L-((4-methylpiperazinyl) hexanoyl)-S-(trans,trans-farnesyl)cysteine cyclooctylamide | 1616271-96-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: L-((4-methylpiperazinyl) hexanoyl)-S-(trans,trans-farnesyl)cysteine cyclooctylamide
• 英文别名: N-[(2R)-1-(cyclooctylamino)-1-oxo-3-[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienyl]sulfanylpropan-2-yl]-6-(4-methylpiperazin-1-yl)hexanamide
• CAS: 1616271-96-5
• 化学式: C₃₇H₆₆N₄O₂S
• 分子量: 631.023
• InChiKey: ASBLOKVVKWBDGH-NQXUUICGSA-N

物化性质

• 沸点：
  782.699±60.00 °C(Press: 760.00 Torr)(predicted)
• 密度：
  1.035±0.10 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  8.5
• 重原子数：
  44
• 可旋转键数：
  19
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  90
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  反,反-法呢基溴 在 氨 、 potassium carbonate 、 三乙胺 作用下， 以 甲醇 、 甲苯 为溶剂， 反应 5.0h， 生成 L-((4-methylpiperazinyl) hexanoyl)-S-(trans,trans-farnesyl)cysteine cyclooctylamide
  参考文献：
  名称：

  Polyisoprenylated methylated protein methyl esterase: A putative biomarker and therapeutic target for pancreatic cancer

  摘要：

  Pancreatic cancer is the most deadly neo plasm with a 5-year survival rate of less than 6%. Over 90% of cases harbor K-Ras mutations, which are the most challenging to treat due to lack of effective therapies. Here, we reveal that polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed in 93% of pancreatic ductal adenocarcinoma. We further present polyisoprenylated cysteinyl amide inhibitors (PCAIs) as novel compounds designed with structural elements for optimal in vivo activities and selective disruption of polyisoprenylation-mediated protein functions. The PCAIs inhibited PMPMEase with K-i values ranging from 3.7 to 20 mu M. The 48 h E-50 values for pancreatic cancer Mia PaCa-2 and BxPC-3 cell lines were as low as 1.9 mu M while salirasib and farnesylthiosalicylamide were ineffective at 20 mu M. The PCAIs thus have the potential to serve as effective therapies for pancreatic and other cancers with hyperactive growth signaling pathways mediated by Ras and related G-proteins. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.05.018

文献信息

• Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide Inhibitors
  作者：Nada Tawfeeq、Yonghao Jin、Nazarius S. Lamango

  DOI：10.3390/cancers13225757

  日期：——

  Abnormalities of the MAPK pathway play vital roles in cancer initiation and progression. RAS GTPases that are key upstream mediators of the pathway are mutated in 30% of human cancers. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed as potential targeted therapies against the RAS-driven cancers. The current study reports on the optimization of the PCAIs and the determination of their mechanisms of action in KRAS-mutant cancer cells. They display ClogP values ranging from 3.01 to 6.35, suppressing the viabilities of KRAS-mutant MDA-MB-231, A549, MIA PaCa-2, and NCI-H1299 cells in 2D and 3D cultures with EC50 values of 2.2 to 6.8, 2.2 to 7.6, 2.3 to 6.5 and 5.0 to 14 µM, respectively. When A549 cells were treated with the PCAIs, NSL-YHJ-2-27, for 48 h, no significant difference was observed in the levels of total or phosphorylated B- and C-Raf proteins. However, at 5 µM, it stimulated the phosphorylation of MEK1/2, ERK1/2, and p90RSK by 84%, 59%, and 160%, respectively, relative to controls. A non-farnesylated analog, NSL-YHJ-2-62, did not elicit similar effects. These data reveal that effects on the RAS-MAPK signaling axis most likely contribute to the anticancer effects of the PCAIs, possibly through the proapoptotic isoforms of p90RSK. The PCAIs may thus have the potential to serve the unmet therapeutic needs of patients with aberrant hyperactive G-protein signaling.

  MAPK通路异常在癌症的发生和发展中起着至关重要的作用。作为该通路的关键上游介质，RAS GTP酶在30%的人类癌症中发生突变。聚异戊二烯基半胱氨酸酰胺抑制剂（PCAIs）被设计为针对RAS驱动的癌症的潜在靶向治疗。当前研究报告了PCAIs的优化以及确定它们在KRAS突变癌细胞中的作用机制。它们的ClogP值范围从3.01到6.35，抑制了KRAS突变的MDA-MB-231、A549、MIA PaCa-2和NCI-H1299细胞在2D和3D培养中的存活率，相应的EC50值分别为2.2至6.8、2.2至7.6、2.3至6.5和5.0至14微米。当A549细胞用PCAIs NSL-YHJ-2-27处理48小时时，总体或磷酸化的B-和C-Raf蛋白水平没有显著差异。然而，在5微米时，相对于对照组，它分别刺激了MEK1/2、ERK1/2和p90RSK的磷酸化分别增加了84%、59%和160%。一种非法尼醇化的类似物NSL-YHJ-2-62没有产生类似效果。这些数据揭示了PCAIs对RAS-MAPK信号通路的影响很可能是其抗癌作用的原因，可能是通过p90RSK的凋亡诱导亚型。因此，PCAIs可能有潜力满足患有异常高活性G蛋白信号的患者的治疗需求。
• Polyisoprenylated methylated protein methyl esterase: A putative biomarker and therapeutic target for pancreatic cancer
  作者：Byron J. Aguilar、Augustine T. Nkembo、Randolph Duverna、Rosemary A. Poku、Felix Amissah、Seth Y. Ablordeppey、Nazarius S. Lamango

  DOI：10.1016/j.ejmech.2014.05.018

  日期：2014.6

  Pancreatic cancer is the most deadly neo plasm with a 5-year survival rate of less than 6%. Over 90% of cases harbor K-Ras mutations, which are the most challenging to treat due to lack of effective therapies. Here, we reveal that polyisoprenylated methylated protein methyl esterase (PMPMEase) is overexpressed in 93% of pancreatic ductal adenocarcinoma. We further present polyisoprenylated cysteinyl amide inhibitors (PCAIs) as novel compounds designed with structural elements for optimal in vivo activities and selective disruption of polyisoprenylation-mediated protein functions. The PCAIs inhibited PMPMEase with K-i values ranging from 3.7 to 20 mu M. The 48 h E-50 values for pancreatic cancer Mia PaCa-2 and BxPC-3 cell lines were as low as 1.9 mu M while salirasib and farnesylthiosalicylamide were ineffective at 20 mu M. The PCAIs thus have the potential to serve as effective therapies for pancreatic and other cancers with hyperactive growth signaling pathways mediated by Ras and related G-proteins. (C) 2014 Elsevier Masson SAS. All rights reserved.