3,4-bis(2-hydroxyethylthio)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrrole-2,5-dione | 863886-46-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯啉
• 英文名称: 3,4-bis(2-hydroxyethylthio)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrrole-2,5-dione
• 英文别名: 3,4-Bis(2-hydroxyethylsulfanyl)-1-[4-(trifluoromethoxy)phenyl]pyrrole-2,5-dione
• CAS: 863886-46-8
• 化学式: C₁₅H₁₄F₃NO₅S₂
• 分子量: 409.407
• InChiKey: VEORNFUWAFVEMC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  26
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  138
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  3,4-dibromo-1-(4-(trifluoromethoxy)phenyl)-1H-pyrrole-2,5-dione 、 2-巯基乙醇 在 咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 以80.6%的产率得到3,4-bis(2-hydroxyethylthio)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrrole-2,5-dione
  参考文献：
  名称：

  Development of antiproliferative phenylmaleimides that activate the unfolded protein response

  摘要：

  The current paper presents the synthesis and evaluation of a series of maleimides that were designed to inhibit the Cdc25 phosphatase by alkylation of catalytically essential cysteine residues. Although in HepB3 cell culture assays the analogues did exhibit antiproliferative IC50 values ranging from sub-micromolar to greater than 100 mu M, inhibition of Cdc25 through cysteine alkylation could not be demonstrated. It was also found that analysis using fluorescence activated cell sorting (FACS) following treatment with the most potent analogue (1t) did not provide data consistent with inhibition at one specific point in the cell cycle, as would be expected if Cdc25A were inhibited. Further studies with a subset of analogues resulted in a correlation of antiproliferative potencies with activation of the unfolded protein response (UPR). The UPR is a regulatory pathway that temporarily suspends protein production when misfolding of proteins occurs within the endoplastic reticulum(ER). In addition, ER chaperones that promote proper refolding become up-regulated. If cellular damage cannot be resolved by these mechanisms, then the UPR can initiate apoptosis. The current study indicates that these maleimide analogues lead to UPR activation, which is predictive of the selective antiproliferative activity of the series. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2010.04.057

文献信息

• Maleiimide anti-tumor phosphatase inhibitors
  申请人：Michejda J. Christopher

  公开号：US20080039518A1

  公开（公告）日：2008-02-14

  The present invention features maleiimide compounds, pharmaceutical compositions of maleiimide compounds and methods of treating a patient suffering from cancer, the method comprising administering to a patient one or more maleiimide compounds of the invention.

  本发明涉及maleiimide化合物、maleiimide化合物的药物组成物以及治疗患有癌症的患者的方法，该方法包括向患者施用本发明中的一个或多个maleiimide化合物。
• US7504430B2
  申请人：——

  公开号：US7504430B2

  公开（公告）日：2009-03-17
• Development of antiproliferative phenylmaleimides that activate the unfolded protein response
  作者：Ulrike Muus、Curtis Hose、Wei Yao、Teresa Kosakowska-Cholody、David Farnsworth、Marzena Dyba、George T. Lountos、David S. Waugh、Anne Monks、Terrence R. Burke Jr.

  DOI：10.1016/j.bmc.2010.04.057

  日期：2010.6.15

  The current paper presents the synthesis and evaluation of a series of maleimides that were designed to inhibit the Cdc25 phosphatase by alkylation of catalytically essential cysteine residues. Although in HepB3 cell culture assays the analogues did exhibit antiproliferative IC50 values ranging from sub-micromolar to greater than 100 mu M, inhibition of Cdc25 through cysteine alkylation could not be demonstrated. It was also found that analysis using fluorescence activated cell sorting (FACS) following treatment with the most potent analogue (1t) did not provide data consistent with inhibition at one specific point in the cell cycle, as would be expected if Cdc25A were inhibited. Further studies with a subset of analogues resulted in a correlation of antiproliferative potencies with activation of the unfolded protein response (UPR). The UPR is a regulatory pathway that temporarily suspends protein production when misfolding of proteins occurs within the endoplastic reticulum(ER). In addition, ER chaperones that promote proper refolding become up-regulated. If cellular damage cannot be resolved by these mechanisms, then the UPR can initiate apoptosis. The current study indicates that these maleimide analogues lead to UPR activation, which is predictive of the selective antiproliferative activity of the series. Published by Elsevier Ltd.