methyl 4,6-bis(tert-butyldimethylsilyloxy)-3-chloro-2-(hex-5-enyl)benzoate | 913622-78-3

• 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-butyldimethylsilyloxy)-3-chloro-2-(hex-5-enyl)benzoate
• 英文别名: Methyl 4,6-bis[[tert-butyl(dimethyl)silyl]oxy]-3-chloro-2-hex-5-enylbenzoate
• CAS: 913622-78-3
• 化学式: C₂₆H₄₅ClO₄Si₂
• 分子量: 513.265
• InChiKey: WFAUDUVPQKYJDC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.79
• 重原子数：
  33
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  44.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 4,6-bis(tert-butyldimethylsilyloxy)-3-chloro-2-(hex-5-enyl)benzoate 在 palladium on activated charcoal 2,6-二甲基吡啶 、 lithium hydroxide 、 sodium chlorite 、 sodium periodate 、 sodium dihydrogenphosphate 、 四氧化锇 、 2-甲基-2-丁烯 、 偶氮二甲酸二异丙酯 、 氢气 、 三苯基膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 水 、 叔丁醇 为溶剂， 反应 19.0h， 生成 2-(4-Carboxy-butyl)-3-chloro-4,6-dihydroxy-benzoic acid 2-(3-amino-6-methoxy-2,5-bis-methoxymethoxy-phenyl)-ethyl ester
  参考文献：
  名称：

  Design, Synthesis, and StructureActivity Relationships for Chimeric Inhibitors of Hsp90

  摘要：

  Inhibition of the 90 kDa heat shock protein (Hsp90) family of molecular chaperones represents a promising new chemotherapeutic approach toward the treatment of several cancers. Previous studies have demonstrated that the natural products, radicicol and geldanamycin, are potent inhibitors of the Hsp90 N-terminal ATP binding site. The cocrystal structures of these molecules bound to Hsp90 have been determined, and through molecular modeling and superimposition of these ligands, hybrids of radicicol and geldanamycin have been designed. A series of macrocylic chimeras of radicicol and geldanamycin and the corresponding seco-agents have been prepared and evaluated for both antiproliferative activity and their ability to induce Hsp90-dependent client protein degradation.

  DOI：

  10.1021/jo061054f
• 作为产物：
  描述：

  methyl 2,4-bis(tert-butyldimethylsilanyloxy)-3-chloro-6-methylbenzoate 、 5-溴-1-戊烯 在 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正庚烷 为溶剂， 以82%的产率得到methyl 4,6-bis(tert-butyldimethylsilyloxy)-3-chloro-2-(hex-5-enyl)benzoate
  参考文献：
  名称：

  Design, Synthesis, and StructureActivity Relationships for Chimeric Inhibitors of Hsp90

  摘要：

  Inhibition of the 90 kDa heat shock protein (Hsp90) family of molecular chaperones represents a promising new chemotherapeutic approach toward the treatment of several cancers. Previous studies have demonstrated that the natural products, radicicol and geldanamycin, are potent inhibitors of the Hsp90 N-terminal ATP binding site. The cocrystal structures of these molecules bound to Hsp90 have been determined, and through molecular modeling and superimposition of these ligands, hybrids of radicicol and geldanamycin have been designed. A series of macrocylic chimeras of radicicol and geldanamycin and the corresponding seco-agents have been prepared and evaluated for both antiproliferative activity and their ability to induce Hsp90-dependent client protein degradation.

  DOI：

  10.1021/jo061054f

文献信息

• Design, Synthesis, and StructureActivity Relationships for Chimeric Inhibitors of Hsp90
  作者：Gang Shen、Mingwen Wang、Timothy R. Welch、Brian S. J. Blagg

  DOI：10.1021/jo061054f

  日期：2006.9.1

  Inhibition of the 90 kDa heat shock protein (Hsp90) family of molecular chaperones represents a promising new chemotherapeutic approach toward the treatment of several cancers. Previous studies have demonstrated that the natural products, radicicol and geldanamycin, are potent inhibitors of the Hsp90 N-terminal ATP binding site. The cocrystal structures of these molecules bound to Hsp90 have been determined, and through molecular modeling and superimposition of these ligands, hybrids of radicicol and geldanamycin have been designed. A series of macrocylic chimeras of radicicol and geldanamycin and the corresponding seco-agents have been prepared and evaluated for both antiproliferative activity and their ability to induce Hsp90-dependent client protein degradation.
• 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.