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.

聚酮类化合物在人类医学中的使用频率比其他任何一类次要物质都要高。 代谢物，约占最畅销小分子药物的20%。尽管他们 要点：(A)人类医药中使用的所有聚酮都来自土壤细菌，并且 通过发酵或半合成制成的(尽管有eribuin)，(B)&lt；5%的土壤细菌 都能适应培养，许多门都逃过了培养，少数几种细菌能适应培养 培养表达10%的生物合成基因，(C)尽管海洋多酮具有 惊人的生物活性，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。从头开始化学 合成可能提供了进入原本难以获得的聚酮及其同系物的途径，但 目前的合成方法往往不能提供足够简明的路线来进行大规模生产。 为了克服这一挑战，我们的实验室开创了一系列广泛的新催化剂 低级醇直接立体选择性转化为高级醇的方法。 正如在许多全合成中所记载的那样，这些方法简化了聚酮结构， 使得目标化合物的制备步骤比以前少得多 有可能。 在拟议的供资期间，提出了3个具体目标：(A)第一类合成的全部 我们将使用催化方法来寻找聚酮类化合物新霉素B和剑兰脂素。新霉素B 是一种U87人胶质母细胞瘤的Femtomolal抑制物。葛兰素林显示出强大的选择性活性 抗结核分枝杆菌对一线抗生素异烟肼和 利福平。(B)第二类多酮类抗生素福美霉素G、H和J、阿伦霉素A和 我们将使用我们的催化方法来制备弧菌毒素的类似物。抗菌药物 这些化合物的性质将与巴里·威尔金森教授合作进行评估。 和Jean Chmielewski教授。(C)与聚酮有关的Ru催化反应 构筑(烯丙化、巴豆化、丙烯酰化等)将会被开发出来。这些方面的优化 方法将得到黄国伟教授进行的计算研究的辅助。因此， 我们的研究推进了一个综合计划，在这个计划中，方法创新为 合成，合成告诉我们药物化学。