bis(2-((naphth-1-yloxy)methyl)morpholin-4-ylthiocarbonyl)disulfide

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: bis(2-((naphth-1-yloxy)methyl)morpholin-4-ylthiocarbonyl)disulfide
• 英文别名: [2-(Naphthalen-1-yloxymethyl)morpholine-4-carbothioyl]sulfanyl 2-(naphthalen-1-yloxymethyl)morpholine-4-carbodithioate；[2-(naphthalen-1-yloxymethyl)morpholine-4-carbothioyl]sulfanyl 2-(naphthalen-1-yloxymethyl)morpholine-4-carbodithioate
• 化学式: C₃₂H₃₂N₂O₄S₄
• 分子量: 636.881
• InChiKey: ZKJMGWRPIJJXKS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  42
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  158
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-benzyl-2-((naphth-1-yloxy)methyl)morpholine 在 palladium 10% on activated carbon 、 氢气 、 potassium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 50.0 ℃ 、101.33 kPa 条件下， 反应 0.5h， 生成 bis(2-((naphth-1-yloxy)methyl)morpholin-4-ylthiocarbonyl)disulfide
  参考文献：
  名称：

  Development of the First Generation of Disulfide-Based Subtype-Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors

  摘要：

  Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, on the basis of the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analogue, 3a, effectively inhibits PDK1 both at the molecular (k(mact)/K-i = 4.17 x 10(3) M-1 s(-1)) and the cellular level (down to 0.1 mu M). In contrast to 16, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4. 3a also significantly alters glucose metabolic pathways in A549 cells by decreasing ECAR and increasing ROS. Moreover, in the xenograft models, 3a shows significant antitumor activity with no negative effect to the mice weight. Collectively, these data demonstrate that 3a may be an excellent lead compound for the treatment of cancer as a first-generation subtype-selective and covalent PDK1 inhibitor.

  DOI：

  10.1021/acs.jmedchem.6b01245

文献信息

• Development of the First Generation of Disulfide-Based Subtype-Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors
  作者：Yifu Liu、Zuoquan Xie、Dan Zhao、Jin Zhu、Fei Mao、Shuai Tang、Hui Xu、Cheng Luo、Meiyu Geng、Min Huang、Jian Li

  DOI：10.1021/acs.jmedchem.6b01245

  日期：2017.3.23

  Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, on the basis of the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analogue, 3a, effectively inhibits PDK1 both at the molecular (k(mact)/K-i = 4.17 x 10(3) M-1 s(-1)) and the cellular level (down to 0.1 mu M). In contrast to 16, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4. 3a also significantly alters glucose metabolic pathways in A549 cells by decreasing ECAR and increasing ROS. Moreover, in the xenograft models, 3a shows significant antitumor activity with no negative effect to the mice weight. Collectively, these data demonstrate that 3a may be an excellent lead compound for the treatment of cancer as a first-generation subtype-selective and covalent PDK1 inhibitor.