1-(chloromethyl)-5-nitro-3-<(5,6,7-trimethoxyindol-2-yl)carbonyl>-1,2-dihydro-3H-benzindole | 193225-65-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 1-(chloromethyl)-5-nitro-3-<(5,6,7-trimethoxyindol-2-yl)carbonyl>-1,2-dihydro-3H-benzindole
• 英文别名: 1-(chloromethyl)-5-nitro-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indole；[1-(chloromethyl)-5-nitro-1,2-dihydrobenzo[e]indol-3-yl]-(5,6,7-trimethoxy-1H-indol-2-yl)methanone
• CAS: 193225-65-9
• 化学式: C₂₅H₂₂ClN₃O₆
• 分子量: 495.919
• InChiKey: HVXXVNCXGUXSCQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  35
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  110
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-(chloromethyl)-5-nitro-3-<(5,6,7-trimethoxyindol-2-yl)carbonyl>-1,2-dihydro-3H-benzindole 在 platinum(IV) oxide 氢气 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以94%的产率得到5-amino-1-(chloromethyl)-<(5,6,7-trimethoxyindol-2-yl)carbonyl>-1,2-dihydro-3H-benzindole
  参考文献：
  名称：

  Synthesis and Cytotoxicity of 5-Amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2- dihydro-3H-benz[e]indole (Amino-seco-CBI-TMI) and Related 5-Alkylamino Analogues:  New DNA Minor Groove Alkylating Agents

  摘要：

  The first synthesis of seco-CBI-TMI alkylating agents with 5-nitrogen substituents is reported. The parent 5-amino compound was prepared in a 15-step synthesis from 1-hydroxynaphthalene-2-carboxylic acid. Reductive alkylation of the 5-amino compound gave the corresponding 5-methylamino and 5-dimethylamino analogues, while resolution of an intermediate by chiral HPLC allowed preparation of the R and S enantiomers of the 5-amino analogue. Absolute configuration was assigned by X-ray crystallography. The S enantiomer was about 65-fold more cytotoxic than the R enantiomer in cell line assays. The 5-amino and 5-methylamino compounds had in vitro cytotoxicities comparable to that of the known 5-hydroxy analogue (0.2-0.5 nM), while the 5-dimethylamino derivative was about 10-fold less potent. The high potencies of the 5-amino and 5-methylamino analogues make them of interest for the formation of relatively stable amine-based prodrugs.

  DOI：

  10.1021/jo981395w
• 作为产物：
  描述：

  3-(tert-butoxycarbonyl)-1,1-di(methoxycarbonyl)-5-nitro-1,2-dihydro-3H-benzindole 在 吡啶 、 盐酸 、 sodium methylate 、 二异丁基氢化铝 、 甲基磺酰氯 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 、 lithium chloride 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 1-(chloromethyl)-5-nitro-3-<(5,6,7-trimethoxyindol-2-yl)carbonyl>-1,2-dihydro-3H-benzindole
  参考文献：
  名称：

  Synthesis and cytotoxicity of amino analogues of the potent DNA alkylating agent seco-CBI-TMI

  摘要：

  The synthesis of racemic seco-CBI-TMI analogues containing nitrogen-based groups in place of the 5-OH is reported, employing a synthetic strategy where the incipient C-5 amino substituent is generated in the last step from a nitro precursor. The resulting amino seco-CBI analogues are up to 1000-fold more potent cytotoxins than the corresponding known amino seco-CI compounds, making them attractive candidates as effecters in prodrug strategies. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0960-894x(97)00259-x

文献信息

• The effect of sulfonate leaving groups on the hypoxia-selective toxicity of nitro analogs of the duocarmycins
  作者：Amir Ashoorzadeh、Graham J. Atwell、Frederik B. Pruijn、William R. Wilson、Moana Tercel、William A. Denny、Ralph J. Stevenson

  DOI：10.1016/j.bmc.2011.06.073

  日期：2011.8

  dol-1-yl)methyl sulfonate (nitroCBI) prodrugs containing sulfonate leaving groups undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents. They were evaluated (along with chloride leaving group analogs for comparison) for their cytotoxicity against cultures of SKOV3 and HT29 human tumor cell lines under both aerobic and hypoxic conditions. Sulfonates with neutral side

  一系列含有磺酸盐离去基团的3-取代的（5-硝基-2,3-二氢-1 H-苯并[ e ]吲哚-1-基）甲基磺酸盐（nitroCBI）前药经历缺氧选择性代谢，形成有效的DNA小分子沟槽烷基化剂。评估了它们（与氯离去基团类似物进行比较）在有氧和低氧条件下对SKOV3和HT29人肿瘤细胞系培养物的细胞毒性。具有中性侧链的磺酸盐（例如5,6,7-三甲氧基吲哚； TMI）在SKOV3细胞中显示出始终比相应的氯代类似物（2.8-3.1）更高的低氧细胞毒性比（HCR）（34-246），但是这些趋势确实不适用于带有阳离子或极性中性侧链的化合物。
• Nitrobenzindoles and Their use in Cancer Therapy
  申请人：Denny William Alexander

  公开号：US20080119442A1

  公开（公告）日：2008-05-22

  The present invention relates generally to nitro-1,2-dihydro-3H-benzo[e]indoles and related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.

  本发明涉及硝基-1,2-二氢-3H-苯并[e]吲哚及其相关类似物，其制备方法以及其作为低氧选择性药物和放射增敏剂在癌症治疗中的使用，可以单独使用或与辐射和/或其他抗癌药物联合使用。
• Hypoxia-Activated Prodrugs: Substituent Effects on the Properties of Nitro <i>seco</i>-1,2,9,9a-Tetrahydrocyclopropa[<i>c</i>]benz[<i>e</i>]indol-4-one (nitroCBI) Prodrugs of DNA Minor Groove Alkylating Agents
  作者：Moana Tercel、Graham J. Atwell、Shangjin Yang、Ralph J. Stevenson、K. Jane Botting、Maruta Boyd、Eileen Smith、Robert F. Anderson、William A. Denny、William R. Wilson、Frederik B. Pruijn

  DOI：10.1021/jm901202b

  日期：2009.11.26

  Nitrochloromethylbenzindolines (nitroCBIs) are a new class of hypoxia-activated prodrugs for antitumor therapy. The recently reported prototypes undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents and are selectively toxic to some but not all hypoxic tumor cell lines. Here we report a series of 31 analogues that bear an extra electron-withdrawing substituent that serves to raise the one-electron reduction potential of the nitroCBI. We identify a subset of compounds, those with a basic side chain and sulfonamide or carboxamide substituent, that have consistently high hypoxic selectivity. The best of these, with a 7-sulfonamide substituent, displays hypoxic cytotoxicity ratios of 275 and 330 in Skov3 and HT29 human tumor cell lines, respectively. This compound (28) is efficiently and selectively metabolized to the corresponding aminoCBI, is selectively cytotoxic tinder hypoxia in all 11 cell lines examined, and demonstrates activity against hypoxic tumor cells in a human tumor xenograft in vivo.
• Synthesis and cytotoxicity of amino analogues of the potent DNA alkylating agent seco-CBI-TMI
  作者：G.J. Atwell、W.R. Wilson、W.A. Denny

  DOI：10.1016/s0960-894x(97)00259-x

  日期：1997.6

  The synthesis of racemic seco-CBI-TMI analogues containing nitrogen-based groups in place of the 5-OH is reported, employing a synthetic strategy where the incipient C-5 amino substituent is generated in the last step from a nitro precursor. The resulting amino seco-CBI analogues are up to 1000-fold more potent cytotoxins than the corresponding known amino seco-CI compounds, making them attractive candidates as effecters in prodrug strategies. (C) 1997 Elsevier Science Ltd.
• 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