methyl (1R,12S)-10-[(E)-3-(2-methoxypyrimidin-5-yl)prop-2-enoyl]-4-methyl-7-oxo-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),3,8-triene-3-carboxylate | 221549-90-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: methyl (1R,12S)-10-[(E)-3-(2-methoxypyrimidin-5-yl)prop-2-enoyl]-4-methyl-7-oxo-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),3,8-triene-3-carboxylate
• CAS: 221549-90-2
• 化学式: C₂₂H₂₀N₄O₅
• 分子量: 420.425
• InChiKey: SAQFYMBVUZIHHH-SEYGGROISA-N

物化性质

• 沸点：
  798.9±70.0 °C(Predicted)
• 密度：
  1.48±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  115
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl (1R,12S)-10-[(E)-3-(2-methoxypyrimidin-5-yl)prop-2-enoyl]-4-methyl-7-oxo-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),3,8-triene-3-carboxylate 在 氢溴酸 、 三乙胺 作用下， 以 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 1.33h， 生成 methyl (1S)-1-(bromomethyl)-7-methyl-5-<(4-methylpiperazinyl)carbonyloxy>-3-<2-(4-methoxy-3,5-pyrimidinyl)ethen-1-ylcarbonyl>-1,2-dihydro-3H-pyrrolo<3,2-e>indole-8-carboxylate
  参考文献：
  名称：

  New Water-Soluble Duocarmycin Derivatives: Synthesis and Antitumor Activity of A-Ring Pyrrole Compounds Bearing β-Heteroarylacryloyl Groups

  摘要：

  A series of A-ring pyrrole compounds of duocarmycin bearing 4'-methoxy-beta-heteroarylacryloyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S-3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. Most of the Li 4'-methoxy-beta-heteroarylacrylates displayed in vitro anticellular activity equivalent to that of 4'-methoxycinnamates, Among the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates, compound 15b having a (4-methoxy-3,5-pyrimidinyl)acryloyl as segment-B (Seg-B) showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in Seg-B, which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates. Moreover, these 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates had high aqueous solubility.

  DOI：

  10.1021/jm980559y
• 作为产物：
  描述：

  3-methoxycarbonyl-2-methylduocarmycin A 在 sodium hydride 作用下， 以 甲醇 为溶剂， 生成 methyl (1R,12S)-10-[(E)-3-(2-methoxypyrimidin-5-yl)prop-2-enoyl]-4-methyl-7-oxo-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),3,8-triene-3-carboxylate
  参考文献：
  名称：

  Synthesis and antitumor activity of duocarmycin derivatives: modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups

  摘要：

  A series of the 8-O-substituted A-ring pyrrole derivatives of duocarmycin bearing the simplified DNA-binding moieties such as cinnamoyl or heteroarylacryloyl groups were synthesized, and evaluated for in vitro anticellular activity against HeLa S-3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the 8-O-substituted analogues in aqueous solution and the conversion to their active form (cyclopropane compound) from the 8-O-substituted analogues in mice or human serum were examined. The 8-O-substituted A-ring pyrrole derivatives bearing the simplified DNA-binding moieties showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the 8-O-substituted A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment-B (Seg-B), which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates and 4'-methoxy-beta-heteroarylacrylates. Moreover, among 8-O-substituted analogues, several compounds can be chemically or enzymatically converted to their active form in human serum. This result indicated that new 8-O-substituted derivatives were different prodrugs from KW-2189 and 8-O-substituted analogues being the same type of prodrug as KW-21S9. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(99)00293-x

文献信息

• Synthesis and antitumor activity of duocarmycin derivatives: modification at C-8 position of A-ring pyrrole compounds bearing the simplified DNA-binding groups
  作者：Nobuyoshi Amishiro、Satoru Nagamura、Chikara Murakata、Akihiko Okamoto、Eiji Kobayashi、Masao Asada、Katsushige Gomi、Tatsuya Tamaoki、Masami Okabe、Naoko Yamaguchi、Kazuo Yamaguchi、Hiromitsu Saito

  DOI：10.1016/s0968-0896(99)00293-x

  日期：2000.2

  A series of the 8-O-substituted A-ring pyrrole derivatives of duocarmycin bearing the simplified DNA-binding moieties such as cinnamoyl or heteroarylacryloyl groups were synthesized, and evaluated for in vitro anticellular activity against HeLa S-3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. In addition, the stability of the 8-O-substituted analogues in aqueous solution and the conversion to their active form (cyclopropane compound) from the 8-O-substituted analogues in mice or human serum were examined. The 8-O-substituted A-ring pyrrole derivatives bearing the simplified DNA-binding moieties showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the 8-O-substituted A-ring pyrrole derivatives having the trimethoxyindole skeleton in segment-B (Seg-B), which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates and 4'-methoxy-beta-heteroarylacrylates. Moreover, among 8-O-substituted analogues, several compounds can be chemically or enzymatically converted to their active form in human serum. This result indicated that new 8-O-substituted derivatives were different prodrugs from KW-2189 and 8-O-substituted analogues being the same type of prodrug as KW-21S9. (C) 2000 Elsevier Science Ltd. All rights reserved.
• New Water-Soluble Duocarmycin Derivatives: Synthesis and Antitumor Activity of A-Ring Pyrrole Compounds Bearing β-Heteroarylacryloyl Groups
  作者：Nobuyoshi Amishiro、Satoru Nagamura、Eiji Kobayashi、Katsushige Gomi、Hiromitsu Saito

  DOI：10.1021/jm980559y

  日期：1999.2.1

  A series of A-ring pyrrole compounds of duocarmycin bearing 4'-methoxy-beta-heteroarylacryloyl groups were synthesized and evaluated for in vitro anticellular activity against HeLa S-3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. Most of the Li 4'-methoxy-beta-heteroarylacrylates displayed in vitro anticellular activity equivalent to that of 4'-methoxycinnamates, Among the 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates, compound 15b having a (4-methoxy-3,5-pyrimidinyl)acryloyl as segment-B (Seg-B) showed remarkably potent in vivo antitumor activity and low peripheral blood toxicity compared with the A-ring pyrrole derivatives having the trimethoxyindole skeleton in Seg-B, which were equal to 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxycinnamates. Moreover, these 8-O-[(N-methylpiperazinyl)carbonyl] derivatives of 4'-methoxy-beta-heteroarylacrylates had high aqueous solubility.