tetraisopropyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenylidene-1,1-bisphosphonate | 126411-40-3

• 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: tetraisopropyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenylidene-1,1-bisphosphonate
• 英文别名: [[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-phosphonic acid tetrakis(1-methylethyl)ester；4-[2,2-Bis[di(propan-2-yloxy)phosphoryl]ethenyl]-2,6-ditert-butylphenol
• CAS: 126411-40-3
• 化学式: C₂₈H₅₀O₇P₂
• 分子量: 560.648
• InChiKey: LVPCHGWFRQEQPE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  37
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  91.3
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  亚甲基二磷酸四异丙酯 、 3,5-二叔丁基-4-羟基苯甲醛 在 N-甲基吗啉 、 四氯化钛 作用下， 以 四氢呋喃 、 四氯化碳 为溶剂， 以55%的产率得到tetraisopropyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenylidene-1,1-bisphosphonate
  参考文献：
  名称：

  芳基膦酸酯的设计，合成和P-gp诱导活性：鉴定四乙基-2-苯基乙烯-1,1-二基二膦酸酯为口服可生物利用的P-gp诱导剂† •

  摘要：

  淀粉样蛋白-β的清除是由位于血脑屏障的P-糖蛋白（P-gp）转运蛋白泵介导的。因此，P-gp的诱导被认为是治疗阿尔茨海默氏病的潜在治疗策略。P-gp的表达受核受体，孕烷X受体（PXR）调节。因此，本文中我们研究了已知的PXR活化剂二膦酸酯SR12813（6a）对P-gp诱导活性的潜力，并进一步研究了其结构与活性之间的关系。二膦酸酯SR12813以及三个类似物系列。合成了芳基亚烷基，芳基炔基和芳基α-氨基膦酸酯，并使用若丹明123外排试验筛选了过表达P-gp的腺癌LS180细胞中P-gp的诱导活性。母体化合物SR12813以及几种新的类似物在5μM下显示P-gp诱导活性。Western印迹分析表明，四乙基-2-苯基乙烯-1,1-二基二膦酸酯（6c）和四乙基-2-（蒽-10-基）乙烯-1,1-二基二膦酸酯（6s）显示P升高7-8倍-gp在LS180细胞中的表达。二膦酸酯6c显示出优异的水溶性，

  DOI：

  10.1039/c6md00300a

文献信息

• Bisphosphonate esters interact with HMG-CoA reductase membrane domain to induce its degradation
  作者：Yosuke Toyota、Hiromasa Yoshioka、Ikuya Sagimori、Yuichi Hashimoto、Kenji Ohgane

  DOI：10.1016/j.bmc.2020.115576

  日期：2020.7

  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.
• Phenol substituted gem-diphosphonate derivatives, process for their preparation and pharmaceutical compositions containing them
  申请人：SYMPHAR S.A.

  公开号：EP0339237B1

  公开（公告）日：1992-12-30
• USE OF PHENOL SUBSTITUTED DIPHOSPHONATES AS ANTINEOPLASTIC AGENTS
  申请人：SYMPHAR S.A.

  公开号：EP0845991B1

  公开（公告）日：2002-02-06
• USE OF ARYL-SUBSTITUTED 1,1-DIPHOSPHONATES FOR THE TREATMENT OF BONE DISEASES
  申请人：Ilex Oncology Research S.A.

  公开号：EP1326618A2

  公开（公告）日：2003-07-16
• BENZYLIDENE COMPOUNDS COMPRISING PHOSPHONO-GROUPS
  申请人：Wagner Barbara

  公开号：US20110212039A1

  公开（公告）日：2011-09-01

  Disclosed is the use of the compounds of formula (1) wherein R 1 and R 2 independently of one another are hydrogen; unsubstituted or substituted C 1 -C 12 alkyl; unsubstituted or substituted C 3 -C 12 cycloalkyl; unsubstituted or substituted C 6 -C 20 aryl; or unsubstituted or substituted C 2 -C 20 alkenyl; R 3 is PO 3 R 1 R 2 ; COOR 6 ; COR 7 ; CONR 7 R 8 ; —SO 2 R 6 ; CN; unsubstituted or substituted C 6 -C 20 aryl; R 4 is unsubstituted C 6 -C 20 aryl; or C 6 -C 20 aryl which is substituted by at least one C 1 -C 18 alkyl, C 1 -C 18 alkoxy, C 3 -C 12 cycloalkyl, hydroxy, amino, mono- or di-C 1 -C 18 alkylamino, —NR 10 COR 11 or the radical of formula (1a) or unsubstituted or substituted C 4 -C 20 heteroaryl; R 5 is hydrogen; substituted or unsubstituted C 1 -C 20 alkyl; unsubstituted or substituted C 3 -C 12 cycloalkyl; unsubstituted or substituted C 6 -C 20 aryl; or unsubstituted or substituted C 4 -C 20 heteroaryl; or R 4 and R 5 form a cycloaliphatic ring; R 6 , R 7 and R 8 independently from each other are hydrogen; C 1 -C 18 alkyl or C 3 -C 12 cycloalkyl, which may be substituted by one or more E and/or interrupted by one or more D; or C 6 -C 20 aryl, which may be substituted by G; or R 7 and R8 together form a five or six membered ring; D is —CO—; —COO—; —S—; —SO; —SO 2 —; —O—; —NR 9 —; SiR 12 R 13 —; —POR 14 —; —CR 15 ═CR 16 —; or —C≡C—; E is —OR 17 ; —SR 17 ; —NR 10 R 11 ; —NR 10 COR 11 ; —COR 11 ; —COOR 11 ; —CONR 10 R 11 ; —CN; halogen; SO 3 R 18 ; SO 2 R 18 ; PO 3 (R 18 ) 2 ; or PO 2 (R 18 ) 2 ; G is E; C 1 -C 18 alkyl, which is optionally interrupted by D; C 1 -C 18 perfluoroalkyl; C 1 -C 18 alkoxy, which is optionally substituted by E and/or interrupted by D; wherein R 9 , R 10 and R 11 , independently of each other are hydrogen; C 6 -C 18 aryl which is optionally substituted by C 1 -C 18 alkyl or C 1 -C 18 alkoxy; C 1 -C 18 alkyl, which is optionally interrupted by —O—; or R 10 and R 11 together form a five or six membered ring; R 12 and R 13 independently of each other are hydrogen; C 1 -C 18 alkyl; or C 6 -C 18 aryl which is optionally substituted by C 1 -C 18 alkyl; R 14 is C 1 -C 18 alkyl; or C 6 -C 18 aryl, which is optionally substituted by C 1 -C 18 alkyl; R 15 and R 16 independently of each other are hydrogen; C 6 -C 18 aryl which is optionally substituted by C 1 -C 18 alkyl or C 1 -C 18 alkoxy; or C 1 -C 18 alkyl which is optionally interrupted by —O—; R 17 is H; C 6 -C 18 aryl which is optionally substituted by C 1 -C 18 alkyl or C 1 -C 18 alkoxy; or C 1 -C 18 alkyl which is optionally interrupted by —O—; and R 18 is hydrogen; C 6 -C 18 aryl, which is optionally substituted by C 1 -C 18 alkyl or C 1 -C 18 alkoxy; or C 1 -C 18 alkyl, which is optionally interrupted by —O—; for the protecting of human and animal hair and skin from UV radiation. The UV filters of the present invention represent oil-soluble substances which advantageously absorb in the UV-A and UV-B region.