(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid ((S)-1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-5,6,7,9-tetrahydro-benzo[a]heptalen-7-yl)-amide | 203584-67-2

• 分子结构分类: 有机化合物 - 碳氢化合物衍生物 - 环庚三烯酮
• 英文名称: (1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid ((S)-1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-5,6,7,9-tetrahydro-benzo[a]heptalen-7-yl)-amide
• 英文别名: (1S,4R)-4,7,7-trimethyl-3-oxo-N-[(7S)-1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-6,7-dihydro-5H-benzo[a]heptalen-7-yl]-2-oxabicyclo[2.2.1]heptane-1-carboxamide
• CAS: 203584-67-2
• 化学式: C₃₀H₃₅NO₇S
• 分子量: 553.676
• InChiKey: GYBKEYUKEQTTKB-WBXDDPHESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  39
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  126
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid ((S)-1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-5,6,7,9-tetrahydro-benzo[a]heptalen-7-yl)-amide 在 盐酸 作用下， 反应 72.0h， 以10%的产率得到(7S)-7-氨基-1,2,3-三甲氧基-10-甲硫基-6,7-二氢-5H-苯并[g]庚搭烯-9-酮
  参考文献：
  名称：

  Antitumor agents—CLXXV. Anti-tubulin action of (+)-thiocolchicine prepared by partial synthesis

  摘要：

  (+)-硫秋水仙素(2b)由(+/-)-秋水仙素(1)经过五步反应制得，其中包括对合适樟脑化衍生物的色谱分离。对(+)-立体异构体进行酸水解，随后乙酰化，得到目标产物2b。与(-)-硫秋水仙素相比，(+)-硫秋水仙素对微管聚合的抑制活性低15倍，且对人骨髓瘤细胞生长的抑制效力低29倍。由(-)-樟脑化立体异构体制备的对映体2a，在所有测定中的活性均与采用其他方法制备的(-)-硫秋水仙素相当。这些结果支持以下假设：秋水仙素相关化合物的正确构型是其抗微管作用的重要要求。 (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0968-0896(97)00171-5
• 作为产物：
  描述：

  N-(1,2,3,10-四甲氧基-9-氧代-5,6,7,9-四氢苯并[a]庚搭烯-7-基)乙酰胺 在 吡啶 、 盐酸 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 60.0h， 生成 (1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxa-bicyclo[2.2.1]heptane-1-carboxylic acid ((S)-1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-5,6,7,9-tetrahydro-benzo[a]heptalen-7-yl)-amide
  参考文献：
  名称：

  Antitumor agents—CLXXV. Anti-tubulin action of (+)-thiocolchicine prepared by partial synthesis

  摘要：

  (+)-硫秋水仙素(2b)由(+/-)-秋水仙素(1)经过五步反应制得，其中包括对合适樟脑化衍生物的色谱分离。对(+)-立体异构体进行酸水解，随后乙酰化，得到目标产物2b。与(-)-硫秋水仙素相比，(+)-硫秋水仙素对微管聚合的抑制活性低15倍，且对人骨髓瘤细胞生长的抑制效力低29倍。由(-)-樟脑化立体异构体制备的对映体2a，在所有测定中的活性均与采用其他方法制备的(-)-硫秋水仙素相当。这些结果支持以下假设：秋水仙素相关化合物的正确构型是其抗微管作用的重要要求。 (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0968-0896(97)00171-5

文献信息

• Antitumor Agents. 185. Synthesis and Biological Evaluation of Tridemethylthiocolchicine Analogues as Novel Topoisomerase II Inhibitors
  作者：Jian Guan、Xiao-Kang Zhu、Yoko Tachibana、Kenneth F. Bastow、Arnold Brossi、Ernest Hamel、Kuo-Hsiung Lee

  DOI：10.1021/jm980007f

  日期：1998.5.1

  Several 1,2,3-tridemethyldeacetylthiocolchicine derivatives have been synthesized and evaluated for cytotoxic activity against various human tumor cell lines and for their inhibitory effects on DNA topoisomerases in vitro. Exhaustive demethylation of thiocolchicine analogues completely changes their biological profiles. Instead of displaying antitubulin activity, most target compounds inhibited topoisomerase II activity. Only compounds with a larger side chain, such as 15a, 23a, and 24a, did not interfere with topoisomerase II enzymatic functions. The cytotoxicity of target compounds was reduced by 3 orders of magnitude compared to that of colchicine in most cell lines, The hydrophilicity of phenolic compounds might prevent drug passage through the cell plasma membrane and, thus, be responsible for the relatively weak cytotoxicity. To test this hypothesis, 27-30 were prepared from 16a by protecting all hydroxy groups with esters with an aim to facilitate drug transportation. In vitro cytotoxicity assays indicated that 27 was more potent than its parent compound in all tested tumor cell lines and showed tissue selective cytotoxicity with a significant inhibitory effect against KB cells (IC50 = 2.7 mu g/mL). Therefore, we propose that 27 acts as a prodrug, liberating 16a to exert its antitopoisomerase activity and, finally, to cause cell death.
• Antitumor agents—CLXXV. Anti-tubulin action of (+)-thiocolchicine prepared by partial synthesis
  作者：Qian Shi、Pascal Verdier-Pinard、Arnold Brossi、Ernest Hamel、Kuo-Hsiung Lee

  DOI：10.1016/s0968-0896(97)00171-5

  日期：1997.12

  (+)-Thiocolchicine (2b) was prepared from (+/-)-colchicine (1) in a five-step reaction sequence that included chromatographic separation of appropriate camphanylated diastereomers. Acid hydrolysis of the (+)-diastereomer, followed by acetylation, yielded the desired product 2b. (+)-Thiocolchicine has 15-fold lower inhibitory activity against tubulin polymerization than (-)-thiocolchicine, and is 29-fold less potent for inhibiting growth of human Burkitt lymphoma cells. The enantiomer 2a, prepared from the (-)-camphanylated diastereomer, had potent activity in all assays comparable to that of (-)-thiocolchicine prepared by other methods. These results support the hypothesis that the proper configuration of colchicine-related compounds is an important requirement for their anti-tubulin action. (C) 1997 Elsevier Science Ltd.

  (+)-硫秋水仙素(2b)由(+/-)-秋水仙素(1)经过五步反应制得，其中包括对合适樟脑化衍生物的色谱分离。对(+)-立体异构体进行酸水解，随后乙酰化，得到目标产物2b。与(-)-硫秋水仙素相比，(+)-硫秋水仙素对微管聚合的抑制活性低15倍，且对人骨髓瘤细胞生长的抑制效力低29倍。由(-)-樟脑化立体异构体制备的对映体2a，在所有测定中的活性均与采用其他方法制备的(-)-硫秋水仙素相当。这些结果支持以下假设：秋水仙素相关化合物的正确构型是其抗微管作用的重要要求。 (C) 1997 Elsevier Science Ltd.