Chemical Synthesis and Biology of Complex Alkaloids

项目总结 从长春花碱到吗啡，生物碱天然产物对治疗糖尿病做出了巨大贡献。 人类健康及其影响几乎触及了疾病生物学的每一个领域。尽管过去取得了成功，但 FDA批准的从复杂生物碱中提取或受其启发的新药数量正在减少。这个 错综复杂的生物碱的多种多样且不易操纵的化学结构，与复杂的 通常未知的细胞靶标特征导致了许多天然产物药物的废弃。 探索计划。高通量筛选方法现在主导着从点击到领先的过程。然而，有一种 人们越来越关注在许多筛选文库中缺乏多样化的三维复杂性，以及自然 产品及其衍生物被认为是生物活性化合物领域的一个重要领域。这 一项提案寻求通过在合成化学途径方面的进展以及 尖端化学蛋白质组学平台绘制各种精选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两个最先进的挑战，即高效 复杂分子合成以及进一步药物化学发现的理想支架。尽管他们 体型小，有可能治疗多种疾病，青蒿素生物碱的成员大约需要30 准备的步骤。需要准备新的抗生素是至关重要的，许多成功的抗生素类别 来自天然产品，通常是含有一个或多个氮原子的产品。柯鲁拉明 生物碱是一种很有前途的新型抗生素，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 从酪氨酸中提取的化合物具有强大的抗癌作用，但其生物靶点尚不清楚。总体而言， 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 及其衍生物以一种高效的方式和前所未有的结构多样性为进一步的生物 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激发的培训，并将 为从事生物医学研究和药物研发做好了充分的准备。

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.