N-(3'-nitrobenzoyl)deacetylthiocolchicine | 147950-71-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(3'-nitrobenzoyl)deacetylthiocolchicine
• 英文别名: 3-nitro-N-[(7S)-1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-6,7-dihydro-5H-benzo[a]heptalen-7-yl]benzamide
• CAS: 147950-71-8
• 化学式: C₂₇H₂₆N₂O₇S
• 分子量: 522.579
• InChiKey: CWFCMSGWUJNTEL-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  37
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  145
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-(3'-nitrobenzoyl)deacetylthiocolchicine 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 以60%的产率得到3-nitro-N-[(7S)-1,2,3-trihydroxy-10-methylsulfanyl-9-oxo-6,7-dihydro-5H-benzo[a]heptalen-7-yl]benzamide
  参考文献：
  名称：

  Antitumor Agents. 185. Synthesis and Biological Evaluation of Tridemethylthiocolchicine Analogues as Novel Topoisomerase II Inhibitors

  摘要：

  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.

  DOI：

  10.1021/jm980007f
• 作为产物：
  描述：

  秋水仙碱 在 盐酸 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 24.0h， 生成 N-(3'-nitrobenzoyl)deacetylthiocolchicine
  参考文献：
  名称：

  抗肿瘤药。141.新型硫代秋水仙碱类似物的合成和生物学评价：N-酰基-，N-芳酰基-和N-（取代的苄基）脱乙酰基硫代秋水仙碱为有效的细胞毒性和抗有丝分裂化合物。

  摘要：

  合成了三个新的硫代秋水仙碱类似物系列，N-酰基-，N-芳酰基-和N-（取代的苄基）-去乙酰基硫代秋水仙碱类，并评估了它们对各种肿瘤细胞系，特别是实体肿瘤细胞系的细胞毒性，以及它们的毒性。体外对微管蛋白聚合的抑制作用。这些化合物中的大多数对微管蛋白的聚合均显示出强大的抑制作用，可与硫代秋水仙碱相比，但大于秋水仙碱。只有在C（7）位置具有长侧链的化合物，例如22-24，才不会抑制微管蛋白聚合。与大多数类秋水仙碱类药物观察到的负旋光度相反，几种活性N-芳酰基脱乙酰基硫代秋水仙碱类似物具有正旋光度。该性质可能归因于联芳构型从正常的aS逆转为aR。因此，通过圆二色性进一步评估了N-芳酰基类似物，该二色性容易区分aS和aR联芳基构型。后一种技术证明了活性N-芳酰基类似物确实具有aS构型，尽管它们具有正旋光度。然而，N-（取代的苄基）-脱乙酰基硫代秋水仙碱与相应的N-芳酰基-脱乙酰基硫代秋水仙碱的1 H

  DOI：

  10.1021/jm00062a021

文献信息

• Antitumor agents. 141. Synthesis and biological evaluation of novel thiocolchicine analogs: N-acyl, N-aroyl-, and N-(substituted benzyl)deacetylthiocolchicines as potent cytotoxic and antimitotic compounds
  作者：Li Sun、Ernest Hamel、Chii M. Lin、Susan B. Hastie、Amy Pyluck、Kuo Hsiung Lee

  DOI：10.1021/jm00062a021

  日期：1993.5

  rotations. However, comparison of 1H NMR and UV spectral data of N-(substituted benzyl)-deacetylthiocolchicines with those of corresponding N-aroyldeacetylthiocolchicines suggested a different biaryl dihedral angle [even though these compounds have the same aS biaryl configuration]. The similar tubulin binding properties of these compounds suggest that a biaryl dihedral angle of 53 degrees is not essential

  合成了三个新的硫代秋水仙碱类似物系列，N-酰基-，N-芳酰基-和N-（取代的苄基）-去乙酰基硫代秋水仙碱类，并评估了它们对各种肿瘤细胞系，特别是实体肿瘤细胞系的细胞毒性，以及它们的毒性。体外对微管蛋白聚合的抑制作用。这些化合物中的大多数对微管蛋白的聚合均显示出强大的抑制作用，可与硫代秋水仙碱相比，但大于秋水仙碱。只有在C（7）位置具有长侧链的化合物，例如22-24，才不会抑制微管蛋白聚合。与大多数类秋水仙碱类药物观察到的负旋光度相反，几种活性N-芳酰基脱乙酰基硫代秋水仙碱类似物具有正旋光度。该性质可能归因于联芳构型从正常的aS逆转为aR。因此，通过圆二色性进一步评估了N-芳酰基类似物，该二色性容易区分aS和aR联芳基构型。后一种技术证明了活性N-芳酰基类似物确实具有aS构型，尽管它们具有正旋光度。然而，N-（取代的苄基）-脱乙酰基硫代秋水仙碱与相应的N-芳酰基-脱乙酰基硫代秋水仙碱的1 H
• 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.