N,N,N-trimethyl-3-(octadec-1-en-2-ylsulfonyl)propan-1-aminium chloride

• 分子结构分类: 有机化合物 - 有机硫化合物 - 磺酰类
• 英文名称: N,N,N-trimethyl-3-(octadec-1-en-2-ylsulfonyl)propan-1-aminium chloride
• 英文别名: Trimethyl(3-octadec-1-en-2-ylsulfonylpropyl)azanium;chloride；trimethyl(3-octadec-1-en-2-ylsulfonylpropyl)azanium;chloride
• 化学式: C₂₄H₅₀NO₂S*Cl
• 分子量: 452.186
• InChiKey: VBWFCMBRYMHQOO-UHFFFAOYSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  3.89
• 重原子数：
  29
• 可旋转键数：
  20
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.92
• 拓扑面积：
  42.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  methyl 2-((3-hydroxypropyl)thio)acetate 在 lithium aluminium tetrahydride 、 sodium hydride 、 碳酸氢钠 、 三乙胺 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 三氟乙酸 、 sodium iodide 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 丙酮 、 mineral oil 为溶剂， 反应 183.17h， 生成 N,N,N-trimethyl-3-(octadec-1-en-2-ylsulfonyl)propan-1-aminium chloride
  参考文献：
  名称：

  Vinyl sulfone analogs of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma

  摘要：

  Autotaxin (ATX) is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. This unique ectonucleotide pyrophosphatase and phosphodiesterase facilitates the removal of a choline headgroup from lysophosphatidylcholine (LPC) to yield lysophosphatidic acid (LPA), which is a potent lipid stimulator of tumorigenesis. Thus, ATX has received renewed attention because it has a prominent role in malignant progression with significant translational potential. Specifically, we sought to develop active site-targeted irreversible inhibitors as anti-cancer agents. Herein we describe the synthesis and biological activity of an LPC-mimetic electrophilic affinity label that targets the active site of ATX, which has a critical threonine residue that acts as a nucleophile in the lysophospholipase D reaction to liberate choline. We synthesized a set of quaternary ammonium derivative-containing vinyl sulfone analogs of LPC that function as irreversible inhibitors of ATX and inactivate the enzyme. The analogs were tested in cell viability assays using multiple cancer cell lines. The IC50 values ranged from 6.74 to 0.39 mu M, consistent with a K-i of 3.50 mu M for inhibition of ATX by the C16H33 vinyl sulfone analog CVS-16 (10b). A phenyl vinyl sulfone control compound, PVS-16, lacking the choline-like quaternary ammonium mimicking head group moiety, had little effect on cell viability and did not inhibit ATX. Most importantly, CVS-16 (10b) significantly inhibited melanoma progression in an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that CVS-16 (10b) is a potent and irreversible ATX inhibitor with significant biological activity both in vitro and in vivo. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.06.054

文献信息

• Vinyl sulfone analogs of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma
  作者：Mandi M. Murph、Guowei W. Jiang、Molly K. Altman、Wei Jia、Duy T. Nguyen、Jada M. Fambrough、William J. Hardman、Ha T. Nguyen、Sterling K. Tran、Ali A. Alshamrani、Damian Madan、Jianxing Zhang、Glenn D. Prestwich

  DOI：10.1016/j.bmc.2015.06.054

  日期：2015.9

  Autotaxin (ATX) is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. This unique ectonucleotide pyrophosphatase and phosphodiesterase facilitates the removal of a choline headgroup from lysophosphatidylcholine (LPC) to yield lysophosphatidic acid (LPA), which is a potent lipid stimulator of tumorigenesis. Thus, ATX has received renewed attention because it has a prominent role in malignant progression with significant translational potential. Specifically, we sought to develop active site-targeted irreversible inhibitors as anti-cancer agents. Herein we describe the synthesis and biological activity of an LPC-mimetic electrophilic affinity label that targets the active site of ATX, which has a critical threonine residue that acts as a nucleophile in the lysophospholipase D reaction to liberate choline. We synthesized a set of quaternary ammonium derivative-containing vinyl sulfone analogs of LPC that function as irreversible inhibitors of ATX and inactivate the enzyme. The analogs were tested in cell viability assays using multiple cancer cell lines. The IC50 values ranged from 6.74 to 0.39 mu M, consistent with a K-i of 3.50 mu M for inhibition of ATX by the C16H33 vinyl sulfone analog CVS-16 (10b). A phenyl vinyl sulfone control compound, PVS-16, lacking the choline-like quaternary ammonium mimicking head group moiety, had little effect on cell viability and did not inhibit ATX. Most importantly, CVS-16 (10b) significantly inhibited melanoma progression in an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that CVS-16 (10b) is a potent and irreversible ATX inhibitor with significant biological activity both in vitro and in vivo. (C) 2015 Elsevier Ltd. All rights reserved.