(1R)-1-[[(2R,3R,11bS)-3-ethyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-yl]methyl]-N-[(4-chlorophenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbothioamide | 1393924-19-0

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 吐根碱生物碱
• 英文名称: (1R)-1-[[(2R,3R,11bS)-3-ethyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-yl]methyl]-N-[(4-chlorophenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbothioamide
• CAS: 1393924-19-0
• 化学式: C₃₇H₄₆ClN₃O₄S
• 分子量: 664.309
• InChiKey: HVOHLZRJSNDUAD-QJKWIJLYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  46
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  87.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  对氯苄胺 在 吡啶 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 2.75h， 生成 (1R)-1-[[(2R,3R,11bS)-3-ethyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-benzo[a]quinolizin-2-yl]methyl]-N-[(4-chlorophenyl)methyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbothioamide
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of pH-Dependent Hydrolyzable Emetine Analogues as Treatment for Prostate Cancer

  摘要：

  The N-2' position of the natural product emetine has been derivatized to thiourea, urea, sulfonamide, dithiocarbamate, carbamate, and pH responsive hydrolyzable amide analogues. In vitro studies of these analogues in PC3 and LNCaP prostate cancer cell lines showed that the analogues are generally less cytotoxic (average IC50 ranging from 0.079 to 10 mu M) than emetine (IC50 ranging from 0.0237 to 0.0329 mu M). The pH sensitive sodium dithiocarbamate salt 13 and the amide analogues 21, 22, 26 (obtained from maleic and citraconic anhydrides) showed the most promise as acid-activatable prodrugs under mildly acidic conditions found in the cancer microenvironment. These prodrugs released 12-83% of emetine at pH 6.5 and 41-95% emetine at pH 5.5. Compounds 13 and 26 were further shown to exhibit increased cytotoxicity in PC3 cell culture medium that was already below pH 7.0 at the time of treatment.

  DOI：

  10.1021/jm300426q

文献信息

• Design, Synthesis, and Evaluation of pH-Dependent Hydrolyzable Emetine Analogues as Treatment for Prostate Cancer
  作者：Emmanuel S. Akinboye、Marc D. Rosen、Samuel R. Denmeade、Bernard Kwabi-Addo、Oladapo Bakare

  DOI：10.1021/jm300426q

  日期：2012.9.13

  The N-2' position of the natural product emetine has been derivatized to thiourea, urea, sulfonamide, dithiocarbamate, carbamate, and pH responsive hydrolyzable amide analogues. In vitro studies of these analogues in PC3 and LNCaP prostate cancer cell lines showed that the analogues are generally less cytotoxic (average IC50 ranging from 0.079 to 10 mu M) than emetine (IC50 ranging from 0.0237 to 0.0329 mu M). The pH sensitive sodium dithiocarbamate salt 13 and the amide analogues 21, 22, 26 (obtained from maleic and citraconic anhydrides) showed the most promise as acid-activatable prodrugs under mildly acidic conditions found in the cancer microenvironment. These prodrugs released 12-83% of emetine at pH 6.5 and 41-95% emetine at pH 5.5. Compounds 13 and 26 were further shown to exhibit increased cytotoxicity in PC3 cell culture medium that was already below pH 7.0 at the time of treatment.