methyl 4,6-bis((tert-butyldimethylsilyl)oxy)-3-chloro-2-(3-oxopropyl)benzoate | 811788-13-3

• 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: methyl 4,6-bis((tert-butyldimethylsilyl)oxy)-3-chloro-2-(3-oxopropyl)benzoate
• 英文别名: methyl 4,6-bis(tert-butyldimethylsilyloxy)-3-chloro-2-(3-oxopropyl)benzoate；Methyl 4,6-bis[[tert-butyl(dimethyl)silyl]oxy]-3-chloro-2-(3-oxopropyl)benzoate
• CAS: 811788-13-3
• 化学式: C₂₃H₃₉ClO₅Si₂
• 分子量: 487.184
• InChiKey: NCBUQBPNVAMFDI-UHFFFAOYSA-N

物化性质

• 沸点：
  489.0±45.0 °C(Predicted)
• 密度：
  1.035±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.03
• 重原子数：
  31
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  61.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl 4,6-bis((tert-butyldimethylsilyl)oxy)-3-chloro-2-(3-oxopropyl)benzoate 在 sodium chlorite 、 sodium dihydrogenphosphate 作用下， 以 various solvent(s) 为溶剂， 生成 methyl 4,6-bis(tert-butyldimethylsilanyloxy)-2-(2-carboxyethyl)-3-chloro-benzoate
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of a Radicicol and Geldanamycin Chimera, Radamide

  摘要：

  A chimera composed of the natural products radicicol and geldanamycin has been prepared through an amide linkage connecting the resorcinol moiety of radicicol to the quinone ring of geldanamycin. The inhibitory activity of these compounds was determined by their ability to inhibit Hsp90's inherent ATPase activity along with degradation of the Hsp90 client protein, HER-2 in MCF-7 breast cancer cells.

  DOI：

  10.1021/ol048266o
• 作为产物：
  描述：

  叔丁基二甲基氯硅烷 在 calcium hypochlorite 、 sodium hydride 、 臭氧 、 溶剂黄146 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 39.33h， 生成 methyl 4,6-bis((tert-butyldimethylsilyl)oxy)-3-chloro-2-(3-oxopropyl)benzoate
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of a Radicicol and Geldanamycin Chimera, Radamide

  摘要：

  A chimera composed of the natural products radicicol and geldanamycin has been prepared through an amide linkage connecting the resorcinol moiety of radicicol to the quinone ring of geldanamycin. The inhibitory activity of these compounds was determined by their ability to inhibit Hsp90's inherent ATPase activity along with degradation of the Hsp90 client protein, HER-2 in MCF-7 breast cancer cells.

  DOI：

  10.1021/ol048266o

文献信息

• Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold
  作者：Vincent M. Crowley、Anuj Khandelwal、Sanket Mishra、Andrew R. Stothert、Dustin J. E. Huard、Jinbo Zhao、Aaron Muth、Adam S. Duerfeldt、James L. Kizziah、Raquel L. Lieberman、Chad A. Dickey、Brian S. J. Blagg

  DOI：10.1021/acs.jmedchem.6b00085

  日期：2016.4.14

  that was used to design isoform-selective inhibitors. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. Structure–activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. These analogues also manifest

  葡萄糖调节蛋白94（Grp94）是分子伴侣蛋白的热休克蛋白90 kDa（Hsp90）家族的内质网居民。Grp94与许多参与细胞黏附和信号传导的蛋白质相关，包括整联蛋白，Toll样受体，免疫球蛋白和突变型myocilin。Grp94被认为是包括青光眼，癌症转移和多发性骨髓瘤在内的多个治疗领域的靶标。虽然与其他Hsp90同工型具有85％的相同性，但Grp94的N末端ATP结合位点具有一个独特的疏水性口袋，该口袋用于设计同工型选择性抑制剂。合并顺式-酰胺生物甾体进入radamide支架导致了最初的Grp94选择性抑制剂BnIm的开发。现在已经对BnIm的芳基侧链进行了结构-活性关系研究，从而得到了改进的类似物，对Grp94表现出了更好的效价和选择性。与BnIm相比，这些类似物在转移模型中还表现出优异的抗迁移活性，并且在青光眼模型中还表现出增强的突变型肌球蛋白降解。
• [EN] GRP94 INHIBITORS<br/>[FR] INHIBITEURS DE GRP94
  申请人：UNIV KANSAS

  公开号：WO2012139010A1

  公开（公告）日：2012-10-11

  The present disclosure provides a series of compounds which exhibit isoform selective inhibition of GRP94, a homologue of Hsp90 that is localized to the endoplasmic recticulum. Through GRP94 inhibition, these compounds are likely to manifest anti-cancer, anti-inflammatory, anti-metastasis, and immunosuppressive activities, as well as utility in the treatment of neurodegenerative diseases, and diabetes.

  本公开提供了一系列化合物，这些化合物表现出对GRP94的异构选择性抑制作用，GRP94是定位于内质网的Hsp90同源物。通过抑制GRP94，这些化合物有可能表现出抗癌、抗炎、抗转移、免疫抑制和在治疗神经退行性疾病和糖尿病方面的用途。
• Compositions and methods of treatment for myocilin glaucoma by selectively inhibiting GRP94
  申请人：Dickey Chad Anthony

  公开号：US09045434B1

  公开（公告）日：2015-06-02

  A compound and method for treating myocilin glaucoma using a selective Grp94 inhibitor is presented. Clearance of mutant myocilin can be promoted by selectively targeting the endoplasmic reticulum (ER) chaperone Grp94 using siRNA knockdown or small molecule inhibitors. Grp94 contributes to the intracellular accumulation of mutant myocilin. Tailored treatments aimed at disrupting the Grp94/mutant myocilin interaction can be used as a new therapeutic strategy for myocilin glaucoma. The inventors developed a compound having a general backbone structure of geldanamycin (GDA) and radicicol (RDC) in which a more hydrophobic surrogate of the quinone in GDA is linked to the resorcinol in RDC through a cis-amide bioisostere.

  本文提出了一种使用选择性Grp94抑制剂治疗myocilin青光眼的化合物和方法。通过选择性靶向内质网（ER）分子伴侣Grp94，使用siRNA敲除或小分子抑制剂可以促进突变myocilin的清除。 Grp94有助于突变myocilin的细胞内积累。旨在破坏Grp94 /突变myocilin相互作用的定制治疗可用作myocilin青光眼的新治疗策略。发明人开发了一种具有geldanamycin（GDA）和radicicol（RDC）的通用骨架结构的化合物，其中GDA中的更亲水的代用喹啉通过顺式酰胺生物同构体连接到RDC中的邻苯二酚上。
• Development of radamide analogs as Grp94 inhibitors
  作者：Aaron Muth、Vincent Crowley、Anuj Khandelwal、Sanket Mishra、Jinbo Zhao、Jessica Hall、Brian S.J. Blagg

  DOI：10.1016/j.bmc.2014.05.075

  日期：2014.8

  Hsp90 isoform-selective inhibition is highly desired as it can potentially avoid the toxic side-effects of pan-inhibition. The current study developed selective inhibitors of one such isoform, Grp94, predicated on the chimeric and pan-Hsp90 inhibitor, radamide (RDA). Replacement of the quinone moiety of RDA with a phenyl ring (2) was found to be better suited for Grp94 inhibition as it can fully interact with a unique hydrophobic pocket present in Grp94. An extensive SAR for this scaffold showed that substitutions at the 2- and 4-positions (8 and 27, respectively) manifested excellent Grp94 affinity and selectivity. Introduction of heteroatoms into the ring also proved beneficial, with a 2-pyridine derivative (38) exhibiting the highest Grp94 affinity (K(d)=820 nM). Subsequent cell-based assays showed that these Grp94 inhibitors inhibit migration of the metastatic breast cancer cell line, MDA-MB-231, as well as exhibit an anti-proliferative affect against the multiple myeloma cell line, RPMI 8226.
• Synthesis and Evaluation of Radamide Analogues, A Chimera of Radicicol and Geldanamycin
  作者：M. Kyle Hadden、Brian S. J. Blagg

  DOI：10.1021/jo900278g

  日期：2009.7.3

  Previously, we reported the Hsp90 inhibitory activity of radamide, an open chain amide chimera of geldanamycin and radicicol. Attempts to further expand upon structure-activity relationships for this class of Hsp90 inhibitors led to the preparation of a series of radamide analogues focused on differing tether lengths and quinone mimics. In addition, the cup-shaped conformation adopted by the two natural products when bound to the Hsp90 N-terminal ATP binding pocket suggests that conformationally biased compounds may demonstrate improved binding and inhibition. The preparation and evaluation of radamide analogues with cisltrans alpha,beta-unsaturated amides yielded compounds that exhibit improved antiproliferative activity. In addition, several analogues demonstrated the ability to induce degradation of Hsp90-dependent oncogenic signaling proteins in vitro, a hallmark of Hsp90 N-terminal inhibition.