5H-indolo(2,3-a)pyrrolo(3,4-c)carbazole-5,7(6h)-dione,1,11-dichloro-12,13-dihydro-12-(4-omethyl-beta-d-glucopyranosyl) | 205386-72-7

• 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: 5H-indolo(2,3-a)pyrrolo(3,4-c)carbazole-5,7(6h)-dione,1,11-dichloro-12,13-dihydro-12-(4-omethyl-beta-d-glucopyranosyl)
• 英文别名: 4’-O-methylrebeccamycin；rebeccamycin；12-(4-O-methyl-β-D-glucopyranosyl)-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione；12-(4-O-methyl-β-D-glucopyranosyl)-6,7,12,13-tetrahydroindolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione；12-(4-O-methyl-beta-D-glucopyranosyl)-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione；3-[(2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]-3,13,23-triazahexacyclo[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: 205386-72-7
• 化学式: C₂₇H₂₃N₃O₇
• 分子量: 501.496
• InChiKey: JNMXCWUKDUQJFF-HHJYCPGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 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：
  146
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5H-indolo(2,3-a)pyrrolo(3,4-c)carbazole-5,7(6h)-dione,1,11-dichloro-12,13-dihydro-12-(4-omethyl-beta-d-glucopyranosyl) 在 吡啶 、 硝酸 作用下， 以 乙醚 为溶剂， 反应 46.0h， 生成
  参考文献：
  名称：

  Semi-synthesis, topoisomerase I and kinases inhibitory properties, and antiproliferative activities of new rebeccamycin derivatives

  摘要：

  In the course of structure-activity relationship studies, new rebeccamycin derivatives substituted in 3,9-positions on the indolocarbazole framework, and a 2,3-anhydro derivative were prepared by semi-synthesis from rebeccamycin. The antiproliferative activities against nine tumor cell lines were determined and the effect on the cell cycle of murine leukemia L1210 cells was examined. Their DNA binding properties and inhibitory properties toward topoisomerase I and three kinases PKCzeta, CDKI/cyclin B, CDK5/p25 and a phosphatase cdc25A were evaluated. The 3,9-dihydroxy derivative is the most efficient compound of this series toward CDKI/cyclin B and CDK5/p25. It is also characterized as a DNA binding topoisomerase I poison. Its broad spectrum of molecular activities likely accounts for its cytotoxic potential. This compound which displays a tumor cell line-selectivity may represent a new lead for subsequent drug design in this series of glycosylated indolocarbazoles. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2003.09.014
• 作为产物：
  描述：

  蝴蝶霉素 在 palladium on activated charcoal 甲酸铵 作用下， 以 甲醇 为溶剂， 反应 72.0h， 以77%的产率得到5H-indolo(2,3-a)pyrrolo(3,4-c)carbazole-5,7(6h)-dione,1,11-dichloro-12,13-dihydro-12-(4-omethyl-beta-d-glucopyranosyl)
  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

• Facile Chemoenzymatic Strategies for the Synthesis and Utilization of<i>S</i>-Adenosyl-<scp>L</scp>-Methionine Analogues
  作者：Shanteri Singh、Jianjun Zhang、Tyler D. Huber、Manjula Sunkara、Katherine Hurley、Randal D. Goff、Guojun Wang、Wen Zhang、Chunming Liu、Jürgen Rohr、Steven G. Van Lanen、Andrew J. Morris、Jon S. Thorson

  DOI：10.1002/anie.201308272

  日期：2014.4.7

  the chemoenzymatic synthesis of 29 non‐native SAM analogues. As a proof of concept for the feasibility of natural product “alkylrandomization”, a small set of differentially‐alkylated indolocarbazole analogues was generated by using a coupled hMAT2–RebM system (RebM is the sugar C4′‐O‐methyltransferase that is involved in rebeccamycin biosynthesis). The ability to couple SAM synthesis and utilization

  据报道，用于合成S-腺苷-L-甲硫氨酸 (SAM) 类似物的化学酶平台与下游 SAM 利用酶兼容。合成了 44 种非天然 S/Se 烷基化 Met 类似物，并将其用于探测五种不同的蛋氨酸腺苷转移酶 (MAT) 的底物特异性。人类 MAT II 是所分析的 MAT 中最受允许的之一，并且能够化学酶合成 29 种非天然 SAM 类似物。作为天然产物“烷基随机化”可行性的概念证明，通过使用耦合的 hMAT2-RebM 系统（RebM 是参与瑞贝卡霉素的糖 C4'- O-甲基转移酶）生成了一小组差异烷基化吲哚并咔唑类似物。生物合成）。在单个容器中耦合 SAM 合成和利用的能力避免了与 SAM 类似物快速分解相关的问题，从而为进一步研究各种 SAM 利用酶打开了大门。
• 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。
• Natural Product Diversification Using a Non-natural Cofactor Analogue of <i>S</i>-Adenosyl-<scp>l</scp>-methionine
  作者：Changsheng Zhang、Rachel L. Weller、Jon S. Thorson、Scott R. Rajski

  DOI：10.1021/ja056231t

  日期：2006.3.1

  synthetic cofactor bearing a pendant 5'-amino acid N-mustard. Unlike previously studied synthetic cofactors, this material is very efficiently used by the natural product biosynthetic enzyme rebeccamycin methyltransferase (RebM) to generate a number of new rebeccamycin analogues. These data promote the notion that natural product methyltransferases can be used with non-natural cofactors to enhance

  带有 5'-氮丙啶或 5'-N-芥末亲电子试剂的腺苷类似物是甲基转移酶依赖性 DNA 烷化剂。我们在此展示了一种带有悬垂 5'-氨基酸 N-芥末的新型合成辅因子。与先前研究的合成辅因子不同，天然产物生物合成酶瑞贝卡霉素甲基转移酶 (RebM) 非常有效地使用这种材料来生成许多新的瑞贝卡霉素类似物。这些数据促进了天然产物甲基转移酶可与非天然辅因子一起使用以增强天然产物类似物的分子多样性以用于药物发现的概念。据我们所知，这是除 DNA 甲基转移酶之外的第一个生物甲基转移酶的文献，它可以利用这种合成辅因子。
• Anizon, Fabrice, Journal of Medicinal Chemistry, 1997, vol. 40, # 21, p. 3456 - 3465
  作者：Anizon, Fabrice

  DOI：——

  日期：——
• Synthesis and biological activities of indolocarbazoles bearing amino acid residues
  作者：P Moreau

  DOI：10.1016/s0223-5234(01)01284-3

  日期：2001.12.1

  Three indolocarbazole compounds bearing a tripeptide or a lysine group attached to one of the indole nitrogens via a propylamino chain and two rebeccamycin derivatives bearing a lysine residue on the sugar moiety were synthesised with the aim of improving the binding to DNA and the antiproliferative activities. Four tumour cell lines, from murine L1210 leukemia, human HT29 colon carcinoma, A549 non-small cell lung carcinoma and K-562 leukemia, were used to evaluate the cytotoxicity of the drugs. Their effects on the cell cycle of L1210 cells and their antimicrobial properties against two Gram-positive bacteria Bacillus cercus and Streptomyces chartreusis, a Gram-negative bacterium Escherichia coli and a yeast Candida albicans were also investigated. (C) 2001 Editions scientifiques et medicales Elsevier SAS.