12-(4-O-methyl-β-D-glucopyranosyl)-12,13-dihydrofuro[3,4-c]-indolo[2,3-a]carbazole-5,7-dione | 156330-65-3

• 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: 12-(4-O-methyl-β-D-glucopyranosyl)-12,13-dihydrofuro[3,4-c]-indolo[2,3-a]carbazole-5,7-dione
• 英文别名: 12-(4-O-methyl-beta-D-glucopyranosyl)-12,13-dihydrofuro[3,4-c]-indolo[2,3-a]carbazole-5,7-dione；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-1,4,6,8,10,15,17,19,21-nonaene-12,14-dione
• CAS: 156330-65-3
• 化学式: C₂₇H₂₂N₂O₈
• 分子量: 502.48
• InChiKey: YQKBDCBVOSOPEA-XTRZKMQQSA-N

物化性质

• 沸点：
  806.5±65.0 °C(predicted)
• 密度：
  1.74±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  37
• 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：

  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+
• 作为产物：
  描述：

  蝴蝶霉素 在 镍 sodium hydroxide 、 氢气 作用下， 生成 12-(4-O-methyl-β-D-glucopyranosyl)-12,13-dihydrofuro[3,4-c]-indolo[2,3-a]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

文献信息

• Novel hydroxyalkyl indolocarbazole derivatives, preparation method and pharmaceutical compositions containing the same
  申请人：——

  公开号：US20040242508A1

  公开（公告）日：2004-12-02

  Compound of formula (I): 1 wherein: R 1 and R 2 each represents a group selected from hydrogen, alkyl, arylalkyl, hydroxy, hydroxyalkyl, dihydroxyalkyl, alkoxy, alkoxyalkyl, amino and aminoalkyl (optionally substituted), Ra and Rb each represents an alkylene chain, X 1 , X 2 and X 3 each represents a group selected from hydroxy, alkoxy, aryloxy, arylalkoxy, alkyl, amino (optionally substituted), halogen, alkylcarbonyloxy and azido, X 4 represents a methylidene group or a group of formula —Rc—X 1 as defined in the description, their isomers and also their addition salts with a pharmaceutically acceptable acid or base.

  化合物的结构式（I）如下：其中：R1和R2分别代表从氢、烷基、芳基烷基、羟基、羟基烷基、二羟基烷基、烷氧基、烷氧基烷基、氨基和氨基烷基（可选择取代）中选择的基团，Ra和Rb各自代表一个烷基链，X1、X2和X3分别代表从羟基、烷氧基、芳氧基、芳基烷氧基、烷基、氨基（可选择取代）、卤素、烷基羰氧基和叠氮基中选择的基团，X4代表一个甲基亚甲基基团或一个按照说明中定义的公式—Rc—X1的基团，它们的异构体以及它们与药学上可接受的酸或碱形成的加合盐。
• 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.
• Dimers from dechlorinated rebeccamycin: synthesis, interaction with DNA, and antiproliferative activities
  作者：Christelle Marminon、Michaël Facompré、Christian Bailly、John Hickman、Alain Pierré、Bruno Pfeiffer、Pierre Renard、Michelle Prudhomme

  DOI：10.1016/s0223-5234(02)01350-8

  日期：2002.5

  In the course of structure-activity relationships on rebeccamycin analogues, two dimers of dechlorinated rebeccamycin were synthesised with the aim to improve the interaction with DNA and in vitro antiproliferative activities. The synthesis of two dimeric compounds obtained by joining two molecules of dechlorinated rebeccamycin via the imide nitrogen is described. Melting temperature and DNase I footprinting studies were performed to investigate their interaction with DNA. Four tumour cell lines, murine L1210 leukaemia, human HT29 colon carcinoma, A549 non-small cell lung carcinoma and K-562 leukaemia, were used to evaluate the cytotoxicity of the drugs. Their effects on the cell cycle of L1210 cells were also investigated. (C) 2002 Editions scientifiques et medicales Elsevier SAS. All rights reserved.
• Analogues of antifungal tjipanazoles from rebeccamycin
  作者：Aline Voldoire、Pascale Moreau、Martine Sancelme、Maria Matulova、Stéphane Léonce、Alain Pierré、John Hickman、Bruno Pfeiffer、Pierre Renard、Nathalie Dias、Christian Bailly、Michelle Prudhomme

  DOI：10.1016/j.bmc.2004.01.024

  日期：2004.4

  Analogues of antifungal tjipanazoles were obtained by semi-synthesis from rebeccamycin, an antitumor antibiotic isolated from cultures of Saccharothrix aerocolonigenes. The anti proliferative activities of the new compounds were evaluated in vitro against nine tumor cell lines. The effect on the cell cycle of murine leukemia L1210 cells was examined and the antimicrobial activities against two Gram positive bacteria, a Gram negative bacterium and a yeast were determined. The inhibitory properties toward four kinases and toward topoisomerase I were evaluated. The most cytotoxic compound in the series was a dinitro derivative characterized as a potent topoisomerase I inhibitor. (C) 2004 Elsevier Ltd. All rights reserved.
• 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.