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）：这是优化甲烷喹硫代氨酸kuammiline支架的骨骼骨骼重排的总体目标，并开发出前方的Fischer浸入式的，以使对照剂的合成是ndoline和30种akuammines essess seplate and akuammines sepainsess seplate and there sepainsess。包括治疗性的活性：D衰减，癌症，炎症和单纯疱疹病毒（HSV）及其生物活性，这些化合物是结构性的。了解阿库米林蛋白的骨骼可能会深入了解分子反应性，影响未来的合成设计，开发新的方法论和未综合的生物学活性akuamamilines。 这个目标是两个具体的目标。 ，抗癌症的生成反应的乘积含有小季中心。最后，我想指出构建的化合物构建了本提案中的作品，将提交生物学评估。