rebeccamycin | 118458-56-3

• 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: rebeccamycin
• 英文别名: 1,11-dichloroindolo<2,3-a>pyrrolo<3,4-c>carbazole-5,7-(6H)-dione；Dichloroarcyriaflavin A；5,21-dichloro-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: 118458-56-3
• 化学式: C₂₀H₉Cl₂N₃O₂
• 分子量: 394.216
• InChiKey: ZGCSNRKSJLVANE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  27
• 可旋转键数：
  0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  77.8
• 氢给体数：
  3
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  rebeccamycin 在 盐酸 、 一水合肼 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 21.0h， 生成 6-formamido-1,11-dichloro-6,7,12,13-tetrahydro-5,7-dioxoindolo[2,3-a]pyrrolo[3,4-c]carbazole
  参考文献：
  名称：

  Structure−Activity Relationships in a Series of Substituted Indolocarbazoles:  Topoisomerase I and Protein Kinase C Inhibition and Antitumoral and Antimicrobial Properties

  摘要：

  A series of compounds structurally related to staurosporine, rebeccamycin, and corresponding aglycones was synthesized, and their activities toward protein kinase C and topoisomerases I and II were tested together with their in vitro antitumor efficiency against murine B16 melanoma and P388 leukemia cells. Their antimicrobial activities were also examined against a Gram-negative bacterium (Escherichia coli), a yeast (Candida albicans), and three Gram-positive bacteria (Bacillus cereus, Streptomyces chartreusis, and Streptomyces griseus). To avoid side effects expected with protein kinase C inhibitors, we introduced substitution on the maleimide nitrogen and/or a sugar moiety linked to one of the indole nitrogens to obtain specific inhibitors of topoisomerase I with minimal activities on protein kinase C. As expected, these structures were inefficient on topoisomerase II, and some of them exhibited a strong activity against topoisomerase I. Generally, dechlorinated compounds were found to be more active than chlorinated analogues against both purified topoisomerase I and protein kinase C. On the other hand, opposite results were obtained in the cell antiproliferative assays. These results suggest lack of cell membrane permeability in the absence of the chlorine residue or cleavage of carbon-chlorine bonds inside the cell.

  DOI：

  10.1021/jm9603779
• 作为产物：
  描述：

  (5E,6E)-5,6-bis[(2-chlorophenyl)hydrazinylidene]-3a,4,7,7a-tetrahydroisoindole-1,3-dione 以79%的产率得到
  参考文献：
  名称：

  BERGMAN, JAN;PELCMAN, BENJAMIN, J. ORG. CHEM., 54,(1989) N, C. 824-828

  摘要：

  DOI：

文献信息

• Staurosporine and Rebeccamycin Aglycones Are Assembled by the Oxidative Action of StaP, StaC, and RebC on Chromopyrrolic Acid
  作者：Annaleise R. Howard-Jones、Christopher T. Walsh

  DOI：10.1021/ja063898m

  日期：2006.9.1

  K252c is the predominant product, while the presence of RebC directs formation of arcyriaflavin A. (18)O-Labeling studies indicate that the oxygen(s) of the pyrrolinone and maleimide functionalities of the aglycones formed are all derived from dioxygen. This work allowed for the in vitro reconstitution of the full biosynthetic pathway from l-tryptophan to the staurosporine and rebeccamycin aglycones, K252c

  在链霉菌对抗肿瘤吲哚并咔唑类瑞贝卡霉素和星形孢菌素的生物合成中，苷元的组装涉及一组复杂的氧化缩合。苷元 K252c 和 arcyriaflavin A 从其生物合成前体铬吡咯酸的总体形成分别涉及四电子和八电子氧化。这个过程是由非凡的酶 StaP 催化的，StaC 和 RebC 的作用是指导新形成的五元环中的氧化水平。芳基-芳基偶联反应对于该转化以及色基吡咯酸的二羧基吡咯部分的氧化脱羧是不可或缺的。在本文中，我们描述了 staP、staC 和 rebC 在大肠杆菌中的异源表达以及相应酶在构建两个不同的六环支架中的活性。StaP 是一种细胞色素 P450 酶，其活性需要分子氧、铁氧还蛋白、黄素氧还蛋白 NADP(+)-还原酶和 NAD(P)H。StaP 自身将色基吡咯酸转化为三种苷元产物，K252c、arcyriaflavin A 和 7-羟基-K252c；在 StaC 存在的情况下，K252c
• Cloning and Expression of a Gene Encoding N-Glycosyltrasferase (ngt) from Saccharothrix aerocolonigenes ATCC39243.
  作者：TAKESHI OHUCHI、ATSUKO IKEDA-ARAKI、AYAKO WATANABE-SAKAMOTO、KATSUHISA KOJIRI、MASAO NAGASHIMA、MASANORI OKANISHI、HIROYUKI SUDA

  DOI：10.7164/antibiotics.53.393

  日期：——

  In the course of our bioconversion studies on the derivatives of an indolocarbazole, J-104303, Saccharothrix aerocolonigenes ATCC39243 was found to convert J-104303, which was added into the culture medium, to its glycosylated derivative, J-1093 84. In order to clone the gene having the ability to convert J-104303 to J-109384, a library of Saccharothrix aerocolonigenes ATCC39243 DNA fragments was constructed using Streptomyces lividans TK21 and pIJ702 as host strain and vector, respectively. By examining more than 5, 000 transformants, one was found to convert J-104303 to J-109384. Sequence analysis of the inserted DNA fragment revealed an open reading frame with 1, 245 base pairs, named ngt. The transformant containing this ngt gene was also found to introduce a D-glucose moiety into 6-N-methylarcyriaflavin C. Furthermore, when ngt was introduced into Streptomyces mobaraensis BA13793, a producer of J-104303, the resulting transformant produced J-109384 directly.

  在对吲哚咔唑衍生物J-104303进行生物转化研究的过程中，发现糖化链霉菌ATCC39243能够将培养基中的J-104303转化为其糖基化衍生物J-109384。为了克隆能够将J-104303转化为J-109384的基因，我们分别以链霉菌TK21和pIJ702为宿主菌株和载体，构建了糖化链霉菌ATCC39243 DNA片段文库。通过检测5000多个转化体，我们发现了一个能够将J-104303转化为J-109384的转化体。插入DNA片段的序列分析显示，其包含一个1245个碱基对的开放阅读框，命名为ngt。我们还发现，含有ngt基因的转化体能够将D-葡萄糖部分引入6-N-甲基紫花黄素C中。此外，当将ngt引入J
• Crystal structures and catalytic mechanism of cytochrome P450 StaP that produces the indolocarbazole skeleton
  作者：Masatomo Makino、Hiroshi Sugimoto、Yoshitsugu Shiro、Shumpei Asamizu、Hiroyasu Onaka、Shingo Nagano

  DOI：10.1073/pnas.0702946104

  日期：2007.7.10

  Staurosporine isolated from Streptomyces sp. TP-A0274 is a member of the family of indolocarbazole alkaloids that exhibit strong antitumor activity. A key step in staurosporine biosynthesis is the formation of the indolocarbazole core by intramolecular C-C bond formation and oxidative decarboxylation of chromopyrrolic acid (CPA) catalyzed by cytochrome P450 StaP (StaP, CYP245A1). In this study, we report x-ray

  从链霉菌属分离的星形孢菌素。TP-A0274是吲哚咔唑生物碱家族的成员，其具有很强的抗肿瘤活性。星形孢菌素生物合成中的关键步骤是通过分子内CC键形成和由细胞色素P450 StaP（StaP，CYP245A1）催化的磷酸吡咯酸（CPA）的氧化脱羧作用形成吲哚并咔唑核心。在这项研究中，我们报告了CPA结合和游离形式的StaP的X射线晶体结构。在底物结合后，StaP采取更有序的构象，并且还观察到活性位点中残基的构象重排。两个羧基的氢键相互作用和与吲哚环的T形pi-pi相互作用将底物保持在底物结合腔中，构象垂直于血红素平面。基于StaP-CPA配合物的晶体结构，我们建议CC键的形成是通过吲哚阳离子自由基中间体发生的，该中间体相当于细胞色素c过氧化物酶化合物I [Sivaraja M，Goodin DB，Smith M，Hoffman BM（1989）Science 245 ：738-740]。还基
• Combinatorial biosynthesis of antitumor indolocarbazole compounds
  作者：César Sánchez、Lili Zhu、Alfredo F. Braña、Aaroa P. Salas、Jürgen Rohr、Carmen Méndez、José A. Salas

  DOI：10.1073/pnas.0407809102

  日期：2005.1.11

  their precursors) in engineered microorganisms as a complementary approach to chemical synthesis. We have dissected and reconstituted the entire biosynthetic pathway for rebeccamycin in a convenient actinomycete host, Streptomyces albus. This task was achieved by coexpressing different combinations of genes isolated from the rebeccamycin-producing microorganism. Also, a gene (staC) was identified in st

  瑞贝卡霉素和星形孢菌素是具有抗肿瘤性质的天然产物，属于吲哚咔唑生物碱家族。目前正在努力生产吲哚并咔唑衍生物，以治疗几种疾病，包括癌症和神经退行性疾病。在这里，我们报告了一种基于组合生物合成的生物过程，用于在工程微生物中生产吲哚并咔唑化合物（或其前体），作为化学合成的补充方法。我们已经在方便的放线菌宿主，白色链霉菌中解剖并重组了瑞贝卡霉素的整个生物合成途径。通过共表达从产生雷贝卡霉素的微生物中分离的基因的不同组合来完成此任务。还，在产生星形孢菌素的微生物中鉴定出一个基因（staC），并且该基因具有区分两种吲哚并咔唑生物合成途径的关键作用。最后，并入编码来自不同微生物的卤化酶的pyrH和thal基因，从而产生了在新位置带有氯原子的衍生物。通过使用这项工作中产生的重组菌株，我们生产了30多种不同的化合物。
• RebG- and RebM-Catalyzed Indolocarbazole Diversification
  作者：Changsheng Zhang、Christoph Albermann、Xun Fu、Noel R. Peters、John D. Chisholm、Guisheng Zhang、Eric J. Gilbert、Peng George Wang、David L. Van Vranken、Jon S. Thorson

  DOI：10.1002/cbic.200500504

  日期：2006.5.5

  revealed RebG to glucosylate a set of indolocarbazole surrogates, the products of which could be further modified by in vitro RebM-catalyzed 4'-O-methylation. Both RebG and RebM displayed substrate promiscuity, and evidence for a remarkable lack of RebG regioselectivity in the presence of asymmetric substrates is also provided. In the context of the created indolocarbazole analogues, cytotoxicity assays also

  瑞贝卡霉素和星形孢菌素代表具有抗肿瘤特性的两大类吲哚并咔唑糖苷天然产物。根据先前的序列注释和体内研究，rebG编码瑞贝卡霉素N-葡萄糖基转移酶，rebM编码必需的4'-O-甲基转移酶。在目前的研究中，在链霉菌和大肠杆菌中都建立了有效的RebG体内生物转化系统。生物转化实验表明，RebG可将一组吲哚并咔唑替代物葡萄糖基化，其产物可通过体外RebM催化的4'-O-甲基化进一步修饰。RebG和RebM均显示底物混杂，并且还提供了在不对称底物存在下RebG区域选择性显着缺乏的证据。