N-(3-chloro-4-fluorophenyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide | 1346113-84-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: N-(3-chloro-4-fluorophenyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide
• 英文别名: NCGC00188799；PKM2 activator 3；N-(3-chloro-4-fluorophenyl)-7-fluoro-2-oxo-3,4-dihydro-1H-quinoline-6-sulfonamide
• CAS: 1346113-84-5
• 化学式: C₁₅H₁₁ClF₂N₂O₃S
• 分子量: 372.78
• InChiKey: VLIHQHQPGAWJCM-UHFFFAOYSA-N

物化性质

• 密度：
  1.564±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO: 100mg/mL, clear, colorless

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  83.6
• 氢给体数：
  2
• 氢受体数：
  6

制备方法与用途

PKM2激活剂3是一种有效的活化剂，其AC50值为90 nM。该激活剂表现出良好的Caco-2渗透性、低外排率以及高微粒体稳定性。因此，它可用于抗癌研究[1]。（注：AC50是指能使酶活性达到50%的浓度。）

反应信息

• 作为反应物：
  描述：

  L-氨基丙醇 、 N-(3-chloro-4-fluorophenyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide 在 三乙胺 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 4.0h， 生成 (S)-N-(3-chloro-4-fluorophenyl)-7-(1-hydroxypropan-2-ylamino)-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide
  参考文献：
  名称：

  2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase

  摘要：

  Compared to normal differentiated cells, cancer cells have altered metabolic regulation to support biosynthesis and the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this anabolic metabolism. While the M1 isoform is a highly active enzyme, the alternatively spliced M2 variant is considerably less active and expressed in tumors. While the exact mechanism by which decreased pyruvate kinase activity contributes to anabolic metabolism remains unclear, it is hypothesized that activation of PKM2 to levels seen with PKM1 may promote a metabolic program that is not conducive to cell proliferation. Here we report the third chemotype in a series of PKM2 activators based on the 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamide scaffold. The synthesis, structure activity relationships, selectivity and notable physiochemical properties are described. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2011.08.114
• 作为产物：
  描述：

  3-氯-4-氟苯胺 、 7-Fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonyl chloride 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 N-(3-chloro-4-fluorophenyl)-7-fluoro-2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamide
  参考文献：
  名称：

  2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase

  摘要：

  Compared to normal differentiated cells, cancer cells have altered metabolic regulation to support biosynthesis and the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this anabolic metabolism. While the M1 isoform is a highly active enzyme, the alternatively spliced M2 variant is considerably less active and expressed in tumors. While the exact mechanism by which decreased pyruvate kinase activity contributes to anabolic metabolism remains unclear, it is hypothesized that activation of PKM2 to levels seen with PKM1 may promote a metabolic program that is not conducive to cell proliferation. Here we report the third chemotype in a series of PKM2 activators based on the 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamide scaffold. The synthesis, structure activity relationships, selectivity and notable physiochemical properties are described. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2011.08.114

文献信息

• PKM2 ACTIVATORS IN COMBINATION WITH REACTIVE OXYGEN SPECIES FOR TREATMENT OF CANCER
  申请人：TOLERO PHARMACEUTICALS, INC.

  公开号：US20200237766A1

  公开（公告）日：2020-07-30

  Combination therapies for treatment of cancer are provided. The disclosed methods comprise administration of a PKM2 activator and an anti-cancer drug having a mechanism of action that increases production of reactive oxygen species in cancer cells to a patient in need thereof.
• [EN] PKM2 ACTIVATORS IN COMBINATION WITH REACTIVE OXYGEN SPECIES FOR TREATMENT OF CANCER<br/>[FR] ACTIVATEURS DE PKM2 EN COMBINAISON AVEC DES ESPÈCES RÉACTIVES DE L'OXYGÈNE POUR LE TRAITEMENT DU CANCER
  申请人：TOLERO PHARMACEUTICALS INC

  公开号：WO2019075367A1

  公开（公告）日：2019-04-18

  Combination therapies for treatment of cancer are provided. The disclosed methods comprise administration of a PKM2 activator and an anti-cancer drug having a mechanism of action that increases production of reactive oxygen species in cancer cells to a patient in need thereof.
• 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase
  作者：Martin J. Walsh、Kyle R. Brimacombe、Henrike Veith、James M. Bougie、Thomas Daniel、William Leister、Lewis C. Cantley、William J. Israelsen、Matthew G. Vander Heiden、Min Shen、Douglas S. Auld、Craig J. Thomas、Matthew B. Boxer

  DOI：10.1016/j.bmcl.2011.08.114

  日期：2011.11

  Compared to normal differentiated cells, cancer cells have altered metabolic regulation to support biosynthesis and the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this anabolic metabolism. While the M1 isoform is a highly active enzyme, the alternatively spliced M2 variant is considerably less active and expressed in tumors. While the exact mechanism by which decreased pyruvate kinase activity contributes to anabolic metabolism remains unclear, it is hypothesized that activation of PKM2 to levels seen with PKM1 may promote a metabolic program that is not conducive to cell proliferation. Here we report the third chemotype in a series of PKM2 activators based on the 2-oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamide scaffold. The synthesis, structure activity relationships, selectivity and notable physiochemical properties are described. Published by Elsevier Ltd.