N-(2,2-diethoxyethyl)-N-(1,4-dimethyl-9H-carbazol-3-ylmethyl)-4-methylbenzenesulfonamide | 65266-48-0

• 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: N-(2,2-diethoxyethyl)-N-(1,4-dimethyl-9H-carbazol-3-ylmethyl)-4-methylbenzenesulfonamide
• 英文别名: 3--1,4-dimethylcarbazole；3-((N-(2,2-diethoxyethyl)-N-tosylamino)methyl)-1,4-dimethylcarbazole；3-[N-(2,2-diethoxyethyl)-N-tosylaminomethyl]-1,4-dimethylcarbazole；N'-tosyl-3-(2,2-diethoxyethylaminomethyl)-1,4-dimethyl-carbazole；N-(2,2-diethoxy-ethyl)-N-(1,4-dimethyl-carbazol-3-ylmethyl)-toluene-4-sulfonamide；N-(2,2-diethoxyethyl)-N-[(1,4-dimethyl-9H-carbazol-3-yl)methyl]-4-methylbenzenesulfonamide
• CAS: 65266-48-0
• 化学式: C₂₈H₃₄N₂O₄S
• 分子量: 494.655
• InChiKey: BUIDABFPUMMZLK-UHFFFAOYSA-N

物化性质

• 熔点：
  183-184 °C
• 沸点：
  673.5±65.0 °C(Predicted)
• 密度：
  1.216±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  80
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(2,2-diethoxyethyl)-N-(1,4-dimethyl-9H-carbazol-3-ylmethyl)-4-methylbenzenesulfonamide 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 0.02h， 以76%的产率得到椭圆玫瑰树碱
  参考文献：
  名称：

  通过N-（1,4-二甲基-9H-咔唑-3-基甲基）-N-甲苯磺酰氨基乙醛二乙基乙缩醛的微波辅助合成玫瑰树碱

  摘要：

  玫瑰树碱（1a）的D环环化中长期存在的问题，即低产率通过N-（1,4-二甲基咔唑-3-基甲基）N-甲苯磺酰基氨基乙醛二乙缩醛的微波辐射得到了显着改善。从吲哚开始的1a的总产量显着提高了25倍。这种新方法在收率和反应时间方面均优于已报道的方法，并且可以有效地获得广泛的玫瑰树碱衍生物。J.杂环化​​学。（2010）。

  DOI：

  10.1002/jhet.319
• 作为产物：
  描述：

  3,4-dihydro-4-methylcarbazol-1(2H)-one 在 氢氧化钾 、 lithium 、 sodium carbonate 、 一水合肼 、 三氯氧磷 、 三乙二醇 作用下， 反应 26.5h， 生成 N-(2,2-diethoxyethyl)-N-(1,4-dimethyl-9H-carbazol-3-ylmethyl)-4-methylbenzenesulfonamide
  参考文献：
  名称：

  Yokoyama, Yuusaku; Okuyama, Naomi; Iwadate, Shinji, Journal of the Chemical Society. Perkin transactions I, 1990, # 5, p. 1319 - 1329

  摘要：

  DOI：

文献信息

• Intramolecular cyclization of ortho-(cyclohex-2-enyl) anilines synthesis of ellipticine
  作者：A. G. Mustafin、I. N. Khalilov、E. V. Tal'vinskii、I. B. Abdrakhmanov、L. V. Spirikhin、G. A. Tolstikov

  DOI：10.1007/bf00630657

  日期：1992.9

  method is proposed for the synthesis of the alkaloid ellipticine, which possesses a pronounced antitumoral activity. The interaction of 3-bromocyclohexene (1 equiv.) and 2,5-xylylidine (4 equiv., 150°C, 5 h) gave a mixture of hexa- and tetrahydrocarbazoles which was dehydrogenated in the presence of Pd/C to the key synthon 1,4-dimethylcarbazole. The formylation of the carbazole by the Vilsmeier-Haack reaction

  提出了一种合成具有显着抗肿瘤活性的生物碱玫瑰树碱的简便方法。3-溴环己烯（1 当量）和 2,5-二甲苯胺（4 当量，150°C，5 小时）的相互作用产生六和四氢咔唑的混合物，在 Pd/C 存在下脱氢成为关键合成子 1,4-二甲基咔唑。通过 Vilsmeier-Haack 反应对咔唑进行甲酰化、与 2,2-二乙氧基乙胺的相互作用以及在雷尼镍上形成的亚胺的还原导致 3-(2,2-二乙氧基乙基氨基甲基)-1,4-二甲基咔唑，沸腾其 N-甲苯磺酸盐以高产率得到玫瑰树碱。
• 一种制备玫瑰树碱或取代玫瑰树碱的方法
  申请人：中国医学科学院药物研究所

  公开号：CN111100123B

  公开（公告）日：2021-08-13

  本发明涉及制备玫瑰树碱的合成工艺。采用六步反应经三步结晶分离得到玫瑰树碱，目标产物总收率高，且中间产物和目标产物无需柱层析分离，特别适合于放大量制备。
• Modifications to the Vilsmeier-Haack formylation of 1,4-dimethylcarbazole and its application to the synthesis of ellipticines
  作者：Fiona M. Deane、Charlotte M. Miller、Anita R. Maguire、Florence O. McCarthy

  DOI：10.1002/jhet.598

  日期：2011.7

  An improved method for the preparation of 3‐formyl‐1,4‐dimethylcarbazole, a key intermediate in the synthesis of ellipticine, is presented. Conditions of the Vilsmeier‐Haack reaction have been modified to facilitate the production of 3‐formyl‐1,4‐dimethylcarbazole as a major product leading to an overall improvement in yield of ellipticine from 3% to 14%. This approach was also applied to the synthesis

  提出了一种制备玫瑰树碱关键中间体3-甲酰基-1,4-二甲基咔唑的改进方法。修改了Vilsmeier-Haack反应的条件，以促进生产作为主要产品的3-甲酰基-1,4-二甲基咔唑，使玫瑰树碱的总产率从3％提高到14％。这种方法也适用于6-甲基玫瑰树碱和9-甲氧基玫瑰树碱的合成。J.杂环化​​学。（2011）。
• SMALL MOLECULES TARGETING REPEAT r(CGG) SEQUENCES
  申请人：THE SCRIPPS RESEARCH INSTITUTE

  公开号：US20150307487A1

  公开（公告）日：2015-10-29

  The invention provides a series of bioactive small molecules that target expanded r(CGG) repeats, termed r(CGG)exp, that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium, binds the 5′C G /3′G G C motifs in r(CGG)exp and disrupts a toxic r(CGG)exp-protein complex. Specifically, dimeric compounds incorporating two 9-hydroxyellipticine analog structures can even more potently bind the 5′C G G/3′G G C motifs in r(CGG)exp and disrupts a toxic r(CGG)exp-protein complex. Structure-activity relationships (SAR) studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition of r(CGG) repeats, such as r(CGG)exp. Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)exp-protein aggregates.

  这项发明提供了一系列针对扩增的r(CGG)重复序列的生物活性小分子，称为r(CGG)exp，导致脆性X相关性震颤共济失调综合征（FXTAS）。该化合物是通过利用相互作用的化学类型和RNA基序的信息来鉴定的。具体来说，9-羟基-5,11-二甲基-2-(2-(哌啶-1-基)乙基)-6H-吡啶并[4,3-b]咔唑-2-离子，结合r(CGG)exp中的5′CG/3′GGC基序，并破坏有毒的r(CGG)exp-蛋白质复合物。具体来说，结合了两个9-羟基椭圆咔啉类似结构的二聚化合物甚至可以更有效地结合r(CGG)exp中的5′CGG/3′GGC基序，并破坏有毒的r(CGG)exp-蛋白质复合物。结构活性关系（SAR）研究确定了烷基化的吡啶基和酚基侧链是驱动对r(CGG)重复序列，如r(CGG)exp的分子识别的重要化学类型。重要的是，该化合物在FXTAS模型细胞系统中表现出疗效，表现为改善FXTAS相关的前mRNA剪接缺陷，并减少r(CGG)exp-蛋白质聚集物的大小和数量。
• Synthesis and evaluation of novel ellipticines as potential anti-cancer agents
  作者：Fiona M. Deane、Elaine C. O'Sullivan、Anita R. Maguire、Jayne Gilbert、Jennette A. Sakoff、Adam McCluskey、Florence O. McCarthy

  DOI：10.1039/c2ob27186a

  日期：——

  Drugs that inhibit DNA topoisomerase I and DNA topoisomerase II have been widely used in cancer chemotherapy. We report herein the results of a focused medicinal chemistry effort around novel ellipticinium salts which target topoisomerase I and II enzymes with improved solubility. The salts were prepared by reaction of ellipticine with the required alkyl halide and evaluated for DNA intercalation, topoisomerase inhibition and growth inhibition against 12 cancer cell lines. Results from the topoisomerase I relaxation assay indicated that all novel ellipticine derivatives behaved as intercalating agents. At a concentration of 100 μM, specific topoisomerase I inhibition was not observed. Two of the derivatives under investigation were found to fully inhibit the DNA decatenation reaction at a concentration of 100 μM, indicative of topoisomerase II inhibition. N-Alkylation of ellipticine was found to enhance the observed growth inhibition across all cell lines and induce growth inhibition comparable to that of Irinotecan (CPT-11; GI50 1–18 μM) and in some cell lines better than Etoposide (VP-16; GI50 = 0.04–5.2 μM). 6-Methylellipticine was the most potent growth inhibitory compound assessed (GI50 = 0.47–0.9 μM). N-Alkylation of 6-methylellipticine was found to reduce this response with GI50 values in the range of 1.3–28 μM.

  抑制 DNA 拓扑异构酶 I 和 II 的药物在癌症化疗中得到了广泛应用。我们在此报告了一项针对新型椭圆土盐的集中药物化学研究结果，这些盐类针对拓扑异构酶 I 和 II 具有改进的溶解度。这些盐是通过椭圆土与所需的烷基卤化物反应制备的，并进行了 DNA 嵌入、拓扑异构酶抑制和对 12 种癌细胞系的生长抑制评估。拓扑异构酶 I 松弛检测的结果表明，所有新型椭圆土衍生物都表现为嵌入剂。在 100 μM 的浓度下，未观察到特异性拓扑异构酶 I 的抑制。研究中发现，两个衍生物能在 100 μM 的浓度下完全抑制 DNA 解缠反应，表明其对拓扑异构酶 II 的抑制作用。椭圆土的 N-烷基化被发现能够增强所有细胞系的生长抑制效果，并诱导出与伊立替康（CPT-11；GI50 1–18 μM）相当的生长抑制，在某些细胞系中优于依托泊苷（VP-16；GI50 = 0.04–5.2 μM）。6-甲基椭圆土是评估的最有效的生长抑制化合物（GI50 = 0.47–0.9 μM）。对 6-甲基椭圆土的 N-烷基化导致其生长抑制反应降低，GI50 值在 1.3–28 μM 范围内。