5-(3-Bromo-2,6-dichlorophenyl)-2-(2-chlorophenyl)sulfanyl-3-hydroxycyclohex-2-en-1-one | 1642114-91-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-(3-Bromo-2,6-dichlorophenyl)-2-(2-chlorophenyl)sulfanyl-3-hydroxycyclohex-2-en-1-one
• 英文别名: 5-(3-bromo-2,6-dichlorophenyl)-2-(2-chlorophenyl)sulfanyl-3-hydroxycyclohex-2-en-1-one
• CAS: 1642114-91-7
• 化学式: C₁₈H₁₂BrCl₃O₂S
• 分子量: 478.621
• InChiKey: ZOOIILKVKCYCJZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  62.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-氨基四氢吡喃 、 5-(3-Bromo-2,6-dichlorophenyl)-2-(2-chlorophenyl)sulfanyl-3-hydroxycyclohex-2-en-1-one 在 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 sodium hydroxide 作用下， 以 甲苯 、 水 为溶剂， 反应 16.0h， 生成 2-(2-Chlorophenyl)sulfanyl-5-[2,6-dichloro-3-(oxan-4-ylamino)phenyl]-3-hydroxycyclohex-2-en-1-one
  参考文献：
  名称：

  Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase

  摘要：

  Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enone using structure-based design strategies resulted in inhibitors with considerable improvement in biochemical potency against human lactate dehydrogenase A (LDHA). These potent inhibitors were typically selective for LDHA over LDHB isoform (4-10 fold) and other structurally related malate dehydrogenases, MDH1 and MDH2 (>500 fold). An X-ray crystal structure of enzymatically most potent molecule bound to LDHA revealed two additional interactions associated with enhanced biochemical potency. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.11.008
• 作为产物：
  描述：

  在 哌啶 、 N-溴代丁二酰亚胺(NBS) 、 sodium methylate 作用下， 以 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 20.0h， 生成 5-(3-Bromo-2,6-dichlorophenyl)-2-(2-chlorophenyl)sulfanyl-3-hydroxycyclohex-2-en-1-one
  参考文献：
  名称：

  Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase

  摘要：

  A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50 = 1.7 mu M) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50 = 0.18 mu M). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure-activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F = 45%). (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.06.076

文献信息

• Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase
  作者：Sharada Labadie、Peter S. Dragovich、Jinhua Chen、Benjamin P. Fauber、Jason Boggs、Laura B. Corson、Charles Z. Ding、Charles Eigenbrot、HongXiu Ge、Qunh Ho、Kwong Wah Lai、Shuguang Ma、Shiva Malek、David Peterson、Hans E. Purkey、Kirk Robarge、Laurent Salphati、Steven Sideris、Mark Ultsch、Erica VanderPorten、BinQing Wei、Qing Xu、Ivana Yen、Qin Yue、Huihui Zhang、Xuying Zhang、Aihe Zhou

  DOI：10.1016/j.bmcl.2014.11.008

  日期：2015.1

  Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enone using structure-based design strategies resulted in inhibitors with considerable improvement in biochemical potency against human lactate dehydrogenase A (LDHA). These potent inhibitors were typically selective for LDHA over LDHB isoform (4-10 fold) and other structurally related malate dehydrogenases, MDH1 and MDH2 (>500 fold). An X-ray crystal structure of enzymatically most potent molecule bound to LDHA revealed two additional interactions associated with enhanced biochemical potency. (C) 2014 Elsevier Ltd. All rights reserved.
• Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase
  作者：Peter S. Dragovich、Benjamin P. Fauber、Jason Boggs、Jinhua Chen、Laura B. Corson、Charles Z. Ding、Charles Eigenbrot、HongXiu Ge、Anthony M. Giannetti、Thomas Hunsaker、Sharada Labadie、Chiho Li、Yichin Liu、Yingchun Liu、Shuguang Ma、Shiva Malek、David Peterson、Keith E. Pitts、Hans E. Purkey、Kirk Robarge、Laurent Salphati、Steve Sideris、Mark Ultsch、Erica VanderPorten、Jing Wang、BinQing Wei、Qing Xu、Ivana Yen、Qin Yue、Huihui Zhang、Xuying Zhang、Aihe Zhou

  DOI：10.1016/j.bmcl.2014.06.076

  日期：2014.8

  A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50 = 1.7 mu M) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50 = 0.18 mu M). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure-activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F = 45%). (C) 2014 Elsevier Ltd. All rights reserved.