isocitric acid | 30810-51-6

• 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: isocitric acid
• 英文别名: lactic acid；ICA；(+)-alloisocitric acid；L_r-1r_F-Hydroxy-propan-1cat_F,2c_F,3-tricarbonsaeure；(1S,2S)-1-Hydroxy-propan-1,2,3-tricarbonsaeure；(+)-Alloisocitronensaeure；D-erythro-Isocitric acid；(1S,2S)-1-hydroxypropane-1,2,3-tricarboxylic acid
• CAS: 30810-51-6
• 化学式: C₆H₈O₇
• 分子量: 192.125
• InChiKey: ODBLHEXUDAPZAU-OKKQSCSOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.8
• 重原子数：
  13
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  132
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  isocitric acid 在 wild type isocitrate hydrogenase 、 烟酰胺腺嘌呤双核苷酸磷酸盐 、 magnesium chloride 作用下， 以 aq. phosphate buffer 为溶剂， 生成 alpha-酮戊二酸
  参考文献：
  名称：

  Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds

  摘要：

  Somatic mutations of isocitrate dehydrogenase 1 (LDH1) at R132 are frequently found in certain cancers such as glioma. With losing the activity of wild-type IDH1, the R132H and R132C mutant proteins can reduce alpha-ketoglutaric acid (alpha-KG) to D-2-hydroxyglutaric acid (D2HG). The resulting high concentration of D2HG inhibits many alpha-KG-dependent dioxygenases, including histone demethylases, to cause broad histone hypermethylation. These aberrant epigenetic changes are responsible for the initiation of these cancers. We report the synthesis, structure activity relationships, enzyme kinetics, and binding thermodynamics of a novel series of 2-thiohydantoin and related compounds, among which several compounds are potent inhibitors of mutant IDH1 with K-i as low as 420 nM. X-ray crystal structures of IDH1(R132H) in complex with two inhibitors are reported, showing their inhibitor-protein interactions. These compounds can decrease the cellular concentration of D2HG, reduce the levels of histone methylation, and suppress the proliferation of stem-like cancer cells in BT142 glioma with IDH1 R132H mutation.

  DOI：

  10.1021/acs.jmedchem.5b00684
• 作为产物：
  描述：

  (+)-alloisocitric acid-lactone 在 sodium hydroxide 作用下， 生成 isocitric acid
  参考文献：
  名称：

  Studies on Diastereoisomeric α-Amino Acids and Corresponding α-Hydroxy Acids. I. Preparation of the Four Optical Isomers of α-Aminotricarballylic Acid and their Conversion to the Corresponding Isocitric Acid Lactones

  摘要：

  DOI：

  10.1021/ja01608a048

文献信息

• Studies on Diastereoisomeric α-Amino Acids and Corresponding α-Hydroxy Acids. VII. Influence of β-Configuration on Enzymic Susceptibility
  作者：Milton Winitz、Leah Bloch-Frankenthal、Nobuo Izumiya、Sanford M. Birnbaum、Carl G. Baker、Jesse P. Greenstein

  DOI：10.1021/ja01592a022

  日期：1956.6
• Beppu et al., Nippon Nogeikagaku Kaishi, 1958, vol. 32, p. 207,208
  作者：Beppu et al.

  DOI：——

  日期：——
• Sakaguchi; Beppu, Archives of Biochemistry, 1959, vol. 83, p. 131,132
  作者：Sakaguchi、Beppu

  DOI：——

  日期：——
• Studies on Diastereoisomeric α-Amino Acids and Corresponding α-Hydroxy Acids. I. Preparation of the Four Optical Isomers of α-Aminotricarballylic Acid and their Conversion to the Corresponding Isocitric Acid Lactones
  作者：Jesse P. Greenstein、Nobuo Izumiya、Milton Winitz、Sanford M. Birnbaum

  DOI：10.1021/ja01608a048

  日期：1955.2.1
• Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds
  作者：Fangrui Wu、Hong Jiang、Baisong Zheng、Mari Kogiso、Yuan Yao、Chao Zhou、Xiao-Nan Li、Yongcheng Song

  DOI：10.1021/acs.jmedchem.5b00684

  日期：2015.9.10

  Somatic mutations of isocitrate dehydrogenase 1 (LDH1) at R132 are frequently found in certain cancers such as glioma. With losing the activity of wild-type IDH1, the R132H and R132C mutant proteins can reduce alpha-ketoglutaric acid (alpha-KG) to D-2-hydroxyglutaric acid (D2HG). The resulting high concentration of D2HG inhibits many alpha-KG-dependent dioxygenases, including histone demethylases, to cause broad histone hypermethylation. These aberrant epigenetic changes are responsible for the initiation of these cancers. We report the synthesis, structure activity relationships, enzyme kinetics, and binding thermodynamics of a novel series of 2-thiohydantoin and related compounds, among which several compounds are potent inhibitors of mutant IDH1 with K-i as low as 420 nM. X-ray crystal structures of IDH1(R132H) in complex with two inhibitors are reported, showing their inhibitor-protein interactions. These compounds can decrease the cellular concentration of D2HG, reduce the levels of histone methylation, and suppress the proliferation of stem-like cancer cells in BT142 glioma with IDH1 R132H mutation.