3,9-dibromo-12-(4-O-methyl-β-D-glucopyranosyl)-6,7,12,13-tetrahydroindolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione | 205386-78-3

• 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: 3,9-dibromo-12-(4-O-methyl-β-D-glucopyranosyl)-6,7,12,13-tetrahydroindolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione
• 英文别名: 7,19-dibromo-3-[(2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]-13-oxa-3,23-diazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1,4(9),5,7,10,15,17(22),18,20-nonaene-12,14-dione
• CAS: 205386-78-3
• 化学式: C₂₇H₂₀Br₂N₂O₈
• 分子量: 660.272
• InChiKey: OYAIAOPGGDONAT-XTRZKMQQSA-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：
  3
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  143
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3,9-dibromo-12-(4-O-methyl-β-D-glucopyranosyl)-6,7,12,13-tetrahydroindolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione 在 乙酸铵 作用下， 反应 3.0h， 以67%的产率得到3,9-dibromo-12-(4-O-methyl-β-D-glucopyranosyl)-6,7,12,13-tetrahydroindolo<2,3-a>pyrrolo<3,4-c>carbazole-5,7-dione
  参考文献：
  名称：

  Synthesis, Mode of Action, and Biological Activities of Rebeccamycin Bromo Derivatives

  摘要：

  Bromo analogues of the natural metabolite rebeccamycin with and without a methyl substituent on the imide nitrogen were synthesized. The effects of the drugs on protein kinase C, the binding to DNA, and the effect on topoisomerase I were determined. The drugs' uptake and their antiproliferative activities against P388 leukemia cells sensitive and resistant to camptothecin, their antimicrobial activity against a Gram-positive bacterium (B. cereus), and their anti-HIV-1 activity were measured and compared to those of the chlorinated and dechlorinated analogues. Dibrominated imide 5 shows a remarkable activity against topoisomerase I, affecting both the kinase and DNA cleavage activity of the enzyme. The marked cytotoxic potency of this compound depends essentially on its capacity to inhibit topoisomerase I.

  DOI：

  10.1021/jm980702n
• 作为产物：
  描述：

  12-(4-O-methyl-β-D-glucopyranosyl)-12,13-dihydrofuro[3,4-c]-indolo[2,3-a]carbazole-5,7-dione 在 N-溴代丁二酰亚胺(NBS) 作用下， 以 四氢呋喃 为溶剂， 反应 168.0h， 以71%的产率得到3,9-dibromo-12-(4-O-methyl-β-D-glucopyranosyl)-6,7,12,13-tetrahydroindolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione
  参考文献：
  名称：

  Syntheses and Biological Evaluation of Indolocarbazoles, Analogues of Rebeccamycin, Modified at the Imide Heterocycle

  摘要：

  A series of 10 indolocarbazole derivatives, analogues to the antitumor antibiotic rebeccamycin, bearing modifications at the imide heterocycle were synthesized. They bear an N-methyl imide, N-methyl amide, or anhydride function instead of the original imide. Their inhibitory potencies toward topoisomerase I were examined using a DNA relaxation assay and by analyzing the drug-induced cleavage of P-32-labeled DNA. Protein kinase C (PKC) inhibition and interaction with DNA were also studied together with the in vitro antiproliferative activities against B16 melanoma and P388 leukemia cells. The antimicrobial activities against two Gram-positive bacteria (Bacillus cereus and Streptomyces chartreusis), a Gram-negative bacterium (Escherichia coli), and a yeast (Candida albicans) were tested as well as their antiviral activities toward HIV-1. The efficiency of the anhydride compounds was compared to that of the parent compound rebeccamycin and its dechlorinated analogue. All the compounds studied were inactive against PKC. The structural requirements for PKC and topoisomerase I inhibition are markedly different. In sharp contrast with the structure-PKC inhibition relationships, we found that an anhydride function does not affect topoisomerase I inhibition, whereas a methyl group on the indole nitrogen prevents the poisoning of topoisomerase I. The compounds exhibiting a marked toxicity to P388 leukemia cells had little or no effect on the growth of P388CPT5 cells which are resistant to the topoisomerase I inhibitor camptothecin. This study reinforces the conclusion that the DNA-topoisomerase I cleavable complex is the primary cellular target of the indolocarbazoles and significantly contributes to their cytotoxicity and possibly to their weak but noticeable anti-HIV-1 activities. The structure-activity relationships are also discussed.

  DOI：

  10.1021/jm970843+

文献信息

• Synthesis, Mode of Action, and Biological Activities of Rebeccamycin Bromo Derivatives
  作者：Pascale Moreau、Fabrice Anizon、Martine Sancelme、Michelle Prudhomme、Danièle Sevère、Jean-François Riou、Jean-François Goossens、Jean-Pierre Hénichart、Christian Bailly、Emmanuel Labourier、Jamal Tazzi、Doriano Fabbro、Thomas Meyer、A. M. Aubertin

  DOI：10.1021/jm980702n

  日期：1999.5.1

  Bromo analogues of the natural metabolite rebeccamycin with and without a methyl substituent on the imide nitrogen were synthesized. The effects of the drugs on protein kinase C, the binding to DNA, and the effect on topoisomerase I were determined. The drugs' uptake and their antiproliferative activities against P388 leukemia cells sensitive and resistant to camptothecin, their antimicrobial activity against a Gram-positive bacterium (B. cereus), and their anti-HIV-1 activity were measured and compared to those of the chlorinated and dechlorinated analogues. Dibrominated imide 5 shows a remarkable activity against topoisomerase I, affecting both the kinase and DNA cleavage activity of the enzyme. The marked cytotoxic potency of this compound depends essentially on its capacity to inhibit topoisomerase I.
• Syntheses and Biological Evaluation of Indolocarbazoles, Analogues of Rebeccamycin, Modified at the Imide Heterocycle
  作者：Pascale Moreau、Fabrice Anizon、Martine Sancelme、Michelle Prudhomme、Christian Bailly、Carolina Carrasco、Monique Ollier、Danièle Sevère、Jean-François Riou、Doriano Fabbro、Thomas Meyer、Anne-Marie Aubertin

  DOI：10.1021/jm970843+

  日期：1998.5.1

  A series of 10 indolocarbazole derivatives, analogues to the antitumor antibiotic rebeccamycin, bearing modifications at the imide heterocycle were synthesized. They bear an N-methyl imide, N-methyl amide, or anhydride function instead of the original imide. Their inhibitory potencies toward topoisomerase I were examined using a DNA relaxation assay and by analyzing the drug-induced cleavage of P-32-labeled DNA. Protein kinase C (PKC) inhibition and interaction with DNA were also studied together with the in vitro antiproliferative activities against B16 melanoma and P388 leukemia cells. The antimicrobial activities against two Gram-positive bacteria (Bacillus cereus and Streptomyces chartreusis), a Gram-negative bacterium (Escherichia coli), and a yeast (Candida albicans) were tested as well as their antiviral activities toward HIV-1. The efficiency of the anhydride compounds was compared to that of the parent compound rebeccamycin and its dechlorinated analogue. All the compounds studied were inactive against PKC. The structural requirements for PKC and topoisomerase I inhibition are markedly different. In sharp contrast with the structure-PKC inhibition relationships, we found that an anhydride function does not affect topoisomerase I inhibition, whereas a methyl group on the indole nitrogen prevents the poisoning of topoisomerase I. The compounds exhibiting a marked toxicity to P388 leukemia cells had little or no effect on the growth of P388CPT5 cells which are resistant to the topoisomerase I inhibitor camptothecin. This study reinforces the conclusion that the DNA-topoisomerase I cleavable complex is the primary cellular target of the indolocarbazoles and significantly contributes to their cytotoxicity and possibly to their weak but noticeable anti-HIV-1 activities. The structure-activity relationships are also discussed.