1-monooctyl α-ketoglutarate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 酮酸及其衍生物
• 英文名称: 1-monooctyl α-ketoglutarate
• 英文别名: octyl α-ketoglutarate；octyl-α-ketoglutarate；octyl-α-KG；2-oxo-pentanedioic acid 1-octyl ester；2-Oxopentanedioic acid 1-octyl ester；5-octoxy-4,5-dioxopentanoic acid
• 化学式: C₁₃H₂₂O₅
• 分子量: 258.315
• InChiKey: QNFIHKFBQFJVKV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  18
• 可旋转键数：
  12
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  80.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  环丁烷甲酸乙酯 在 4-二甲氨基吡啶 、 sodium chlorite 、 sodium dihydrogenphosphate 、 N-溴代丁二酰亚胺(NBS) 、 2-甲基-2-丁烯 、 偶氮二异丁腈 、 臭氧 、 N,N'-二环己基碳二亚胺 、 potassium hydroxide 作用下， 以 四氯化碳 、 二氯甲烷 、 水 、 甲苯 、 叔丁醇 为溶剂， 反应 17.0h， 生成 1-monooctyl α-ketoglutarate
  参考文献：
  名称：

  Synthesis of the 1-Monoester of 2-Ketoalkanedioic Acids, for Example, Octyl α-Ketoglutarate

  摘要：

  Oxidative cleavage of cycloalkene-1-carboxylates, made from the corresponding carboxylic acids, and subsequent oxidation of the resulting ketoaldehyde afforded the important 1-monoesters of 2-ketoalkanedioic acids. Thus ozonolysis of octyl cyclobutene-1-carboxylate followed by sodium chlorite oxidation afforded the 1-monooctyl 2-ketoglutarate. This is a cell-permeable prodrug form of alpha-ketoglutarate, an important intermediate in the tricarboxylic acid (TCA, Krebs) cycle and a promising therapeutic agent in its own right.

  DOI：

  10.1021/jo302308q

文献信息

• The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR
  作者：Randall M. Chin、Xudong Fu、Melody Y. Pai、Laurent Vergnes、Heejun Hwang、Gang Deng、Simon Diep、Brett Lomenick、Vijaykumar S. Meli、Gabriela C. Monsalve、Eileen Hu、Stephen A. Whelan、Jennifer X. Wang、Gwanghyun Jung、Gregory M. Solis、Farbod Fazlollahi、Chitrada Kaweeteerawat、Austin Quach、Mahta Nili、Abby S. Krall、Hilary A. Godwin、Helena R. Chang、Kym F. Faull、Feng Guo、Meisheng Jiang、Sunia A. Trauger、Alan Saghatelian、Daniel Braas、Heather R. Christofk、Catherine F. Clarke、Michael A. Teitell、Michael Petrascheck、Karen Reue、Michael E. Jung、Alison R. Frand、Jing Huang

  DOI：10.1038/nature13264

  日期：2014.6

  Ageing in the worm Caenorhabditis elegans is shown to be delayed by supplementation with α-ketoglutarate, an effect that is probably mediated by ATP synthase—which is identified as a direct target of α-ketoglutarate—and target of rapamycin (TOR). Calorie restriction can extend lifespan and delay age-related deterioration in a range of organisms. A few small-molecule metabolites have been shown to regulate the ageing process, but little is known about the mechanisms involved. Here Jing Huang and colleagues report that the tricarboxylic acid cycle intermediate α-ketoglutarate (α-KG) extends the lifespan of adult Caenorhabditis elegans roundworms by approximately 50%. The molecular target of α-KG is the β subunit of ATPase. α-KG is dependent on the TOR (target of rapamycin) pathway and it does not extend the lifespan of dietary-restricted animals, suggesting a link between the effects of α-KG and starvation/dietary restriction. Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms1,2. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits3,4. Recently, several metabolites have been identified that modulate ageing5,6; however, the molecular mechanisms underlying this are largely undefined. Here we show that α-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit β is identified as a novel binding protein of α-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS)7. The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution8,9. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan10,11,12,13. We show that α-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by α-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by α-KG requires ATP synthase subunit β and is dependent on target of rapamycin (TOR) downstream. Endogenous α-KG levels are increased on starvation and α-KG does not extend the lifespan of dietary-restricted animals, indicating that α-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.

  研究表明，补充δ-酮戊二酸可以延缓草履虫的衰老，这种作用可能是通过ATP合成酶和雷帕霉素靶标（TOR）产生的。限制热量摄入可以延长一系列生物的寿命，延缓与年龄相关的衰退。一些小分子代谢物已被证明能调节衰老过程，但人们对其中的机制知之甚少。黄晶及其同事在此报告说，三羧酸循环中间体δ-酮戊二酸（δ-KG）可使成年草履虫蛔虫的寿命延长约 50%。δ-KG的分子靶标是ATP酶的δ²亚基。δ-KG依赖于TOR（雷帕霉素靶标）途径，它不会延长饮食限制动物的寿命，这表明δ-KG的作用与饥饿/饮食限制之间存在联系。新陈代谢与衰老密切相关。在进化过程中，与自由摄食相比，饮食限制能持续延长生物的寿命并延缓与年龄相关的疾病1,2。类似的营养素限制条件和遗传或药物对营养素或能量代谢的扰动也有延年益寿的作用3,4。最近，人们发现了几种可调节衰老的代谢物5,6；然而，其分子机制在很大程度上尚未明确。在这里，我们发现三羧酸循环中间体δ-酮戊二酸（δ-KG）可延长成年秀丽隐杆线虫的寿命。ATP 合成酶亚基δ² 被确定为δ-KG 的新型结合蛋白，其采用的小分子靶标鉴定策略被称为药物亲和力反应靶标稳定性（DARTS）7。 ATP 合成酶又称线粒体电子传递链的复合体 V，是细胞的主要能量生成机制，在整个进化过程中高度保守8,9。虽然完全丧失线粒体功能是有害的，但部分抑制电子传递链已被证明能延长秀丽隐杆线虫的寿命10,11,12,13。我们发现δ-KG 可抑制 ATP 合成酶，与 ATP 合成酶敲除类似，δ-KG 的抑制作用可导致线虫和哺乳动物细胞中 ATP 含量降低、耗氧量减少以及自噬增加。我们提供的证据表明，δ-KG 延长寿命需要 ATP 合成酶亚基δ²，并依赖于下游的雷帕霉素靶标（TOR）。饥饿时内源性δ-KG水平升高，而δ-KG不能延长限食动物的寿命，这表明δ-KG是通过限食介导长寿的关键代谢物。我们的分析发现了一种常见的代谢物、一种普遍的细胞能量发生器和饮食限制在调节生物体寿命方面的新的分子联系，从而为预防和治疗衰老和与年龄相关的疾病提出了新的策略。
• [EN] ALPHA-KETOGLUTARATES AND THEIR USE AS THERAPEUTIC AGENTS<br/>[FR] ALPHA-KÉTOGLUTARATES ET LEUR UTILISATION EN TANT QU'AGENTS THÉRAPEUTIQUES
  申请人：CANCER REC TECH LTD

  公开号：WO2006016143A1

  公开（公告）日：2006-02-16

  The present invention relates generally to the field of pharmaceuticals and medicine. More particularly, the present invention relates to certain compounds (e.g., α-ketoglutarate compounds; compounds that activate HIFα hydroxylase; compounds that increases the level of α ketoglutarate, etc.) and their use in medicine, for example, in the treatment of cancer (e.g., cancer in which the activity of one of the enzymes in the tricarboxylic acid (TCA) cycle is down regulated), in the treatment of angiogenesis (e.g., hypoxia-induced angiogenesis). One preferred class of compounds are α-ketoglutarate compounds having a hydrophobic moiety that is, or is part of, an ester group formed from one of the acid groups of α ketogluartic acid; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, N oxides, chemically protected forms, and prodrugs thereof.

  本发明涉及制药和医学领域，更具体地涉及某些化合物（例如α-酮戊二酸化合物；激活HIFα羟化酶的化合物；增加α-酮戊二酸水平的化合物等）及其在医学中的应用，例如用于癌症治疗（例如TCA循环中的一种酶活性下调的癌症），用于血管生成（例如缺氧诱导的血管生成）。其中一种优选的化合物类别是具有亲水性基团的α-酮戊二酸化合物，该亲水性基团是α-酮戊二酸中的酸基之一形成的酯基，以及其药用可接受的盐、溶剂化合物、酰胺、酯、醚、N-氧化物、化学保护形式和前药。
• Alpha-Ketoglutarates and Their Use as Therapeutic Agents
  申请人：Gottlieb Eyal

  公开号：US20090005437A1

  公开（公告）日：2009-01-01

  The present invention relates generally to the field of pharmaceuticals and medicine. More particularly, the present invention relates to certain compounds (e.g., α-ketoglutarate compounds; compounds that activate HIFα hydroxylase; compounds that increases the level of α-ketoglutarate, etc.) and their use in medicine, for example, in the treatment of cancer (e.g., cancer in which the activity of one of the enzymes in the tricarboxylic acid (TCA) cycle is down regulated), in the treatment of angiogenesis (e.g., hypoxia-induced angiogenesis). One preferred class of compounds are α-ketoglutarate compounds having a hydrophobic moiety that is, or is part of, an ester group formed from one of the acid groups of α-ketogluartic acid; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, N-oxides, chemically protected forms, and prodrugs thereof.

  本发明一般涉及制药和医学领域。更具体地说，本发明涉及某些化合物（例如α-酮戊二酸化合物；激活HIFα羟化酶的化合物；增加α-酮戊二酸水平的化合物等）及其在医学上的应用，例如治疗癌症（例如三羧酸循环中的酶活性被下调的癌症），治疗血管生成（例如缺氧诱导的血管生成）。一种首选的化合物类别是具有亲水性基团的α-酮戊二酸化合物，该亲水性基团是α-酮戊二酸的酸基之一形成的酯基或其一部分；以及其药学上可接受的盐、溶剂化物、酰胺、酯、醚、N-氧化物、化学保护形式和其前药。
• ALPHA-KETOGLUTARATES AND THEIR USE AS THERAPEUTIC AGENTS
  申请人：Cancer Research Technology Limited

  公开号：EP1778616A1

  公开（公告）日：2007-05-02
• PROCESS OF MAKING CALCIUM ALPHA-KETOGLUTARATE
  申请人：Ponce de Leon Health Designated Activity Company

  公开号：EP3856166A1

  公开（公告）日：2021-08-04