2-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carbamoyl]terephthalic acid | 302602-92-2

• 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: 2-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carbamoyl]terephthalic acid
• 英文别名: 2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl-carbamoyl)terephthalic acid；2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylcarbamoyl)terephthalic acid；BV02；2-((1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carbamoyl)terephthalic acid；2-[(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl)carbamoyl]terephthalic acid
• CAS: 302602-92-2
• 化学式: C₂₀H₁₇N₃O₆
• 分子量: 395.371
• InChiKey: UDJSQFGBVNAWSU-UHFFFAOYSA-N

物化性质

• 密度：
  1.53±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  127
• 氢给体数：
  3
• 氢受体数：
  7

制备方法与用途

一种新的非肽抑制剂可以促进表达野生型Bcr-Abl构建体或T315I突变的细胞的凋亡，并且能显著降低表达野生型和T315I的Ba/F3细胞的增殖能力，其LD50分别为1.04 μM 和1.47 μM。这种抑制剂能够促使c-Abl从14-3-3σ中释放，并消除细胞质中的c-Abl表达，但不会影响14-3-3σ的水平，从而诱导慢性粒细胞白血病细胞对伊马替尼的敏感或耐药状态发生凋亡。

反应信息

• 作为产物：
  描述：

  2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid 在 水 作用下， 以 aq. buffer 为溶剂， 反应 50.0h， 生成 2-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carbamoyl]terephthalic acid
  参考文献：
  名称：

  Molecular insights to the bioactive form of BV02 , a reference inhibitor of 14-3-3σ protein–protein interactions

  摘要：

  BV02 is a reference inhibitor of 14-3-3 protein-protein interactions, which is currently used as chemical biology tool to understand the role of 14-3-3 proteins in pathological contexts. Due to chemical instability in certain conditions, its bioactive form has remained unclear. Here, we use NMR spectroscopy to prove for the first time the direct interaction between the molecule and 14-3-3 sigma, and to depict its bioactive form, namely the phthalimide derivative 9. Our work provides molecular insights to the bioactive form of the 14-3-3 PPI inhibitor and facilitates further development as candidate therapeutic agent. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.12.066

文献信息

• A New Nonpeptidic Inhibitor of 14-3-3 Induces Apoptotic Cell Death in Chronic Myeloid Leukemia Sensitive or Resistant to Imatinib
  作者：Manuela Mancini、Valentina Corradi、Sara Petta、Enza Barbieri、Fabrizio Manetti、Maurizio Botta、Maria Alessandra Santucci

  DOI：10.1124/jpet.110.172536

  日期：2011.3

  Resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitor imatinib mesylate (IM) is most often due to point mutations in the Bcr-Abl fusion gene. T315I mutation (resulting in substitution of Ile for a Thr residue at the “gatekeeper” position 315) raises particular concern, because it also provides resistance to second-generation kinase inhibitors already approved for clinical use (nilotinib and dasatinib). Much effort is therefore focused on alternative molecular-based strategies. Previous studies proved that binding to 14-3-3 scaffolding proteins leads to cytoplasmic compartmentalization and suppression of proapoptotic and antiproliferative signals associated with Bcr-Abl protein kinase, hence contributing to leukemic clone expansion. Here we investigated the effect of 14-3-3 inhibition disruption on hematopoietic cells expressing the IM-sensitive wild type Bcr-Abl and the IM-resistant T315I mutation. Using a virtual screening protocol and docking simulations, we identified a nonpeptidic inhibitor of 14-3-3, named BV02, that exhibits a remarkable cytotoxicity against both cell types. c-Abl release from 14-3-3σ, promoting its relocation to nuclear compartment (where it triggers transcription of p73-dependent proapoptotic genes) and to mitochondrial membranes (where it induces the loss of mitochondrial transmembrane potential) combined with c-Abl enhanced association with caspase 9 (a critical step of sequential caspase activation further contributing to c-Abl pro-apoptotic function) has a prominent role in the effect of BV02 on Bcr-Abl-expressing cells. In conclusion, BV02 may be considered as a treatment option for CML and, in particular, for more advanced phases of the disease that developed IM resistance as a consequence of Bcr-Abl point mutations.

  慢性髓性白血病（CML）对酪氨酸激酶抑制剂甲磺酸伊马替尼（IM）的耐药性最常见于Bcr-Abl融合基因的点突变。T315I突变（导致 "守门员 "315位上的Ile取代Thr残基）尤其令人担忧，因为它也会对已批准临床使用的第二代激酶抑制剂（尼洛替尼和达沙替尼）产生耐药性。因此，人们将大量精力集中在基于分子的替代策略上。以前的研究证明，与 14-3-3 蛋白支架的结合会导致细胞质分区，抑制与 Bcr-Abl 蛋白激酶相关的促凋亡和抗增殖信号，从而导致白血病克隆扩增。在这里，我们研究了 14-3-3 抑制干扰对表达 IM 敏感野生型 Bcr-Abl 和 IM 抗性 T315I 突变的造血细胞的影响。通过虚拟筛选方案和对接模拟，我们发现了一种名为 BV02 的 14-3-3 非肽抑制剂，它对这两种细胞类型都有显著的细胞毒性。BV02对Bcr-Abl表达细胞的作用中，c-Abl从14-3-3σ中释放出来，促进其迁移到核区（在核区它能触发依赖p73的促凋亡基因的转录）和线粒体膜（在线粒体膜它能诱导线粒体跨膜电位的丧失），再加上c-Abl与caspase 9的关联增强（caspase顺序激活的关键步骤，进一步促进了c-Abl的促凋亡功能）。总之，BV02 可被视为治疗 CML 的一种选择，尤其是治疗因 Bcr-Abl 点突变而产生 IM 抗性的晚期 CML。
• Identification of the first non-peptidic small molecule inhibitor of the c-Abl/14-3-3 protein–protein interactions able to drive sensitive and Imatinib-resistant leukemia cells to apoptosis
  作者：Valentina Corradi、Manuela Mancini、Fabrizio Manetti、Sara Petta、Maria Alessandra Santucci、Maurizio Botta

  DOI：10.1016/j.bmcl.2010.08.019

  日期：2010.10

  An in silico structure-based ligand design approach resulted in the identification of the first non-peptidic small molecule able to inhibit protein-protein interactions between 14-3-3 and c-Abl. This compound shows an anti-proliferative effect on human leukemia cells either sensitive or resistant to Imatinib, in consequence of the T315I mutation. It also mediates c-Abl release from 14-3-3 in a way similar to that found in response to Imatinib treatment. (C) 2010 Elsevier Ltd. All rights reserved.
• US8895600B2
  申请人：——

  公开号：US8895600B2

  公开（公告）日：2014-11-25