。此外，刘小组（科罗拉多大学）将评估所开发的化合物对细胞周期调节的影响。拟开展的研究项目的目的是：1）合成双吲哚生物碱天然产物gliocladin C、deoxyleptosin D、deoxybionectin A和plectosphaeroic Acid A，实现异二聚双(吡咯并吲哚啉)生物碱asperdimin和WIN 64745的合成，承担使用光氧化还原介导的一系列吲哚里西啶生物碱，吡咯上的立体控制自由基环化，并利用光氧化还原催化片段偶联策略实现放线菌酸的合成。 2）开发光氧化还原催化胺类α-C-H官能化的新方法，并将其应用于生物碱天然产物crispine A、harmicine、tangutorine和undulifoline的合成。