methyl 1-(chloromethyl)-5-nitro-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate | 204915-56-0

• 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-(chloromethyl)-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 8-(chloromethyl)-4-nitro-6-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-7,8-dihydro-3H-pyrrolo[3,2-e]indole-2-carboxylate
• CAS: 204915-56-0
• 化学式: C₂₅H₂₃ClN₄O₈
• 分子量: 542.933
• InChiKey: DQUZJKNVYSYKDE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 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：
  152
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl 1-(chloromethyl)-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 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 以97%的产率得到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 、 三苯基二氯化膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 吡啶 、 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 110.59h， 生成 methyl 1-(chloromethyl)-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

• Processes for preparing 3-substituted 1-(chloromethyl)-1,2-dihydro-3h-[ring fused indol-5-yl-(amine- derived)] compounds and analogues thereof, and to products obtained therefrom
  申请人：Denny Alexander William

  公开号：US20050148651A1

  公开（公告）日：2005-07-07

  The invention provides processes of preparing 3-substituted 1-(chloromethyl)-1,2-dihydro-3H-[ring fused indol-5-yl(amine-derived)] compounds of formula (I) and its analogues, or a physiologically functional derivative thereof, (I), wherein A and B together may represent a fused optionally substituted benezene, naphthalene, pyridine, furan or a pyrrole ring, where the optional substituents are represented by Y; X is halogen or OSO 2 R, and W is selected from NO 2 , NHOH, N(R 3 ) 2 NHR 3 , NHCO 2 R 3 , N(phthaloyl) or NH 2 , or W is further selected from the group (a), wherein J is selected from OH or R, and P is a group which is a substrate suitable for a nitroreductase or carboxypeptidase enzyme. The invention is also directed to the use of compounds of formula (I) prepared by the processes of the invention as cytotoxins for cancer therapy and as prodrugs for gene-directed enzyme-prodrug therapy (GDEPT) and antibody-directed enzyme-prodrug therapy (ADEPT).

  本发明提供了制备式(I)及其类似物或其生理功能衍生物的3-取代-1-(氯甲基)-1,2-二氢-3H-[环融合吲哚-5-基(氨基衍生)]化合物的过程，其中A和B在一起可以表示为融合的可选取代苯、萘、吡啶、呋喃或吡咯环，其中可选的取代基由Y表示；X是卤素或OSO2R，W从NO2、NHOH、N(R3)2NHR3、NHCO2R3、N(phthaloyl)或NH2中选择，或者W进一步从(a)组中选择，其中J从OH或R中选择，P是适用于硝基还原酶或羧肽酶酶的底物基团。本发明还涉及使用通过本发明的方法制备的式(I)化合物作为癌症治疗的细胞毒素以及基因导向酶前药治疗(GDEPT)和抗体导向酶前药治疗(ADEPT)的前药。
• 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
• US7235578B2
  申请人：——

  公开号：US7235578B2

  公开（公告）日：2007-06-26