tetraethyl 2-(3,5-di-tert-butylphenyl)ethenylidene-1,1-bisphosphonate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: tetraethyl 2-(3,5-di-tert-butylphenyl)ethenylidene-1,1-bisphosphonate
• 英文别名: 1-[2,2-Bis(diethoxyphosphoryl)ethenyl]-3,5-ditert-butylbenzene；1-[2,2-bis(diethoxyphosphoryl)ethenyl]-3,5-ditert-butylbenzene
• 化学式: C₂₄H₄₂O₆P₂
• 分子量: 488.541
• InChiKey: XVMWELNRLBAKPF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  32
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  71.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  亚甲基二磷酸四乙酯 、 3,5-双(叔丁基)苯甲醛 在 四氯化钛 、 N-甲基吗啉氧化物 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 以29%的产率得到tetraethyl 2-(3,5-di-tert-butylphenyl)ethenylidene-1,1-bisphosphonate
  参考文献：
  名称：

  Bisphosphonate esters interact with HMG-CoA reductase membrane domain to induce its degradation

  摘要：

  HMG-CoA reductase (HMGCR) is a rate-limiting enzyme in the cholesterol biosynthetic pathway, and its catalytic domain is the well-known target of cholesterol-lowering drugs, statins. HMGCR is subject to layers of negative feedback loops; excess cholesterol inhibits transcription of the gene, and lanosterols and oxysterols accelerate degradation of HMGCR. A class of synthetic small molecules, bisphosphonate esters exemplified by SR12813, has been known to induce accelerated degradation of HMGCR and reduce the serum cholesterol level. Although genetic and biochemical studies revealed that the accelerated degradation requires the membrane domain of HMGCR and Insig, an oxysterol sensor on the endoplasmic reticulum membrane, the direct target of the bisphosphonate esters remains unclear. In this study, we developed a potent photoaffinity probe of the bisphosphonate esters through preliminary structure-activity relationship study and demonstrated binding of the bisphosphonate esters to the HMGCR membrane domain. These results provide an important clue to understand the elusive mechanism of the SR12813-mediated HMGCR degradation and serve as a basis to develop more potent HMGCR degraders that target the non-catalytic, membrane domain of the enzyme.

  DOI：

  10.1016/j.bmc.2020.115576

文献信息

• METHOD FOR BINDING SITE IDENTIFICATION USING A MULTI-SCALE APPROACH
  申请人：ISIS INNOVATION LIMITED

  公开号：EP1468392B1

  公开（公告）日：2007-04-04