1,11-dichloro-12-(4-O-methyl-β-D-glucopyranosyl)-6,13-dimethyl-6,7,12,13-tetrahydroindolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione | 205386-71-6

• 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: 1,11-dichloro-12-(4-O-methyl-β-D-glucopyranosyl)-6,13-dimethyl-6,7,12,13-tetrahydroindolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione
• 英文别名: 5,21-dichloro-3-[(2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]-13,23-dimethyl-3,13,23-triazahexacyclo[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: 205386-71-6
• 化学式: C₂₉H₂₅Cl₂N₃O₇
• 分子量: 598.439
• InChiKey: MPVYKSPETVLKLL-LSSWXCIKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  41
• 可旋转键数：
  3
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  126
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1,11-dichloro-12-(4-O-methyl-β-D-glucopyranosyl)-6,13-dimethyl-6,7,12,13-tetrahydroindolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione 在 sodium hydroxide 、 Ra-Ni 作用下， 反应 3.0h， 以45%的产率得到12-(4-O-methyl-β-D-glucopyranosyl)-13-N-methyl-6,7,12,13-tetrahydro-5,7-dioxo(5H)indolo[2,3-a]furo[3,4-c]carbazole
  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+
• 作为产物：
  描述：

  蝴蝶霉素 、 碘甲烷 在 sodium hydride 作用下， 生成 1,11-dichloro-12-(4-O-methyl-β-D-glucopyranosyl)-6,13-dimethyl-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

• 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.