PKC抑制剂(NSC305787HYDROCHLORIDE) | 53868-26-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: PKC抑制剂(NSC305787HYDROCHLORIDE)
• 英文名称: NSC305787
• 英文别名: NSC305787 (hydrochloride)；[2-(1-adamantyl)-6,8-dichloroquinolin-4-yl]-piperidin-2-ylmethanol;hydrochloride
• CAS: 53868-26-1
• 化学式: C₂₅H₃₀Cl₂N₂O*ClH
• 分子量: 481.893
• InChiKey: JQALIVSYOXLOBE-UHFFFAOYSA-N

物化性质

• 溶解度：
  二甲基亚砜：8 mg/mL（16.60 mM）

计算性质

• 辛醇/水分配系数(LogP)：
  6.61
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  45.2
• 氢给体数：
  3
• 氢受体数：
  3

制备方法与用途

生物活性

NSC305787 hydrochloride 是一种 ezrin 抑制剂，Kd 值为 5.85 μM，抑制 PKCΙ 导致的 ezrin 磷酸化，IC50 of 8.3 μM，具有抗肿瘤活性。

靶点

Kd: 5.85 μM (ezrin)
IC50: 8.3 μM (ezrin)

体外研究

NSC305787 hydrochloride is an inhibitor of ezrin with a K _d of 5.85 μM, and has antitumor activity. NSC305787 inhibits PKCΙ phosphorylation of Ezrin, Moesin, Radixin, MBP, with IC ₅₀ s of 8.3, 9.4, 55, 58.9 μM, respectively. NSC305787 binds to PKCΙ with a K _d value of 172.4 μM, and inhibits ezrin T567 phosphorylation primarily via its binding to ezrin and not through inhibition of PKCΙ kinase activity. NSC305787 (1, 10 μM) shows inhibitory activity against ezrin-mediated invasion of K7M2 osteosarcoma (OS) cells. Moreover, NSC305787 (10 μM) reduces cell motility phenotypes in zebrafish and blocks OS metastatic growth in lung organ culture.

体内研究

NSC305787 (0.240 mg/kg/day, i.p.) suppresses ezrin-dependent osteosarcoma metastatic growth in mouse lung. NSC305787 (240 μg/kg, i.p.) dramatically inhibits pulmonary metastasis in a transgenic mouse model of osteosarcoma (Osx-Cre ⁺ p53 ^fl/fl pRB ^fl/fl ) and shows a more favorable pharmacokinetic profile compared with NSC668394 in the mouse model.

反应信息

• 作为产物：
  描述：

  (2-(adamantan-1-yl)-6,8-dichloroquinolin-4-yl)(piperidin-2-yl)methanol 在 盐酸 作用下， 以 乙醚 为溶剂， 以60%的产率得到PKC抑制剂(NSC305787HYDROCHLORIDE)
  参考文献：
  名称：

  Synthesis and initial evaluation of quinoline-based inhibitors of the SH2-containing inositol 5′-phosphatase (SHIP)

  摘要：

  Recently, inhibition of the SH2-containing inositol 5'-phosphatase 1 (SHIP1) has become an attractive strategy for facilitating engraftment of MHC-I mismatched bone marrow grafts, increasing the number of adult stem cells in vivo, and inducing mobilization of hematopoietic stem cells. Utilizing high-throughput screening, two quinoline small molecules (NSC13480 and NSC305787) that inhibit SHIP1 enzymatic activity were discovered. New syntheses of these inhibitors have been developed which verified the relative stereochemistry of these structures. Utilizing this synthetic route, some analogs of these quinolines have been prepared and tested for their ability to inhibit SHIP. These structure activity studies determined that an amine tethered to the quinoline core is required for SHIP inhibition. SHIP inhibition may explain the antitumor effects of similar quinoline amino alcohols and provides an impetus for further synthetic studies in this class of compounds. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.09.034