(R)-(-)-2,4-bis-ethoxymethoxy-6-methylbenzoic acid 1-methylbut-3-enyl ester | 853645-36-0

• 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)-(-)-2,4-bis-ethoxymethoxy-6-methylbenzoic acid 1-methylbut-3-enyl ester
• 英文别名: [(2R)-pent-4-en-2-yl] 2,4-bis(ethoxymethoxy)-6-methylbenzoate
• CAS: 853645-36-0
• 化学式: C₁₉H₂₈O₆
• 分子量: 352.428
• InChiKey: IJBLEHUHDFSBKD-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  25
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  63.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (R)-(-)-2,4-bis-ethoxymethoxy-6-methylbenzoic acid 1-methylbut-3-enyl ester 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 盐酸 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲苯 为溶剂， 反应 3.17h， 生成 (4R,6E)-10-chloro-16,18-dihydroxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,15,17-tetraene-2,12-dione
  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
• 作为产物：
  描述：

  (S)-(+)-4-戊烯-2-醇 在 PS-DEAD 、 三(3-氯苯基)膦 、 四丁基碘化铵 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 0.17h， 生成 (R)-(-)-2,4-bis-ethoxymethoxy-6-methylbenzoic 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

• [EN] POCHOXIME CONJUGATES USEFUL FOR THE TREATMENT OF HSP90 RELATED PATHOLOGIES<br/>[FR] DÉRIVÉS DE POCHOXIME CONVENANT POUR LE TRAITEMENT DE PATHOLOGIES EN RAPPORT AVEC HSP90
  申请人：UNIV STRASBOURG

  公开号：WO2012052843A1

  公开（公告）日：2012-04-26

  The present invention includes novel derivatives, analogs, and intermediates of the natural products radicicol, pochonins, pochoximes, and their syntheses. The present invention also provides a pharamceutical composition comprising the present compound and the use of the compound as inhibitors of kinases and of the enzyme family known as heat shock protein 90 (HSP90).

  本发明包括天然产物radicicol、pochonins、pochoximes的新颖衍生物、类似物和中间体，以及它们的合成方法。本发明还提供了一种包含本化合物的药物组合物，以及将该化合物用作激酶抑制剂和热休克蛋白90（HSP90）酶家族的用途。
• Asymmetric Synthesis of Pochonin E and F, Revision of Their Proposed Structure, and Their Conversion to Potent Hsp90 Inhibitors
  作者：Ganesan Karthikeyan、Claudio Zambaldo、Sofia Barluenga、Vincent Zoete、Martin Karplus、Nicolas Winssinger

  DOI：10.1002/chem.201200546

  日期：2012.7.16

  A concise and modular synthesis of pochonin E and F, and their epimers at C‐6 established the correct stereochemistry of these two natural products. Several members of the pochonin family have been shown to bind the heat shock protein 90 (Hsp90), which has been the focus of intense drug discovery efforts. Pochonin E and F as well as their epimers were derivatized into the corresponding pochoximes and

  软骨素E和F以及它们在C-6上的差向异构体的简明和模块化合成建立了这两种天然产物的正确立体化学。软骨素家族的几个成员已显示与热激蛋白90（Hsp90）结合，而热激蛋白90已成为药物研发的重点。Pochonin E和F以及它们的差向异构体被衍生化为相应的Poxiximes，并在C-6位置进一步修饰。进行了分子动力学模拟，对接研究和Hsp90亲和力测量，以评估这些修饰的影响。
• 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。