methyl 1-(hydroxymethyl)-5-nitro-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate | 204916-11-0

• 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: methyl 1-(hydroxymethyl)-5-nitro-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate
• 英文别名: methyl 1-hydroxymethyl-5-nitro-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate；methyl 8-(hydroxymethyl)-4-nitro-6-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-7,8-dihydro-3H-pyrrolo[3,2-e]indole-2-carboxylate
• CAS: 204916-11-0
• 化学式: C₂₅H₂₄N₄O₉
• 分子量: 524.487
• InChiKey: ALBYZHPKGIWYMA-UHFFFAOYSA-N

物化性质

• 沸点：
  785.7±60.0 °C(predicted)
• 密度：
  1.490±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  38
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  172
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  methyl 1-(hydroxymethyl)-5-nitro-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate 在 platinum(IV) oxide 氢气 、 三苯基二氯化膦 作用下， 以 四氢呋喃 、 吡啶 为溶剂， 20.0 ℃ 、344.74 kPa 条件下， 反应 0.83h， 生成 methyl 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate
  参考文献：
  名称：

  Synthesis and Cytotoxicity of Amino-seco-DSA:  An Amino Analogue of the DNA Alkylating Agent Duocarmycin SA

  摘要：

  This paper describes the synthesis of methyl 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate 8, an amino analogue of the anticancer antibiotic and potent DNA minor groove alkylating agent seco-duocarmycin SA. Key points in the synthesis are sequential radical cyclization and Hemetsberger reaction steps to construct the indoline and indole rings of the target compound from a 1,2,3-trisubstituted benzene precursor. An intermediate has been resolved by chiral chromatography to provide the separate enantiomers of 8. Racemic 8 alkylates DNA at adenine in AT rich sequences, similar to seco-duocarmycin SA and the previously reported amino-seco-CBI 7, but is 15-60 times less potent than 7 in an in vitro cytotoxicity test. Derivatives of 8 in which the amino group is replaced by an electron-withdrawing nitro or nitrobenzylcarbamate substituent are considerably less toxic and may have application as prodrugs to be activated selectively in a tumor environment.

  DOI：

  10.1021/jo990464j
• 作为产物：
  描述：

  2-碘-3-硝基-苯甲酸 在 盐酸 、 4-二甲氨基吡啶 、 manganese(IV) oxide 、 硼酸三甲酯 、 硝酸 、 三正丁基氢锡 、 sodium hexamethyldisilazane 、 铁粉 、 sodium hydride 、 potassium carbonate 、 溶剂黄146 、 甲基磺酰氯 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 锌 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 硝基甲烷 、 乙醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 、 xylene 为溶剂， 反应 110.26h， 生成 methyl 1-(hydroxymethyl)-5-nitro-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate
  参考文献：
  名称：

  Synthesis and Cytotoxicity of Amino-seco-DSA:  An Amino Analogue of the DNA Alkylating Agent Duocarmycin SA

  摘要：

  This paper describes the synthesis of methyl 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate 8, an amino analogue of the anticancer antibiotic and potent DNA minor groove alkylating agent seco-duocarmycin SA. Key points in the synthesis are sequential radical cyclization and Hemetsberger reaction steps to construct the indoline and indole rings of the target compound from a 1,2,3-trisubstituted benzene precursor. An intermediate has been resolved by chiral chromatography to provide the separate enantiomers of 8. Racemic 8 alkylates DNA at adenine in AT rich sequences, similar to seco-duocarmycin SA and the previously reported amino-seco-CBI 7, but is 15-60 times less potent than 7 in an in vitro cytotoxicity test. Derivatives of 8 in which the amino group is replaced by an electron-withdrawing nitro or nitrobenzylcarbamate substituent are considerably less toxic and may have application as prodrugs to be activated selectively in a tumor environment.

  DOI：

  10.1021/jo990464j

文献信息

• Condensed N-aclyindoles as antitumor agents
  申请人：Cancer Research Campaign Technology Limited

  公开号：US06130237A1

  公开（公告）日：2000-10-10

  The invention provides compounds of general formula (I), wherein: X is halogen or OSO.sub.2 R, where R represents H or is unsubstituted or hydroxy-or amino-substituted lower alkyl; Y is a nitro or amine group or a substituted derivative thereof; W is selected from the structures of formulae (Ia, Ib or Ic), where E is --N.dbd. or --CH.dbd., G is O, S, or NH, and Q is either up to three of R, OR, NRR, NO.sub.2, CONHR, NHCOR or NHCONHR, or is an additional group of formulae (Ia, Ib or Ic) and HET represents a 5- or 6-membered carbocycle or heterocycle; and A and B collectively represent a fused benzene or 2-CO.sub.2 R pyrrole ring. In one embodiment, the group Y is an amine derivative substituted by a group which is a substrate for a nitroreductase or carboxypeptidase enzyme such that one of said enzymes is able to bring about removal of that group. ##STR1##

  本发明提供了一般式（I）的化合物，其中：X是卤素或OSO.sub.2 R，其中R代表H或未取代或羟基或氨基取代的低碳基；Y是硝基或胺基或其取代衍生物；W从式（Ia、Ib或Ic）的结构中选择，其中E是--N.dbd.或--CH.dbd.，G是O、S或NH，Q是R、OR、NRR、NO.sub.2、CONHR、NHCOR或NHCONHR中的最多三个，或是公式（Ia、Ib或Ic）的另外一个基团，HET代表一个5-或6-成员的碳环或杂环；A和B共同代表融合苯或2-CO.sub.2R吡咯环。在一个实施例中，群Y是胺衍生物，被一个硝基还原酶或羧肽酶酶的底物取代，以便其中一种酶能够去除该基团。##STR1##
• CYCLOPROPYLINDOLE COMPOUNDS AND THEIR USE AS PRODRUGS
  申请人：AUCKLAND UNISERVICES LIMITED

  公开号：EP0938474B1

  公开（公告）日：2005-11-23
• US6130237A
  申请人：——

  公开号：US6130237A

  公开（公告）日：2000-10-10
• Synthesis and Cytotoxicity of Amino-<i>s</i><i>eco</i>-DSA:  An Amino Analogue of the DNA Alkylating Agent Duocarmycin SA
  作者：Moana Tercel、Michael A. Gieseg、William A. Denny、William R. Wilson

  DOI：10.1021/jo990464j

  日期：1999.8.1

  This paper describes the synthesis of methyl 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate 8, an amino analogue of the anticancer antibiotic and potent DNA minor groove alkylating agent seco-duocarmycin SA. Key points in the synthesis are sequential radical cyclization and Hemetsberger reaction steps to construct the indoline and indole rings of the target compound from a 1,2,3-trisubstituted benzene precursor. An intermediate has been resolved by chiral chromatography to provide the separate enantiomers of 8. Racemic 8 alkylates DNA at adenine in AT rich sequences, similar to seco-duocarmycin SA and the previously reported amino-seco-CBI 7, but is 15-60 times less potent than 7 in an in vitro cytotoxicity test. Derivatives of 8 in which the amino group is replaced by an electron-withdrawing nitro or nitrobenzylcarbamate substituent are considerably less toxic and may have application as prodrugs to be activated selectively in a tumor environment.