Chemical Synthesis and Biology of Complex Alkaloids

复杂生物碱的化学合成和生物学

• 批准号: 10372050
• 负责人: Thomas John Maimone
• 金额: $ 46.09万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372050
• 关键词: 3-Dimensional; Address; Alkaloids; Amino Acyl-tRNA Synthetases; Anabolism; Anti-Bacterial Agents; Antibiotics; Architecture; Area; Bacterial Infections; Binding Sites; Biological; Biological Assay; Biology; Biomedical Research; Chemical Structure; Chemicals; Chemistry; Clinical; Communicable Diseases; Complex; Cysteine; Development; Disease; Evaluation; FDA approved; Family; Fishes; Goals; Health; Human; Laboratories; Lead; Libraries; Malignant Neoplasms; Maps; Medicine; Monoterpenes; Morphine; Natural Products; Nitrogen; Organic Chemicals; Organic Chemistry; Pathway interactions; Pharmaceutical Chemistry; Phenotype; Porifera; Postdoctoral Fellow; Process; Property; Protein Inhibition; Proteins; Proteome; Pyrroles; Reporting; Research; Route; Scombridae; Skeleton; Students; Synthesis Chemistry; Terpenes; Time; Touch sensation; Training; Tropical Disease; Tyrosine; Ursidae Family; Vinblastine; Work; anti-cancer; base; career; cellular targeting; chemical synthesis; chemoproteomics; cost; covalent bond; cytotoxic; dimer; drug discovery; fungus; gut microbes; high throughput screening; human disease; inhibitor; innovation; interest; member; novel; novel antibiotic class; pathogen; programs; pyridine; scaffold; screening; small molecule; small molecule therapeutics; student training; success; triple-negative invasive breast carcinoma; wasting

PROJECT SUMMARY From Vinblastine to Morphine, alkaloid natural products have contributed enormously to the treatment of human health and their impact has touched nearly every area of disease biology. Despite past successes, the number of new FDA-approved medicines derived from, or inspired by, complex alkaloids are waning. The multifarious and not-easily-manipulated chemical structures of intricate alkaloids, combined with complex, and often unknown, cellular target profiles has contributed to the abandonment of many natural product-based drug discovery programs. High-throughput screening approaches now dominate the hit-to-lead process. Yet there is growing concern over the lack of diverse three-dimensional complexity in many screening libraries, and natural products, and their derivatives, are recognized as filling an important area in bioactive compound space. This proposal seeks to address such limitation through both advances in synthetic chemistry pathways as well as cutting-edge chemoproteomics platforms to map the protein targets of a variety of judiciously chosen alkaloid natural products. The targets selected for this program represent both state of the art challenges for efficient complex molecule synthesis as well as scaffolds ideal for further medicinal chemistry discovery. Despite their small size, and potential to treat a variety of diseases, members of the altemicidin alkaloids require roughly thirty steps to prepare. The need to prepare new antibiotics is critical and many successful antibiotic classes have been derived from natural products, often ones with one or more nitrogen atom. The curvulamine alkaloids represent a promising new antibiotic class with reported activity against both gram negative and positive pathogens and possess a completely novel chemical structure. Finally, covalently acting alkaloids derived from tyrosine show potent anti-cancer effects yet their biological targets are unknown. Overall this work will utilize innovative synthetic chemistry approaches to synthesize complex alkaloid natural products and their derivatives in an efficient manner and with unprecedented structural diversity for further biological evaluation. Using cutting-edge chemoproteomics platforms, we will determine the cellular targets responsible for a given phenotype. In the process of carrying out this work, students and post-docs will be provided with rigorous and intellectually stimulating training in synthetic chemistry and chemical biology and will be well prepared for careers in biomedical research and drug discovery.

项目摘要 从长春碱到吗啡，生物碱类天然产物对治疗慢性阻塞性肺疾病做出了巨大贡献。 人类健康及其影响几乎涉及疾病生物学的每一个领域。尽管过去取得了成功， 一些FDA批准的新药物，从复杂的生物碱中衍生出来，或受其启发，正在减少。的 复杂生物碱的化学结构多种多样且不易操作，与复杂的， 通常未知的细胞靶向谱导致许多天然产物为基础的药物被放弃 探索计划高通量筛选方法现在占主导地位的命中铅的过程。然而有 越来越多的关注缺乏多样性的三维复杂性，在许多筛选库，和自然 产品及其衍生物被认为填补了生物活性化合物领域的重要领域。这 该提案旨在通过合成化学途径的进展以及 尖端的化学蛋白质组学平台，用于绘制各种明智选择的生物碱的蛋白质靶点 天然产品。为该计划选择的目标既代表了最先进的挑战， 复杂的分子合成以及理想的支架用于进一步的药物化学发现。尽管他们 小的尺寸和治疗多种疾病的潜力，阿替西汀生物碱的成员需要大约30 步骤准备。制备新抗生素的需求是至关重要的，许多成功的抗生素类别 通常来自天然产物，通常含有一个或多个氮原子。曲维胺 生物碱代表了一种有前途的新抗生素类别， 和阳性病原体，并具有全新的化学结构。最后，共价作用的生物碱 衍生自酪氨酸的化合物显示出有效的抗癌作用，但它们的生物靶点是未知的。总的来说这 工作将利用创新的合成化学方法来合成复杂的生物碱天然产物 及其衍生物，并具有前所未有的结构多样性， 评价使用尖端的化学蛋白质组学平台，我们将确定负责的细胞靶点 对于给定的表型。在开展这项工作的过程中，将为学生和博士后提供 在合成化学和化学生物学方面进行严格和智力刺激的培训，并将 为生物医学研究和药物发现的职业生涯做好准备。