methyl 4,6-bis(tert-butyldimethylsilanyloxy)-2-(2-carboxyethyl)-3-chloro-benzoate | 811788-14-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: methyl 4,6-bis(tert-butyldimethylsilanyloxy)-2-(2-carboxyethyl)-3-chloro-benzoate
• 英文别名: 3-[3,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-chloro-6-methoxycarbonylphenyl]propanoic acid
• CAS: 811788-14-4
• 化学式: C₂₃H₃₉ClO₆Si₂
• 分子量: 503.183
• InChiKey: KZDVLCFLXRGHHU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.91
• 重原子数：
  32
• 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：
  82.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 4,6-bis(tert-butyldimethylsilanyloxy)-2-(2-carboxyethyl)-3-chloro-benzoate 在 4-二甲氨基吡啶 、 四丁基氟化铵 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 3.33h， 生成 methyl 3-chloro-4,6-dihydroxy-2-[2-(4-methoxy-2,5-bis(methoxymethoxy)phenylcarbamoyl)ethyl]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：

  methyl 2-(but-3-enyl)-4,6-bis(tert-butyldimethylsilanyloxy)-3-chlorobenzoate 在 sodium chlorite 、 sodium dihydrogenphosphate 、 臭氧 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 25.25h， 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

文献信息

• 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.