Chemical Synthesis and Biology of Complex Alkaloids

复杂生物碱的化学合成和生物学

基本信息

批准号：
10598537
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
项目类别：
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/10598537
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 Touch sensation Training Tropical Disease Tyrosine Vinblastine Work anti-cancer career career preparation cellular targeting chemical synthesis chemoproteomics cost covalent bond cytotoxic dimer drug discovery fungus gut microbes high throughput screening human disease inhibitor innovation interest member natural product derivative novel novel antibiotic class pathogen programs pyridine scaffold screening small molecule small molecule therapeutics student training success triple-negative invasive breast carcinoma wasting

项目摘要

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.

项目概要从长春花碱到吗啡，生物碱天然产物为治疗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个领域。尽管过去取得了成功， FDA 批准的源自复杂生物碱或受复杂生物碱启发的新药物数量正在减少。这复杂的生物碱的复杂且不易操作的化学结构，以及复杂的组合通常未知的细胞靶点概况导致许多基于天然产物的药物被放弃发现计划。高通量筛选方法现在主导着从命中到先导的过程。然而还有人们越来越关注许多筛选库中缺乏多样化的三维复杂性，并且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步以及尖端的化学蛋白质组学平台，用于绘制各种精心选择的生物碱的蛋白质靶标天然产品。为该计划选择的目标代表了高效的两个最先进的挑战复杂的分子合成以及支架是进一步药物化学发现的理想选择。尽管他们的阿替西丁生物碱的成员体积小，具有治疗多种疾病的潜力，大约需要三十种准备步骤。制备新抗生素的需求至关重要，许多成功的抗生素类别衍生自天然产物，通常具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型抗生素类别，据报道具有抗革兰氏阴性菌的活性和阳性病原体，并具有全新的化学结构。最后，共价作用生物碱源自酪氨酸的化合物显示出有效的抗癌作用，但其生物学靶点尚不清楚。总体来说这个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以有效的方式并具有前所未有的结构多样性，用于进一步的生物学研究评估。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标对于给定的表型。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接受严格且智力刺激的培训，并将为生物医学研究和药物发现职业做好充分准备。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chemoproteomic Profiling Reveals that Anticancer Natural Product Dankastatin B Covalently Targets Mitochondrial VDAC3.

化学蛋白质组学分析揭示抗癌天然产物 Dankastatin™B 共价靶向线粒体 VDAC3。

DOI：
发表时间：
2023-07-17
期刊：
影响因子：
0
作者：
Belcher, Bridget P;Machicao, Paulo A;Tong, Binqi;Ho, Emily;Friedli, Julia;So, Brian;Bui, Helen;Isobe, Yosuke;Maimone, Thomas J;Nomura, Daniel K
通讯作者：
Nomura, Daniel K