Total Synthesis of Bioactive Indole Alkaloids

生物活性吲哚生物碱的全合成

• 批准号: 9223572
• 负责人: Elias Picazo
• 金额: $ 3.72万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9223572
• 关键词: Alkaloids; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Antineoplastic Agents; Area; Biological; Breathing; Chemistry; Complex; Diabetes Mellitus; Doctor of Philosophy; Evaluation; Family; Family member; Future; Goals; Health; Human; Indole Alkaloids; Inflammation; Interruption; Learning; Malignant Neoplasms; Mental Depression; Methodology; Modeling; Molecular; Multi-Drug Resistance; Natural Products; Organic Synthesis; Pain; Pharmaceutical Preparations; Phase; Reaction; Recording of previous events; Research; Route; Simplexvirus; Structure; System; Testing; Therapeutic; Variant; Work; bioactive natural products; chemical synthesis; design; enantiomer; fighting; indoline; innovation; insight; public health relevance; scaffold; skeletal; strictamine

 DESCRIPTION (provided by applicant): The overall goal of this proposal is to optimize a challenging skeletal rearrangement of the methanoquinolizidine akuammiline scaffold and to develop an advanced interrupted Fischer indolization reaction for the enantioselective synthesis of indoline- or indolenine-containing natural products. More than 30 akuammilines have been isolated and these alkaloids possess promising biological activities encompassing the following therapeutic areas: pain, depression, cancer, diabetes, inflammation, and herpes simplex virus (HSV). Along with their bioactivities, these compounds are structurally complex; only four akuammilines have been synthesized since the fist isolation in 1875. With the chemistry proposed, I will: learn about the skeletal reactivity of akuammilines that may give insight into molecular reactivity that may impact future synthetic designs, develop new methodologies, and access structurally diverse and biologically active akuammilines that have not been synthesized. The goals of this proposal will be accomplished through two specific aims. First, the exploration and optimization of the methanoquinolizidine rearrangement of some akuammilines will provide rapid access to related natural products comprised of pyrrolidinoindoline frameworks from related systems. This chemistry will yield the first total synthesis of akuammiline (-)-11-methoxyvincorine, an anti-cancer agent that reverses multi-drug resistance. Next, an interrupted Fischer indolization reaction will be developed such that the product of the complexity-generating reaction contains vicinal quaternary centers. This unprecedented reaction will allow for the synthesis of two additional akuammiline alkaloids that have not yet been accessed synthetically, namely (+)-akuammiline and biologically active (-)-Ψ-akuammigine. Lastly, I would like to state that the compounds constructed throughout the work presented in this proposal will be submitted for biological evaluation.

 描述（由申请人提供）：该提案的总体目标是优化甲氨基喹嗪胺akuammiline支架的挑战性骨架重排，并开发用于对映选择性合成二氢吲哚或含二氢吲哚的天然产物的高级中断Fischer吲哚化反应。已经分离出超过30种akuammilines，这些生物碱具有有前途的生物活性，包括以下治疗领域：疼痛，抑郁症，癌症，糖尿病，炎症和单纯疱疹病毒（HSV）。沿着它们的生物活性，这些化合物结构复杂;自1875年首次分离以来，仅合成了四种akuammilines。随着化学提出，我将：了解akuammilines的骨架反应性，这可能会给深入了解分子反应性，可能会影响未来的合成设计，开发新的方法，并访问尚未合成的结构多样性和生物活性akuammilines。 本提案的目标将通过两个具体目标来实现。首先，一些akuammilines的methanoquinolizidine重排的探索和优化将提供从相关系统中快速获得由吡咯烷吲哚啉框架组成的相关天然产物。这种化学反应将产生第一个全合成的阿库阿米林（-）-11-甲氧基长春新碱，一种逆转多药耐药性的抗癌剂。接下来，将开发中断的Fischer吲哚化反应，使得络合物生成反应的产物含有邻位季中心。这种前所未有的反应将允许合成两种尚未合成的另外的阿库阿米林生物碱，即（+）-阿库阿米林和生物活性（-）-β-阿库阿米碱。最后，我想声明的是，将提交本提案中所述工作中构建的化合物进行生物学评价。