5-[bis(2-chloroethyl)amino]-2,4-dinitrobenzoyl chloride | 156423-11-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-[bis(2-chloroethyl)amino]-2,4-dinitrobenzoyl chloride
• 英文别名: 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzoyl chloride
• CAS: 156423-11-9
• 化学式: C₁₁H₁₀Cl₃N₃O₅
• 分子量: 370.577
• InChiKey: ZFIYTKSOWMCDGV-UHFFFAOYSA-N

物化性质

• 沸点：
  526.2±50.0 °C(Predicted)
• 密度：
  1.588±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  112
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-[bis(2-chloroethyl)amino]-2,4-dinitrobenzoyl chloride 在 盐酸羟胺 、 sodium carbonate 作用下， 以 乙醚 、 水 为溶剂， 反应 0.08h， 以54%的产率得到5-[bis(2-chloroethyl)amino]-N-hydroxy-2,4-dinitrobenzamide
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships for 2,4-Dinitrobenzamide-5-mustards as Prodrugs for the Escherichia coli nfsB Nitroreductase in Gene Therapy

  摘要：

  A series of 2,4-dinitrobenzamide mustards were prepared from 5-chloro-2,4-dinitrobenzoic acid or the corresponding 5-dimesylate mustard as potential prodrugs for gene-directed enzyme prodrug therapy (GDEPT) with the E. coli nfsB nitroreductase (NTR). The compounds, including 32 new examples, were evaluated in four pairs of NTR+ve/-ve cell lines for selective cytotoxicity (IC50 and IC50 ratios), in multicellular layer (MCL) cultures for bystander effects, and for in vivo activity against tumors grown from stably NTR transfected EMT6 and WiDr cells in nude mice. Multivariate regression analysis of the IC50 results was undertaken using a partial least-squares projection to latent structures model. In NTR-ve lines, cytotoxicity correlated positively with logP, negatively with hydrogen bond acceptors (HA) and donors (HD) in the amide side chain, and positively with the reactivity of the less-reactive leaving group of the mustard function, likely reflecting toxicity due to DNA monoadducts. Potency and selectivity for NTR+ve lines was increased by logP and HD, decreased by HA, and was positively correlated with the leaving group efficiency of the more-reactive group, likely reflecting DNA crosslinking. NTR selectivity was greatest for asymmetric chloro/mesylate and bromo/mesylate mustards. Bystander effects in the MCL assay also correlated positively with logP and negatively with leaving group reactivity, presumably reflecting the transcellular diffusion/reaction properties of the activated metabolites. A total of 18 of 22 mustards showed equal or greater bystander efficiencies in MCLs than the aziridinylbenzamide CB 1954, which is currently in clinical trial for NTR-GDEPT. The dibromo and bromomesylate mustards were surprisingly well tolerated in mice. High MTD/IC50 (NTR+ve) ratios translated into curative activity of several compounds against NTR+ve tumors. A bromomesylate mustard showed superior activity against WiDr tumors grown from 1:9 mixtures of NTR+ve and NTR-ve cells, indicating a strong bystander effect in vivo.

  DOI：

  10.1021/jm061062o
• 作为产物：
  描述：

  methyl 5-chloro-2,4-dinitrobenzoate 在 氢氧化钾 、 氯化亚砜 、 三乙胺 、 N,N-二甲基甲酰胺 、 lithium chloride 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.84h， 生成 5-[bis(2-chloroethyl)amino]-2,4-dinitrobenzoyl chloride
  参考文献：
  名称：

  缺氧选择性抗肿瘤药。图9.5- [N，N-双（2-氯乙基）氨基] -2，4-二硝基苯甲酰胺类似物的低氧选择性细胞毒性的结构活性关系。

  摘要：

  为了寻找保留高缺氧性的化合物，已经制备并评估了一系列新型缺氧选择性细胞毒素5- [N，N-双（2-氯乙基）氨基] -2,4-二硝基苯甲酰胺的类似物（6）。选择性但具有增强的效能和/或水溶性。具有可电离或偶极羧酰胺侧链的几种类似物显示出改善的溶解度，但通常具有降低的细胞毒性和低氧选择性。芥菜离去基团的修饰或羧酰胺部分的取代为某些化合物提供了卓越的效力，但只有混合的氯/甲磺酸芥菜碱20相对于溶解度提供了效力，同时保持了6的低氧选择性。相关的氮丙啶7 [CB 1954，5-（N-氮丙啶基）-2 [4-二硝基苯甲酰胺]在Walker 256腺癌细胞中，并且不是DT-diaphorase的有效底物，后者通过Walker细胞中的需氧硝化作用激活了后者。二硝基苯甲酰胺芥末中低氧选择性的变化似乎不是由于该酶对活化的敏感性不同。沃克细胞对单（2-氯乙基）类似物26表现出中等敏感性，但对相关的半芥子味27没有

  DOI：

  10.1021/jm00040a009

文献信息

• [EN] NOVEL NITROPHENYL MUSTARD AND NITROPHENYLAZIRIDINE ALCOHOLS AND THEIR CORRESPONDING PHOSPHATES AND THEIR USE AS TARGETED CYTOTOXIC AGENTS<br/>[FR] NOUVELLE MOUTARDE NITROPHENYLE ET NOUVEAUX ALCOOLS NITROPHENYLAZIRIDINE, PHOSPHATES CORRESPONDANTS ET UTILISATION DE CES DERNIERS EN TANT QU'AGENTS CYTOTOXIQUES CIBLES
  申请人：AUCKLAND UNISERVICES LTD

  公开号：WO2005042471A1

  公开（公告）日：2005-05-12

  The present invention relates to novel nitrophenyl mustard and nitrophenylaziridine alcohols, to their corresponding phosphates, to their use as targeted cytotoxic agents; as bioreductive drugs in hypoxic tumours, and to their use in cell ablation, including gene-directed enzyme-prodrug therapy (GDEPT) and antibody-directed enzyme­prodrug therapy (ADEPT), in conjunction with nitroreductase enzymes.

  本发明涉及新型硝基苯基芥和硝基苯基环丙胺醇，它们的相应磷酸盐，以及它们作为靶向细胞毒性药剂的用途；作为缺氧肿瘤中的生物还原药物，并且它们在细胞消融中的应用，包括基因导向酶前药治疗（GDEPT）和抗体导向酶前药治疗（ADEPT），与硝基还原酶酶一起。
• Nitroaniline derivatives and their use as anti-tumour agents
  申请人：Cancer Research Campaign Technology Limited

  公开号：US05750782A1

  公开（公告）日：1998-05-12

  The invention provides nitroaniline derivatives represented by general formula (1) where the nitro group is substituted at any one of the available benzene positions 2-6; where R and A separately represent the groups NO.sub.2, CN,COOR.sup.1, CONR.sup.1 R.sup.2, CSNR.sup.1 R.sup.2 or SO.sub.2 NR.sup.1 R.sup.2 and A is substituted at any one of the available benzene positions 2-6; where B represents N(CH.sub.2 CH.sub.2 halogen).sub.2 or N(CH.sub.2 CH.sub.2 OSO.sub.2 R.sup.3).sub.2 substituted at any one of the available benzene positions; and where R.sup.1, R.sup.2 and R.sup.3 separately represent H, or lower alkyl optionally substituted with hydroxyl, ether, carboxy or amino functions, including cyclic structures, or R.sup.1 and R.sup.2 together with the nitrogen form a heterocyclic structure, and pharmaceutical preparations containing them. These compounds have activity as hypoxia-selective cytotoxins, reductively-activated prodrugs for cytotoxins, hypoxic cell radiosensitisers, and anticancer agents. ##STR1##

  本发明提供了一种由一般式(1)表示的硝基苯胺衍生物，其中硝基基团取代在可用苯位2-6之一;其中R和A分别表示NO.sub.2，CN，COOR.sup.1，CONR.sup.1 R.sup.2，CSNR.sup.1 R.sup.2或SO.sub.2 NR.sup.1 R.sup.2基团，且A取代在可用苯位2-6之一;其中B代表取代在可用苯位的N(CH.sub.2 CH.sub.2 halogen).sub.2或N(CH.sub.2 CH.sub.2 OSO.sub.2 R.sup.3).sub.2; R.sup.1，R.sup.2和R.sup.3分别表示H，或者取代羟基，醚，羧基或氨基功能的低烷基，包括环结构，或R.sup.1和R.sup.2与氮一起形成杂环结构；以及含有它们的制药制剂。这些化合物具有选择性缺氧细胞毒素、还原激活的细胞毒素前药、缺氧细胞放射增敏剂和抗癌剂的活性。
• Markowska; Rozanski, Acta poloniae pharmaceutica, 2000, vol. 57, # SUPPL., p. 71 - 76
  作者：Markowska、Rozanski

  DOI：——

  日期：——
• Synthesis and biological activity of carbocyclic lexitropsins with a bioreductive fragment
  作者：Agnieszka Markowska、Andrzej Różański、Sławomir Wołczyński、Krystyna Midura-Nowaczek

  DOI：10.1016/s0014-827x(02)01289-2

  日期：2002.12

  Carbocyclic oligopeptides containing of two, three or four aromatic rings with N,N-dimethylpropyl-1,3-diamine group as G terminus fragment of compounds and 5-[bis(2-chloroethyl)amino]-2,4-dinitrobenzamide as N-terminal were synthesized. These lexitropsins present antitumour activity on the neoplastic cells hepatoblastoma HEP G2. These experiments were evaluated in hypoxic and oxygen conditions. Significant differences of activity in oxygen and hypoxic conditions were shown only in compound N-(3-dimethylaminopropyl)-N'-(3-[5-bis(2-chlorethyl)amino]-2,4-dinitrobenzamide})-phenyl]urea dihydrochloride 1 (IC50 = 8545 nM in oxygen vs. IC50 = 710 nM in hypoxia). The rest of compounds (2-6) do not indicate differences of Activity in oxygen and hypoxia. (C) 2002 Editions scientifiques et medicales Elsevier SAS. All rights reserved.
• Palmer Brian D., Wilson William R., Atwell Graham J., Schultz Diane, Xu X+, J. Med. Chem, 37 (1994) N 14, S 2175-2184
  作者：Palmer Brian D., Wilson William R., Atwell Graham J., Schultz Diane, Xu X+

  DOI：——

  日期：——