Synthesis and Evaluation of Biologically Active Natural Products

生物活性天然产物的合成与评价

• 批准号: 8506615
• 负责人: Joseph M Ready
• 金额: $ 29.47万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506615
• 关键词: Affect; Algorithms; Antibiotics; Antifungal Agents; Area; Bacteria; Biochemical; Bioinformatics; Biological; Biological Factors; Carbon; Cell Cycle Proteins; Cells; Chemicals; Chemistry; Communicable Diseases; Complex; Cyclization; Cytoskeleton; Cytotoxin; DNA; Data; Data Set; Development; Drug resistance; Electrons; Enzymes; Evaluation; Fatty Acids; Gene Expression Profile; Genes; Genetic; Gram-Positive Bacteria; HCT116 Cells; Human; Human Genome; Ion Channel; Learning; Malignant Neoplasms; Malignant neoplasm of lung; Marketing; Methodology; Methods; Microtubules; Molecular Profiling; Molecular Target; Mutate; Mutation; Organic Synthesis; Pathway interactions; Pattern; Pattern Recognition; Pharmaceutical Preparations; Pharmacologic Substance; Phosphoric Monoester Hydrolases; Phosphotransferases; Plants; Proteins; Pump; RNA Interference; RNA chemical synthesis; Radiolabeled; Reagent; Resistance; Resources; Sentinel; Source; Stimulus; Structure; Synthesis Chemistry; Testing; Work; Xanthones; antineoplastic antibiotics; bacterial resistance; complex biological systems; cycloaddition; cytotoxic; cytotoxicity; diene; drug candidate; drug discovery; fungus; kinase inhibitor; loss of function; mutant; novel; protein transport; public health relevance; radiotracer; research study; response; small molecule; stereochemistry; tool

DESCRIPTION (provided by applicant): Natural products constitute a valuable source of drug leads and tools to probe complex biological systems. Nearly half of the drugs introduced for cancer over the last six decades are natural products or are inspired by natural products. Likewise, around 75% of new antibiotics described over the last 25 years emerged from studies of natural products. Historically, even natural products that are unsuitable as drug candidates have been used to study complex biological systems such as ion channels, microtubules, the cytoskeleton, the cell cycle and protein trafficking among others. Finally, the synthesis of natura products leads to the discovery and development of synthetic methodologies and strategies. These discoveries may be useful more broadly to the field of organic synthesis. Overall, the synthesis and evaluation of natural products provides the opportunity to advance the state of synthetic chemistry, biological understanding, and drug discovery. Aim 1. Synthesize complex, biologically active, polyaromatic xanthone natural products. We will develop convergent, enantioselective syntheses of polyaromatic xanthone natural products. None of these compounds has been synthesized previously, and all display potent biological activity. For example, the kibdelones, simaomicin a, kigamicin A, actinoplanone, and IB-00208 are low-nM anti-cancer antibiotics with unknown targets. Sch-56036 displays robust antifungal activity, but no molecular target is known. Additionally, we will synthesize the isokibdelones, which inhibit export pumps. These efforts will confirm the structure of the natural products, assign their absolute stereochemistry, and provide access to both the natural products and their derivatives. Moreover, to facilitate our efforts and contribute to practice of organic synthesis, we will develo new methods for the synthesis of isoquinolinones and dihydroisocoumarins; we will explore a novel synthesis of aryl ketenes; we will invent an asymmetric catalytic synthesis of chiral aminals; and we will discover an asymmetric catalytic [4+2] cycloaddition between electron rich dienes and benzopyranones to yield hexahydro-xanthones. Aim 2. Use genetic and biochemical methods to discover the mechanism of action of xanthone natural products. We will culture Gram-positive bacteria in the presence of increasing concentrations of antibiotic natural products to induce resistance. Mutants showing specific resistance to the natural product will be sequenced to identify the protein or proteins that were mutated to provide resistance. Aim 3. Use expression profiling to discover the mechanism of action of xanthone natural products. We will determine the expression of 16 highly variable genes in response to sub-lethal concentrations of cytotoxins. The pattern of expression will be compared to the patterns of expression generated by RNAi knockdown of every gene in the human genome, thus correlating the natural product to a specific loss of function. Biochemical experiments will be used to test predicted modes of action.

描述（由申请人提供）：天然产品构成了探测复杂生物系统的药物铅和工具的宝贵来源。在过去的六十年中，将近一半用于癌症引入的药物是天然产物，或受到天然产品的启发。同样，在过去25年中，大约有75％的新抗生素来自对天然产物的研究。从历史上看，即使是不适合作为候选药物的天然产物，也已用于研究复杂的生物系统，例如离子通道，微管，细胞骨架，细胞周期和蛋白质运输等。最后，Natura产品的合成导致合成方法和策略的发现和开发。这些发现可能对有机合成领域更广泛。总体而言，天然产品的合成和评估为推进合成化学，生物学理解和药物发现状态提供了机会。 AIM 1。合成复合物，生物活性，多芳族黄酮天然产物。我们将开发收敛的，对照型的叶黄酮天然产物的合成。这些化合物均未合成，并且都显示出有效的生物学活性。例如，kibdelones，simaomicin A，kigamicin A，actinoplanone和ib-00208是具有未知靶标的低NM抗癌抗生素。 SCH-56036显示出强大的抗真菌活性，但尚无分子靶标。此外，我们将合成抑制出口泵的Isokibdelones。这些努力将确认天然产品的结构，分配其绝对立体化学，并提供对天然产品及其衍生物的访问。此外，为了促进我们的努力并为有机合成实践做出贡献，我们将为综合异喹啉酮和二羟基摩蛋白酶的合成新方法。我们将探索一种新颖的芳基酮合成。我们将发明手性氨基的不对称催化合成；而且，我们将发现富含电子二烯和苯二吡喃酮之间的一个不对称催化[4+2]，以产生六氢 - 黄酮。 AIM 2。使用遗传和生化方法来发现黄酮天然产物的作用机理。我们将在增加抗生素天然产物诱导抗性的情况下培养革兰氏阳性细菌。表现出对天然产物的特定耐药性的突变体将进行测序，以鉴定突变以提供抗性的蛋白质或蛋白质。 AIM 3。使用表达谱分析发现黄酮天然产物的作用机理。我们将根据亚致死性细胞毒素的响应来确定16个高度可变基因的表达。将表达模式与人类基因组中每个基因的RNAi敲低产生的表达模式进行比较，从而将天然产物与特定功能丧失相关联。生化实验将用于测试预测的作用模式。