Polyketides via Redox-Triggered Alcohol C-H Functionalization

通过氧化还原触发醇 C-H 官能化的聚酮化合物

• 批准号: 10567345
• 负责人: MICHAEL J KRISCHE
• 金额: $ 30.99万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567345
• 关键词: Affect; Alcohols; Anti-Bacterial Agents; Antibiotics; Bacteria; Biological; Brain Neoplasms; Carbon; Catalysis; Collaborations; Family; Fermentation; Funding; Genes; Glioblastoma; Glycols; Human; Hydrogen; Iridium; Laboratories; Malignant - descriptor; Medicine; Methodology; Methods; Mycobacterium tuberculosis; Natural Products; Oxidation-Reduction; Pharmaceutical Chemistry; Pharmaceutical Preparations; Process; Property; Reaction; Research; Rifampin; Route; Ruthenium; Science; Site; Soil; Work; analog; anti-cancer; catalyst; chemical synthesis; computer studies; cost; cycloaddition; inhibitor; innovation; isoniazid; large scale production; marine; polyketides; programs; resistant strain; secondary metabolite; small molecule; symbiont

Polyketides are used more frequently in human medicine than any other class of secondary metabolites, and comprise roughly 20% of top-selling small-molecule drugs. Despite their importance: (a) All polyketides used in human medicine are derived from soil bacteria and are prepared via fermentation or semi-synthesis (notwithstanding eribulin), (b) <5% of soil bacteria are amenable to culture, many phyla have eluded culture, and the few bacteria amenable to culture express <10% of their biosynthetic genes, (c) although marine polyketides possess an astonishing array of biological activities, commercial fermentation processes involving marine bacteria (which are often symbionts) remain exceptionally uncommon. De novo chemical synthesis potentially offers entry to otherwise inaccessible polyketides and their congeners, yet current synthetic methods often do not avail sufficiently concise routes for large scale production. To overcome this challenge, our laboratory has pioneered a broad, new family of catalytic methods for the direct stereo- and site-selective conversion of lower alcohols to higher alcohols. As documented in numerous total syntheses, these methods streamline polyketide construction, allowing the target compounds to be prepared in significantly fewer steps than previously possible. In the proposed funding period, 3 specific aims are proposed: (a) Total syntheses of the type I polyketides neaumycin B and gladiolin will be pursued using our catalytic methods. Neaumycin B is a femtomolar inhibitor of U87 human glioblastoma. Gladiolin displays potent, selective activity against M. tuberculosis strains that are resistant to the frontline antibiotics isoniazid and rifampicin. (b) The type II polyketide antibiotics formicamycins G, H and J, arenimycin A and analogues of viridicatumtoxin will be prepared using our catalytic methods. Antibacterial properties of these compounds will be evaluated in collaboration with Prof. Barrie Wilkinson and Prof. Jean Chmielewski. (c) Ruthenium-catalyzed reactions relevant to polyketide construction (allylation, crotylation, propargylation, etc.) will be developed. Optimization of these methods will be assisted by computational studies performed by Prof. Kuo-Wei Huang. Thus, our studies advance an integrated program in which methodological innovation informs synthesis, and synthesis informs medicinal chemistry.

聚酮化合物在人类医学中的使用频率比任何其他类别的次要 代谢物，约占最畅销的小分子药物的20％。尽管他们 重要性：（a）人类医学中使用的所有聚酮化合物均来自土壤细菌，是 通过发酵或半合成（尽管有艾伯蛋白）制备，（b）<5％的土壤细菌 有许多天性的培养物具有培养物，并且有少数细菌可正常 培养表达<10％的生物合成基因，（c），尽管海洋聚酮化合物具有 惊人的生物活动，涉及海洋的商业发酵过程 细菌（通常是共生体）仍然非常罕见。从头化学 合成可能会进入其他无法接近的聚酮化合物及其同类物 当前的合成方法通常无法通过足够简洁的路线进行大规模生产。 为了克服这一挑战，我们的实验室开创了一个广阔的新催化家庭 低酒精至上醇的直接立体和现场选择性转化的方法。 正如许多总合成所记录的那样，这些方法简化了聚酮化合物的结构， 允许目标化合物以比以前更少的步骤制备 可能的。 在拟议的资金期间，提出了3个具体目标：（a）I型的总合成 Polyketides Neaumycin B和Gladiolin将使用我们的催化方法进行。 Neaumycin b 是U87人胶质母细胞瘤的femtomall抑制剂。 Gladiolin展示有力的选择性活动 针对对前线抗生素异念珠菌具有抗性的结核分枝杆菌菌株和 利福平。 （b）II型聚酮化合物抗生素甲霉素G，H和J，Arenimycin A和 使用我们的催化方法制备病毒蛋白毒素的类似物。抗菌 这些化合物的特性将与巴里·威尔金森教授合作评估 和让·凯梅尔斯基教授。 （c）与聚酮化合物有关的钌催化反应 将开发构建（烯丙基化，crotylation，propargy等）。这些优化 Kuo-Wei Huang教授进行的计算研究将协助方法。因此， 我们的研究推进了一项综合计划，方法论创新为此提供了信息 合成和合成为药物化学提供了信息。