12-(dimethylamino)-N-(2-hydroxy-2-pyridin-3-ylethyl)dodecanamide | 1422379-15-4

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: 12-(dimethylamino)-N-(2-hydroxy-2-pyridin-3-ylethyl)dodecanamide
• CAS: 1422379-15-4
• 化学式: C₂₁H₃₇N₃O₂
• 分子量: 363.544
• InChiKey: BBXAGRFPLYJTHX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  26
• 可旋转键数：
  15
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  65.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  12-溴十二烷酸 在 吡啶 、 草酰氯 、 sodium acetate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 环己烷 、 水 为溶剂， 反应 15.0h， 生成 12-(dimethylamino)-N-(2-hydroxy-2-pyridin-3-ylethyl)dodecanamide
  参考文献：
  名称：

  Effective inhibition of acid and neutral ceramidases by novel B-13 and LCL-464 analogues

  摘要：

  Induction of apoptosis mediated by the inhibition of ceramidases has been shown to enhance the efficacy of conventional chemotherapy in several cancer models. Among the inhibitors of ceramidases reported in the literature, B-13 is considered as a lead compound having good in vitro potency towards acid ceramidase. Furthermore, owing to the poor activity of B-13 on lysosoamal acid ceramidase in living cells, LCL-464 a modified derivative of B-13 containing a basic omega-amino group at the fatty acid was reported to have higher potency towards lysosomal acid ceramidase in living cells. In a search for more potent inhibitors of ceramidases, we have designed a series of compounds with structural modifications of B-13 and LCL-464. In this study, we show that the efficacy of B-13 in vitro as well as in intact cells can be enhanced by suitable modification of functional groups. Furthermore, a detailed SAR investigation on LCL-464 analogues revealed novel promising inhibitors of aCDase and nCDase. In cell culture studies using the breast cancer cell line MDA-MB-231, some of the newly developed compounds elevated endogenous ceramide levels and in parallel, also induced apoptotic cell death. In summary, this study shows that structural modification of the known ceramidase inhibitors B-13 and LCL-464 generates more potent ceramidase inhibitors that are active in intact cells and not only elevates the cellular ceramide levels, but also enhances cell death. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.12.014

文献信息

• Effective inhibition of acid and neutral ceramidases by novel B-13 and LCL-464 analogues
  作者：Krishna P. Bhabak、Burkhard Kleuser、Andrea Huwiler、Christoph Arenz

  DOI：10.1016/j.bmc.2012.12.014

  日期：2013.2

  Induction of apoptosis mediated by the inhibition of ceramidases has been shown to enhance the efficacy of conventional chemotherapy in several cancer models. Among the inhibitors of ceramidases reported in the literature, B-13 is considered as a lead compound having good in vitro potency towards acid ceramidase. Furthermore, owing to the poor activity of B-13 on lysosoamal acid ceramidase in living cells, LCL-464 a modified derivative of B-13 containing a basic omega-amino group at the fatty acid was reported to have higher potency towards lysosomal acid ceramidase in living cells. In a search for more potent inhibitors of ceramidases, we have designed a series of compounds with structural modifications of B-13 and LCL-464. In this study, we show that the efficacy of B-13 in vitro as well as in intact cells can be enhanced by suitable modification of functional groups. Furthermore, a detailed SAR investigation on LCL-464 analogues revealed novel promising inhibitors of aCDase and nCDase. In cell culture studies using the breast cancer cell line MDA-MB-231, some of the newly developed compounds elevated endogenous ceramide levels and in parallel, also induced apoptotic cell death. In summary, this study shows that structural modification of the known ceramidase inhibitors B-13 and LCL-464 generates more potent ceramidase inhibitors that are active in intact cells and not only elevates the cellular ceramide levels, but also enhances cell death. (C) 2012 Elsevier Ltd. All rights reserved.