5-O-tert-butyl 3a-O-ethyl (3S,3aS)-1-[(2,4-dichlorophenyl)methyl]-3-[2-(3-methoxypropylamino)-2-oxoethyl]-2-oxo-4,6-dihydro-3H-pyrrolo[3,2-c]pyridine-3a,5-dicarboxylate | 1353275-41-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 英文名称: 5-O-tert-butyl 3a-O-ethyl (3S,3aS)-1-[(2,4-dichlorophenyl)methyl]-3-[2-(3-methoxypropylamino)-2-oxoethyl]-2-oxo-4,6-dihydro-3H-pyrrolo[3,2-c]pyridine-3a,5-dicarboxylate
• CAS: 1353275-41-8
• 化学式: C₂₈H₃₇Cl₂N₃O₇
• 分子量: 598.524
• InChiKey: PNBKYONNSAJSCD-PIIWDFAUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  40
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  115
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  5-O-tert-butyl 3a-O-ethyl (3S,3aS)-1-[(2,4-dichlorophenyl)methyl]-3-[2-(2,5-dioxopyrrolidin-1-yl)oxy-2-oxoethyl]-2-oxo-4,6-dihydro-3H-pyrrolo[3,2-c]pyridine-3a,5-dicarboxylate 、 3-甲氧基丙胺 以 二氯甲烷 为溶剂， 生成 5-O-tert-butyl 3a-O-ethyl (3S,3aS)-1-[(2,4-dichlorophenyl)methyl]-3-[2-(3-methoxypropylamino)-2-oxoethyl]-2-oxo-4,6-dihydro-3H-pyrrolo[3,2-c]pyridine-3a,5-dicarboxylate
  参考文献：
  名称：

  A Pairwise Chemical Genetic Screen Identifies New Inhibitors of Glucose Transport

  摘要：

  Oxidative phosphorylation (OXPHOS) and glycolysis are the two main pathways that control energy metabolism of a cell. The Warburg effect, in which glycolysis remains active even under aerobic conditions, is considered a key driver for cancer cell proliferation, malignancy, metastasis, and therapeutic resistance. To target aerobic glycolysis, we exploited the complementary roles of OXPHOS and glycolysis in ATP synthesis as the basis for a chemical genetic screen, enabling rapid identification of novel small-molecule inhibitors of facilitative glucose transport. Blocking mitochondrial electron transport with antimycin A or leucascandrolide A had little effect on highly glycolytic A549 lung carcinoma cells, but adding known glycolytic inhibitors 2-deoxy-D-glucose, iodoacetate or cytochalasin B, rapidly depleted intracellular ATP, displaying chemical synthetic lethality. Based on this principle, we exposed antimycin A-treated A549 cells to a newly synthesized 955 member diverse scaffold small-molecule library, screening for compounds that rapidly depleted ATP levels. Two compounds potently suppressed ATP synthesis, induced G1 cell-cycle arrest and inhibited lactate production. Pathway analysis revealed that these novel probes inhibited GLUT family of facilitative transmembrane transporters but, unlike cytochalasin B, had no effect on the actin cytoskeleton. Our work illustrated the utility of a pairwise chemical genetic screen for discovery of novel chemical probes, which would be useful not only to study the system-level organization of energy metabolism but could also facilitate development of drugs targeting upregulation of aerobic glycolysis in cancer.

  DOI：

  10.1016/j.chembiol.2010.12.015

文献信息

• METHOD FOR ASSEMBLING HIGH-PURITY CHEMICAL LIBRARIES, COMPOUNDS SUPPRESSING ACETYL COENZYME A CARBOXYLASE ACTIVITIES DISCOVERED BY SAME
  申请人：Kozmin Sergey A.

  公开号：US20100035892A1

  公开（公告）日：2010-02-11

  The present disclosure provides novel compounds of the formula (I): wherein R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined in the detailed description. Two preferred compounds of formulae (IX) and (X) are disclosed.
• US8445481B2
  申请人：——

  公开号：US8445481B2

  公开（公告）日：2013-05-21
• A Pairwise Chemical Genetic Screen Identifies New Inhibitors of Glucose Transport
  作者：Olesya A. Ulanovskaya、Jiayue Cui、Stephen J. Kron、Sergey A. Kozmin

  DOI：10.1016/j.chembiol.2010.12.015

  日期：2011.2

  Oxidative phosphorylation (OXPHOS) and glycolysis are the two main pathways that control energy metabolism of a cell. The Warburg effect, in which glycolysis remains active even under aerobic conditions, is considered a key driver for cancer cell proliferation, malignancy, metastasis, and therapeutic resistance. To target aerobic glycolysis, we exploited the complementary roles of OXPHOS and glycolysis in ATP synthesis as the basis for a chemical genetic screen, enabling rapid identification of novel small-molecule inhibitors of facilitative glucose transport. Blocking mitochondrial electron transport with antimycin A or leucascandrolide A had little effect on highly glycolytic A549 lung carcinoma cells, but adding known glycolytic inhibitors 2-deoxy-D-glucose, iodoacetate or cytochalasin B, rapidly depleted intracellular ATP, displaying chemical synthetic lethality. Based on this principle, we exposed antimycin A-treated A549 cells to a newly synthesized 955 member diverse scaffold small-molecule library, screening for compounds that rapidly depleted ATP levels. Two compounds potently suppressed ATP synthesis, induced G1 cell-cycle arrest and inhibited lactate production. Pathway analysis revealed that these novel probes inhibited GLUT family of facilitative transmembrane transporters but, unlike cytochalasin B, had no effect on the actin cytoskeleton. Our work illustrated the utility of a pairwise chemical genetic screen for discovery of novel chemical probes, which would be useful not only to study the system-level organization of energy metabolism but could also facilitate development of drugs targeting upregulation of aerobic glycolysis in cancer.