dimethyl 2-(4-(4-((3-((2-methylbenzo[d]thiazol-6-yl)amino)-3-oxopropyl)amino)-4-oxobutyl)benzyl)malonate | 1391622-95-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: dimethyl 2-(4-(4-((3-((2-methylbenzo[d]thiazol-6-yl)amino)-3-oxopropyl)amino)-4-oxobutyl)benzyl)malonate
• 英文别名: dimethyl 2-(4-(4-(3-(2-methylbenzo[d]thiazol-6-ylamino)-3-oxopropylamino)-4-oxobutyl)benzyl)malonate；Dimethyl 2-[[4-[4-[[3-[(2-methyl-1,3-benzothiazol-6-yl)amino]-3-oxopropyl]amino]-4-oxobutyl]phenyl]methyl]propanedioate
• CAS: 1391622-95-9
• 化学式: C₂₇H₃₁N₃O₆S
• 分子量: 525.626
• InChiKey: DKWJDWAXWJNXJE-UHFFFAOYSA-N

物化性质

• 沸点：
  765.2±60.0 °C(Predicted)
• 密度：
  1.278±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  37
• 可旋转键数：
  14
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  152
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  dimethyl 2-(4-(4-((3-((2-methylbenzo[d]thiazol-6-yl)amino)-3-oxopropyl)amino)-4-oxobutyl)benzyl)malonate 在 lithium hydroxide monohydrate 、 盐酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 2.0h， 以83%的产率得到3-methoxy-2-(4-(4-((3-((2-methylbenzo[d]thiazol-6-yl)amino)-3-oxopropyl)amino)-4-oxobutyl)benzyl)-3-oxopropanoic acid
  参考文献：
  名称：

  Assessing the differential action on cancer cells of LDH-A inhibitors based on the N-hydroxyindole-2-carboxylate (NHI) and malonic (Mal) scaffolds

  摘要：

  对N-羟基吲哚-2-羧酸（NHI）和丙二酸衍生物（Mal）作为LDH-A抑制剂的典型实例进行了对比研究，比较了酶抑制效力、细胞摄取、癌细胞乳酸生成减少和抗增殖活性。在测试的化合物中，甲基1-羟基-6-苯基-4-(三氟甲基)-1H-吲哚-2-羧酸酯（2，NHI-2）是一种属于NHI类的甲基酯，在细胞试验中表现出最佳特性，证明是一种有效的抗糖酵解剂，可对抗癌细胞。

  DOI：

  10.1039/c3ob40870a
• 作为产物：
  描述：

  4-苯基丁酸 在 咪唑 、 lithium hydroxide monohydrate 、 硫酸 、 水 、 sodium 、 N,N'-羰基二咪唑 、 三氟乙酸 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 236.0h， 生成 dimethyl 2-(4-(4-((3-((2-methylbenzo[d]thiazol-6-yl)amino)-3-oxopropyl)amino)-4-oxobutyl)benzyl)malonate
  参考文献：
  名称：

  Design and Synthesis of Novel Lactate Dehydrogenase A Inhibitors by Fragment-Based Lead Generation

  摘要：

  Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.

  DOI：

  10.1021/jm201734r

文献信息

• Design and Synthesis of Novel Lactate Dehydrogenase A Inhibitors by Fragment-Based Lead Generation
  作者：Richard A. Ward、Claire Brassington、Alexander L. Breeze、Alessandro Caputo、Susan Critchlow、Gareth Davies、Louise Goodwin、Giles Hassall、Ryan Greenwood、Geoffrey A. Holdgate、Michael Mrosek、Richard A. Norman、Stuart Pearson、Jonathan Tart、Julie A. Tucker、Martin Vogtherr、David Whittaker、Jonathan Wingfield、Jon Winter、Kevin Hudson

  DOI：10.1021/jm201734r

  日期：2012.4.12

  Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.
• Assessing the differential action on cancer cells of LDH-A inhibitors based on the N-hydroxyindole-2-carboxylate (NHI) and malonic (Mal) scaffolds
  作者：Carlotta Granchi、Emilia C. Calvaresi、Tiziano Tuccinardi、Ilaria Paterni、Marco Macchia、Adriano Martinelli、Paul J. Hergenrother、Filippo Minutolo

  DOI：10.1039/c3ob40870a

  日期：——

  A head-to-head study of representative examples of N-hydroxyindole-2-carboxylates (NHI) and malonic derivatives (Mal) as LDH-A inhibitors was conducted, comparing the enzyme inhibition potency, cellular uptake, reduction of lactate production in cancer cells and anti-proliferative activity. Among the compounds tested, methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (2, NHI-2), a methyl ester belonging to the NHI class, displayed optimal properties in the cell-based assays, proving to be an efficient anti-glycolytic agent against cancer cells.

  对N-羟基吲哚-2-羧酸（NHI）和丙二酸衍生物（Mal）作为LDH-A抑制剂的典型实例进行了对比研究，比较了酶抑制效力、细胞摄取、癌细胞乳酸生成减少和抗增殖活性。在测试的化合物中，甲基1-羟基-6-苯基-4-(三氟甲基)-1H-吲哚-2-羧酸酯（2，NHI-2）是一种属于NHI类的甲基酯，在细胞试验中表现出最佳特性，证明是一种有效的抗糖酵解剂，可对抗癌细胞。