(R)-(+)-3-chloro-4,6-bis-ethoxymethoxy-2-(2-oxoocta-3,7-dienyl)benzoic acid 1-methylbut-3-enyl ester | 853645-39-3

• 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: (R)-(+)-3-chloro-4,6-bis-ethoxymethoxy-2-(2-oxoocta-3,7-dienyl)benzoic acid 1-methylbut-3-enyl ester
• 英文别名: [(2R)-pent-4-en-2-yl] 3-chloro-4,6-bis(ethoxymethoxy)-2-[(3E)-2-oxoocta-3,7-dienyl]benzoate
• CAS: 853645-39-3
• 化学式: C₂₆H₃₅ClO₇
• 分子量: 495.013
• InChiKey: AKRYKUTVKSYFGL-XYDKVEKUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  34
• 可旋转键数：
  19
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  80.3
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (R)-(+)-3-chloro-4,6-bis-ethoxymethoxy-2-(2-oxoocta-3,7-dienyl)benzoic acid 1-methylbut-3-enyl ester 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 4-二甲氨基吡啶 、 morpholinomethyl polystyrene 、 borohydride exchange resin 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 24.5h， 生成 [(4R,6E,10E)-15-chloro-16,18-bis(ethoxymethoxy)-4-methyl-2-oxo-3-oxabicyclo[12.4.0]octadeca-1(14),6,10,15,17-pentaen-12-yl] acetate
  参考文献：
  名称：

  方向性的软骨素合成和针对一组激酶的生物学评估。

  摘要：

  Pochonins AF最近被表征为自然存在的14元间苯二酸内酯家族的6个新成员。由于天然间苯二酚内酯中存在大量的ATPase和激酶抑制剂，因此建立了基于软骨素支架的文库，该文库具有五个多样性点，其中包括超出天然类似物的多样性。该文库是通过使用适合自动化的固体支持试剂合成的。测试该文库在10 microM下对一组24种激酶的抑制作用后，命中率> 14％。这些结果证明了间苯二酚对抑制治疗相关激酶的潜力。

  DOI：

  10.1002/chem.200600553
• 作为产物：
  描述：

  5-碘-1-戊烯 在 lithium diisopropyl amide 作用下， 以 四氢呋喃 为溶剂， 反应 0.17h， 生成 (R)-(+)-3-chloro-4,6-bis-ethoxymethoxy-2-(2-oxoocta-3,7-dienyl)benzoic acid 1-methylbut-3-enyl ester
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of HSP90 Inhibitors Based on Conformational Analysis of Radicicol and Its Analogues

  摘要：

  The molecular chaperone HSP90 is an attractive target for chemotherapy because its activity is required for the functional maturation of a number of oncogenes. Among the know inhibitors, radicicol, a 14-member macrolide, stands out as the most potent. A molecular dynamics/minimization of radicicol showed that there were three low energy conformers of the macrocycle. The lowest of these is the bioactive conformation observed in the cocrystal structure of radicicol with HSP90. Corresponding conformational analyses of several known analogues gave a good correlation between the bioactivity and the energy of the bioactive conformer, relative to other conformers. Based on this observation, a number of proposed analogues were analyzed for their propensity to adopt the bioactive conformation prior to synthesis. This led to the identification of pochonin D, a recently isolated secondary metabolite of Pochonia chlarnydosporia, as a potential inhibitor of HSP90. Pochonin D was synthesized using polymer-bound reagents and shown to be nearly as potent an HSP90 inhibitor as radicicol.

  DOI：

  10.1021/ja043101w

文献信息

• Diversity-Oriented Synthesis of Pochonins and Biological Evaluation against a Panel of Kinases
  作者：Emilie Moulin、Sofia Barluenga、Frank Totzke、Nicolas Winssinger

  DOI：10.1002/chem.200600553

  日期：2006.11.24

  14-membered resorcylic acid lactones. As there are a high number of ATPase and kinase inhibitors among natural resorcylic lactones, a library based on the pochonin scaffold, with five points of diversity, was prepared which includes diversity beyond that of the natural analogues. The library was synthesized by using solid-supported reagents amenable to automation. Testing the library for its inhibition

  Pochonins AF最近被表征为自然存在的14元间苯二酸内酯家族的6个新成员。由于天然间苯二酚内酯中存在大量的ATPase和激酶抑制剂，因此建立了基于软骨素支架的文库，该文库具有五个多样性点，其中包括超出天然类似物的多样性。该文库是通过使用适合自动化的固体支持试剂合成的。测试该文库在10 microM下对一组24种激酶的抑制作用后，命中率> 14％。这些结果证明了间苯二酚对抑制治疗相关激酶的潜力。
• Design, Synthesis, and Biological Evaluation of HSP90 Inhibitors Based on Conformational Analysis of Radicicol and Its Analogues
  作者：Emilie Moulin、Vincent Zoete、Sofia Barluenga、Martin Karplus、Nicolas Winssinger

  DOI：10.1021/ja043101w

  日期：2005.5.1

  The molecular chaperone HSP90 is an attractive target for chemotherapy because its activity is required for the functional maturation of a number of oncogenes. Among the know inhibitors, radicicol, a 14-member macrolide, stands out as the most potent. A molecular dynamics/minimization of radicicol showed that there were three low energy conformers of the macrocycle. The lowest of these is the bioactive conformation observed in the cocrystal structure of radicicol with HSP90. Corresponding conformational analyses of several known analogues gave a good correlation between the bioactivity and the energy of the bioactive conformer, relative to other conformers. Based on this observation, a number of proposed analogues were analyzed for their propensity to adopt the bioactive conformation prior to synthesis. This led to the identification of pochonin D, a recently isolated secondary metabolite of Pochonia chlarnydosporia, as a potential inhibitor of HSP90. Pochonin D was synthesized using polymer-bound reagents and shown to be nearly as potent an HSP90 inhibitor as radicicol.