1-羟基-6-苯基-4-(三氟甲基)-1H-吲哚-2-羧酸甲酯 | 1269802-97-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: 1-羟基-6-苯基-4-(三氟甲基)-1H-吲哚-2-羧酸甲酯
• 英文名称: methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate
• 英文别名: NHI-2；methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)indole-2-carboxylate
• CAS: 1269802-97-2
• 化学式: C₁₇H₁₂F₃NO₃
• 分子量: 335.282
• InChiKey: YPPFWRWCZNXINO-UHFFFAOYSA-N

物化性质

• 沸点：
  495.7±55.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Predicted)
• 溶解度：
  溶于 DMSO（高达 25 mg/ml）。

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  51.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-羟基-6-苯基-4-(三氟甲基)-1H-吲哚-2-羧酸甲酯 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 以94%的产率得到1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indol-2-carboxylic acid
  参考文献：
  名称：

  Discovery of N-Hydroxyindole-Based Inhibitors of Human Lactate Dehydrogenase Isoform A (LDH-A) as Starvation Agents against Cancer Cells

  摘要：

  Highly invasive tumor cells are characterized by a metabolic switch, known as the Warburg effect, from "normal" oxidative phosphorylation to increased glycolysis even under. sufficiently oxygenated conditions. This dependence on glycolysis also confers a growth advantage to cells present in hypoxic regions of the tumor. One of the key enzymes involved in glycolysis, the muscle isoform of lactate dehydrogenase (LDH-A), is overexpressed by metastatic cancer cells and is linked to the vitality of tumors in hypoxia. This enzyme may be considered as a potential target for new anticancer agents, since its inhibition cuts cancer energetic and anabolic supply, thus reducing the metastatic and invasive potential of cancer cells. We have discovered new and efficient N-hydroxyindole-based inhibitors of LDH-A, which are isoform-selective (over LDH-B) and competitive with both the substrate (pyruvate) and the cofactor (NADH). The antiproliferative activity of these compounds was confirmed on a series of cancer cell lines, and they proved to be particularly effective under hypoxic conditions. Moreover, NMR experiments showed that these compounds are able to reduce the glucose-to-lactate conversion inside the cell.

  DOI：

  10.1021/jm101007q
• 作为产物：
  描述：

  5-iodo-2-methyl-1-nitro-3-(trifluoromethyl)benzene 在 tin(II) chloride dihdyrate 、 potassium tert-butylate 、 四丁基溴化铵 、 palladium diacetate 、 sodium carbonate 作用下， 以 甲醇 、 乙二醇二甲醚 、 乙醚 、 水 为溶剂， 反应 0.33h， 生成 1-羟基-6-苯基-4-(三氟甲基)-1H-吲哚-2-羧酸甲酯
  参考文献：
  名称：

  Discovery of N-Hydroxyindole-Based Inhibitors of Human Lactate Dehydrogenase Isoform A (LDH-A) as Starvation Agents against Cancer Cells

  摘要：

  Highly invasive tumor cells are characterized by a metabolic switch, known as the Warburg effect, from "normal" oxidative phosphorylation to increased glycolysis even under. sufficiently oxygenated conditions. This dependence on glycolysis also confers a growth advantage to cells present in hypoxic regions of the tumor. One of the key enzymes involved in glycolysis, the muscle isoform of lactate dehydrogenase (LDH-A), is overexpressed by metastatic cancer cells and is linked to the vitality of tumors in hypoxia. This enzyme may be considered as a potential target for new anticancer agents, since its inhibition cuts cancer energetic and anabolic supply, thus reducing the metastatic and invasive potential of cancer cells. We have discovered new and efficient N-hydroxyindole-based inhibitors of LDH-A, which are isoform-selective (over LDH-B) and competitive with both the substrate (pyruvate) and the cofactor (NADH). The antiproliferative activity of these compounds was confirmed on a series of cancer cell lines, and they proved to be particularly effective under hypoxic conditions. Moreover, NMR experiments showed that these compounds are able to reduce the glucose-to-lactate conversion inside the cell.

  DOI：

  10.1021/jm101007q

文献信息

• [EN] INDOLE DERIVATIVES INHIBITORS OF ENZYME LACTATE DEHYDROGENASE (LDH)<br/>[FR] INHIBITEURS DE DÉRIVÉS D'INDOLE DE L'ENZYME LACTATE DÉHYDROGÉNASE (LDH)
  申请人：UNIV PISA

  公开号：WO2013092753A1

  公开（公告）日：2013-06-27

  The present invention encompasses compounds having general formula (I) able to inhibit the lactate production (lactic acid) involved in the angiogenesis of tumoral tissues, in the glycolytic metabolic process of tumoral cells, of immune system cells in asthmatic diseases, in vascular cells in the pulmonary hypertension, in the treatment of chronic back pain or hyperoxaluria, and in the process by which the parasites protozoan causing malaria obtain most of the necessary energy

  本发明涵盖了具有一般式（I）的化合物，能够抑制与肿瘤组织血管生成中涉及的乳酸产生（乳酸）有关的过程，抑制肿瘤细胞的糖酵解代谢过程，抑制哮喘疾病中免疫系统细胞的过程，抑制肺动脉高压中血管细胞的过程，用于治疗慢性背痛或高草酸尿症，并抑制引起疟疾的原虫寄生虫获得大部分必要能量的过程。
• Synthesis and Biological Evaluation of New Glycoconjugated LDH Inhibitors as Anticancer Agents
  作者：Felicia D’Andrea、Giulia Vagelli、Carlotta Granchi、Lorenzo Guazzelli、Tiziano Tuccinardi、Giulio Poli、Dalila Iacopini、Filippo Minutolo、Valeria Di Bussolo

  DOI：10.3390/molecules24193520

  日期：——

  of d-galacto, d-manno, d-gluco, and d-lactose glycoconjugates of an established N-hydroxyindole-based (NHI) inhibitor of lactated dehydrogenase (LDH). Structural variations involved the sugar stereochemistry and size as well as the anchoring point of the NHI on the carbohydrate frame (either C-1 or C-6). In the case of the galactose anomeric glycoconjugate (C-1), intriguing solvent-dependent effects

  将已知的生物活性分子与碳水化合物框架结合代表了制备杂合的、结构相关的化合物家族的一个有价值的选择，目的是调节它们的生物反应。因此，我们在此提出了一项关于制备已建立的 N-羟基吲哚基 (NHI) 乳酸脱氢酶 (LDH) 抑制剂的 d-半乳糖、d-甘露糖、d-葡萄糖和 d-乳糖糖缀合物的研究。结构变化涉及糖的立体化学和大小以及 NHI 在碳水化合物框架上的锚定点（C-1 或 C-6）。就半乳糖异头糖复合物 (C-1) 而言，在糖基化立体化学结果中观察到了有趣的溶剂依赖性效应。描述了去保护的糖缀合物在对比乳酸形成和癌细胞增殖方面的生物活性。
• Synthesis and biological evaluation of non-glucose glycoconjugated N-hydroyxindole class LDH inhibitors as anticancer agents
  作者：Valeria Di Bussolo、Emilia C. Calvaresi、Carlotta Granchi、Linda Del Bino、Ileana Frau、Maria Chiara Dasso Lang、Tiziano Tuccinardi、Marco Macchia、Adriano Martinelli、Paul J. Hergenrother、Filippo Minutolo

  DOI：10.1039/c5ra00946d

  日期：——

  Conjugation ofN-hydroxyindole (NHI)-based LDH inhibitors to monosaccharide portions reveals that, among this series, α-d-mannose-NHI conjugate possesses the best properties in cancer cellular assays in terms of both antiglycolytic and antiproliferative activity.

  使用N-羟基吲哚（NHI）为基础的LDH抑制剂与单糖部分的共轭反应表明，在该系列中，α-D-甘露糖-NHI共轭物在抗糖酵解和抗增殖活性方面在癌细胞实验中具有最佳性能。
• Pancreatic cancer therapy and diagnosis
  申请人：Deutsches Krebsforschungszentrum Stiftung des Öffentlichen Rechts

  公开号：US10874685B2

  公开（公告）日：2020-12-29

  The present disclosure provides a novel method for treating pancreatic cancer and pancreatitis in which a combination of a dopamine receptor antagonist (pimozide, haloperidol, and/or L-741,626), 2-deoxy-D-glucose and atorvastatin are used, optionally in combination with gemcitabine.

  本公开提供了一种治疗胰腺癌和胰腺炎的新方法，其中使用多巴胺受体拮抗剂（匹莫齐特、氟哌啶醇和/或 L-741,626）、2-脱氧-D-葡萄糖和阿托伐他汀的组合，可选择与吉西他滨联合使用。
• Discovery of <i>N</i>-Hydroxyindole-Based Inhibitors of Human Lactate Dehydrogenase Isoform A (LDH-A) as Starvation Agents against Cancer Cells
  作者：Carlotta Granchi、Sarabindu Roy、Chiara Giacomelli、Marco Macchia、Tiziano Tuccinardi、Adriano Martinelli、Mario Lanza、Laura Betti、Gino Giannaccini、Antonio Lucacchini、Nicola Funel、Leticia G. León、Elisa Giovannetti、Godefridus J. Peters、Rahul Palchaudhuri、Emilia C. Calvaresi、Paul J. Hergenrother、Filippo Minutolo

  DOI：10.1021/jm101007q

  日期：2011.3.24

  Highly invasive tumor cells are characterized by a metabolic switch, known as the Warburg effect, from "normal" oxidative phosphorylation to increased glycolysis even under. sufficiently oxygenated conditions. This dependence on glycolysis also confers a growth advantage to cells present in hypoxic regions of the tumor. One of the key enzymes involved in glycolysis, the muscle isoform of lactate dehydrogenase (LDH-A), is overexpressed by metastatic cancer cells and is linked to the vitality of tumors in hypoxia. This enzyme may be considered as a potential target for new anticancer agents, since its inhibition cuts cancer energetic and anabolic supply, thus reducing the metastatic and invasive potential of cancer cells. We have discovered new and efficient N-hydroxyindole-based inhibitors of LDH-A, which are isoform-selective (over LDH-B) and competitive with both the substrate (pyruvate) and the cofactor (NADH). The antiproliferative activity of these compounds was confirmed on a series of cancer cell lines, and they proved to be particularly effective under hypoxic conditions. Moreover, NMR experiments showed that these compounds are able to reduce the glucose-to-lactate conversion inside the cell.