4-[3-(2-氯苯基)-2-丙烯-1-叉基]-1-苯基-3,5-吡唑烷二酮 | 310460-39-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 4-[3-(2-氯苯基)-2-丙烯-1-叉基]-1-苯基-3,5-吡唑烷二酮
• 中文别名: 4-(3-(2-氯苯基)亚烯丙基)-1-苯基吡唑烷-3,5-二酮
• 英文名称: CPYPP
• 英文别名: 4-[3'-(2''-chlorophenyl)-2'-propen-1'-ylidene]-1-phenyl-3,5-pyrazolidinedione；4-[3-(2-Chlorophenyl)prop-2-enylidene]-1-phenylpyrazolidine-3,5-dione
• CAS: 310460-39-0
• 化学式: C₁₈H₁₃ClN₂O₂
• 分子量: 324.766
• InChiKey: VVZJFICTTKPNCK-UHFFFAOYSA-N

物化性质

• 密度：
  1.405±0.06 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：50 mM

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  49.4
• 氢给体数：
  1
• 氢受体数：
  2

安全信息

• 危险性防范说明：
  P261,P280,P301+P312,P302+P352,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

CPYPP 是一种 DOCK2-Rac1 相互作用的抑制剂。CPYPP 结合 DOCK2DHR-2 结构域，并以剂量依赖性方式抑制 DOCK2DHR-2 对 Rac1 的鸟嘌呤核苷酸交换因子活性，IC50 为 22.8 µM。CPYPP 还抑制 DOCK180 和 DOCK5，对 DOCK9 的抑制活性较少。

靶点

IC50: 22.8 µM (GEF activity of DOCK2 ^DHR-2 for Rac1)

体外研究

CPYPP binds to DOCK2 DHR-2 domain in a reversible manner and inhibited its catalytic activity in vitro. When lymphocytes are treated with CPYPP, both chemokine receptor- and antigen receptor-mediated Rac activation are blocked, resulting in marked reduction of chemotactic response and T cell activation.
Although overexpression of DOCK2 induces Rac activation in HEK293T cells, this activation is markedly suppressed by treating the cells with CPYPP at 100 µM for 1 hr before assay.

体内研究

When 2.5 mg/kg of CPYPP is administrated intravenously, the plasma concentration of CPYPP is only 2.4 µM at 30 min. However, by intraperitoneally injecting 250 mg/kg of CPYPP into mice, the plasma concentration of CPYPP reached to 11.3 µM at 30 min and 10.9 µM at 1 hr, respectively.
The adoptively transferred spleen cells from mice that has been made by a ‘‘knock-in’’ strategy to express endogenous DOCK2 as a fusion protein with green fluorescent protein (GFP). Intraperitoneal injection of CPYPP (5 mg per mouse) 1 hr before adoptive transfer reduces the percentage of the migrated T cells to <25% of the control level.

反应信息

• 作为反应物：
  描述：

  4-[3-(2-氯苯基)-2-丙烯-1-叉基]-1-苯基-3,5-吡唑烷二酮 在 氯仿 作用下， 以 四氢呋喃 、 氯仿 为溶剂， 生成
  参考文献：
  名称：

  Blockade of Inflammatory Responses by a Small-Molecule Inhibitor of the Rac Activator DOCK2

  摘要：

  Tissue infiltration of activated lymphocytes is a hallmark of transplant rejection and organ-specific autoimmune diseases. Migration and activation of lymphocytes depend on DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 does not contain Dbl homology domain typically found in guanine nucleotide exchange factors, DOCK2 mediates the GTP-GDP exchange reaction for Rac through its DHR-2 domain. Here, we have identified 4-[3'-(2 ''-chlorophenyl)-2'-propen-1'-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP) as a small-molecule inhibitor of DOCK2. CPYPP bound to DOCK2 DHR-2 domain in a reversible manner and inhibited its catalytic activity in vitro. When lymphocytes were treated with CPYPP, both chemokine receptor- and antigen receptor-mediated Rac activation were blocked, resulting in marked reduction of chemotactic response and T cell activation. These results provide a rational of and a chemical scaffold for development of the DOCK2-targeting immunosuppressant.

  DOI：

  10.1016/j.chembiol.2012.03.008