8-O-(tert-butyldimethylsilyl)-2-methyl-3-carboxy-A-ring-pyrrole-duocarmicyn B2 | 205051-58-7

• 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: 8-O-(tert-butyldimethylsilyl)-2-methyl-3-carboxy-A-ring-pyrrole-duocarmicyn B2
• CAS: 205051-58-7
• 化学式: C₃₁H₃₈BrN₃O₇Si
• 分子量: 672.648
• InChiKey: CJLFFOCFAHMRKG-QGZVFWFLSA-N

物化性质

• 沸点：
  773.874±60.00 °C(Press: 760.00 Torr)(predicted)
• 密度：
  1.376±0.06 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  43.0
• 可旋转键数：
  8.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  126.11
• 氢给体数：
  3.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  8-O-(tert-butyldimethylsilyl)-2-methyl-3-carboxy-A-ring-pyrrole-duocarmicyn B2 在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 0.75h， 以79%的产率得到(1R,12S)-4-methyl-7-oxo-10-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),3,8-triene-3-carboxylic acid
  参考文献：
  名称：

  Synthesis and Antitumor Activity of Duocarmycin Derivatives:  Modification of Segment-A of A-Ring Pyrrole Compounds

  摘要：

  A series of S-substituted A-ring pyrrole compounds of duocarmycin 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. These compounds were evaluated on the peripheral blood toxicity and delayed lethal toxicity. Further, to expand our investigation of their peripheral blood toxicity, the toxicity to bone marrow cells (CFU-GM, CFU-Meg) was investigated. Among S-substituted A-ring pyrrole compounds of duocarmycin bearing a 5',6',7'-trimethoxy-2'-indolecarboxyl group as segment-B (Seg-B), several analogues showed remarkably potent antitumor activity with low peripheral blood toxicity. The 3-formyl compound 12h, one of such analogues, showed stronger antitumor activity with lower toxicity to bone marrow cells compared to DU-86 (2a), an active metabolite of KW-2189 (2b). However, compound 12h caused delayed death. On the other hand, the 3-bromo compound 15f, one of the 3-substituted A-ring pyrrole derivatives bearing a 4'-methoxycinnamoyl group as Seg-B, showed the most potent antitumor activity among the 4'-methoxycinnamate analogues with low toxicity to bone marrow cells. Furthermore, compound 15f did not cause delayed death similarly to 2d. These results would indicate the importance of the C-3 substituents of A-ring pyrrole duocarmycin derivatives for exhibiting antitumor activity and decreasing toxicity.

  DOI：

  10.1021/jm990094r
• 作为产物：
  描述：

  (2R,8S)-8-Bromomethyl-4-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-2-methyl-6-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-1,2,3,6,7,8-hexahydro-pyrrolo[3,2-e]indole-2-carboxylic acid benzyl ester 在 palladium on activated charcoal 三氟化硼乙醚 、 甲酸铵 作用下， 以 四氢呋喃 、 氯仿 为溶剂， 反应 18.0h， 生成 8-O-(tert-butyldimethylsilyl)-2-methyl-3-carboxy-A-ring-pyrrole-duocarmicyn B2
  参考文献：
  名称：

  Synthesis and Antitumor Activity of Duocarmycin Derivatives:  Modification of Segment-A of A-Ring Pyrrole Compounds

  摘要：

  A series of S-substituted A-ring pyrrole compounds of duocarmycin 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. These compounds were evaluated on the peripheral blood toxicity and delayed lethal toxicity. Further, to expand our investigation of their peripheral blood toxicity, the toxicity to bone marrow cells (CFU-GM, CFU-Meg) was investigated. Among S-substituted A-ring pyrrole compounds of duocarmycin bearing a 5',6',7'-trimethoxy-2'-indolecarboxyl group as segment-B (Seg-B), several analogues showed remarkably potent antitumor activity with low peripheral blood toxicity. The 3-formyl compound 12h, one of such analogues, showed stronger antitumor activity with lower toxicity to bone marrow cells compared to DU-86 (2a), an active metabolite of KW-2189 (2b). However, compound 12h caused delayed death. On the other hand, the 3-bromo compound 15f, one of the 3-substituted A-ring pyrrole derivatives bearing a 4'-methoxycinnamoyl group as Seg-B, showed the most potent antitumor activity among the 4'-methoxycinnamate analogues with low toxicity to bone marrow cells. Furthermore, compound 15f did not cause delayed death similarly to 2d. These results would indicate the importance of the C-3 substituents of A-ring pyrrole duocarmycin derivatives for exhibiting antitumor activity and decreasing toxicity.

  DOI：

  10.1021/jm990094r