4-[N,N-bis(2-chloroethyl)amino]-3,5-dinitrobenzoic acid | 150272-20-1

• 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: 4-[N,N-bis(2-chloroethyl)amino]-3,5-dinitrobenzoic acid
• 英文别名: 4-[bis(2-chloroethyl)amino]-3,5-dinitrobenzoic acid
• CAS: 150272-20-1
• 化学式: C₁₁H₁₁Cl₂N₃O₆
• 分子量: 352.131
• InChiKey: OHGXIYUJSCMDKA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 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：
  132
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-[N,N-bis(2-chloroethyl)amino]-3,5-dinitrobenzoic acid 在 氯化亚砜 、 N,N-二甲基甲酰胺 作用下， 以 水 、 1,2-二氯乙烷 、 丙酮 为溶剂， 反应 5.0h， 生成 4-[bis(2-chloroethyl)amino]-N-(2,3-dihydroxypropyl)-3,5-dinitrobenzamide
  参考文献：
  名称：

  Hypoxia-Selective Antitumor Agents. 14. Synthesis and Hypoxic Cell Cytotoxicity of Regioisomers of the Hypoxia-Selective Cytotoxin 5-[N,N-Bis(2-chloroethyl)amino]-2,4-dinitrobenzamide

  摘要：

  A series of regioisomers of the novel hypoxia-selective cytotoxin (HSC) 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrabepzamide (2a) have been prepared by displacement of the chloro group from methyl chlorodinitrobenzoates or the corresponding carboxamides with diethanolamine, followed by dimesylation and mesylate displacement with LiCl. The compounds fall into two classes, where the two nitro groups have either a meta or an ortho (or para) disposition to each other. The four meta derivatives had one-electron reduction potentials in the range -340 to -375 mV, similar to that of the known isomer 2a, while the other isomers had much higher values (-262 to -285 mV). The meta derivatives were much less cytotoxic to AA8 cells under aerobic conditions (IC(50)s from 75 to 470 mu M) than were the other compounds (IC(50)s from 1.6 to 20 mu M). However, the ratios of IC(50)s Of the compounds in repair-proficient (AA8) and repair-deficient (UV4) cell lines varied, indicating differing contributions of DNA alkylation to aerobic toxicity between the isomers, with no clear relationship between this and nitro group disposition. The hypoxic selectivities of the (dimethylamino)ethylcarboxamide analogues for each isomer were determined by clonogenic assay against both AA8 and UV4 cells. With one exception, the meta derivatives showed excellent hypoxic selectivities (ca. 45-115-fold) against UV4 cells, while the ortho or para isomers had little selectivity (ca. 2-7-fold). A possible reason may be that the latter compounds, with higher reduction potentials, undergo rapid bioreduction even under aerobic conditions. None showed hypoxic selectivities greater than 2-3-fold against AA8 cells. The 3-[N,N-bis(2-chloroethyl)amino]-2,6-dinitrobenzamide isomer (5b), which showed the highest hypoxic selectivity for UV4 cells in this series, was active against both hypoxic and aerobic cells in KHT tumors in mice at well-tolerated doses, and showed superior in vivo activity to the previously studied 2,4-dinitro isomer 2b.

  DOI：

  10.1021/jm960057p
• 作为产物：
  描述：

  methyl 4-[N,N-bis(2-hydroxyethyl)amino]-3,5-dinitrobenzoate 在 氢氧化钾 、 三乙胺 、 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 3.33h， 生成 4-[N,N-bis(2-chloroethyl)amino]-3,5-dinitrobenzoic acid
  参考文献：
  名称：

  Hypoxia-Selective Antitumor Agents. 14. Synthesis and Hypoxic Cell Cytotoxicity of Regioisomers of the Hypoxia-Selective Cytotoxin 5-[N,N-Bis(2-chloroethyl)amino]-2,4-dinitrobenzamide

  摘要：

  A series of regioisomers of the novel hypoxia-selective cytotoxin (HSC) 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrabepzamide (2a) have been prepared by displacement of the chloro group from methyl chlorodinitrobenzoates or the corresponding carboxamides with diethanolamine, followed by dimesylation and mesylate displacement with LiCl. The compounds fall into two classes, where the two nitro groups have either a meta or an ortho (or para) disposition to each other. The four meta derivatives had one-electron reduction potentials in the range -340 to -375 mV, similar to that of the known isomer 2a, while the other isomers had much higher values (-262 to -285 mV). The meta derivatives were much less cytotoxic to AA8 cells under aerobic conditions (IC(50)s from 75 to 470 mu M) than were the other compounds (IC(50)s from 1.6 to 20 mu M). However, the ratios of IC(50)s Of the compounds in repair-proficient (AA8) and repair-deficient (UV4) cell lines varied, indicating differing contributions of DNA alkylation to aerobic toxicity between the isomers, with no clear relationship between this and nitro group disposition. The hypoxic selectivities of the (dimethylamino)ethylcarboxamide analogues for each isomer were determined by clonogenic assay against both AA8 and UV4 cells. With one exception, the meta derivatives showed excellent hypoxic selectivities (ca. 45-115-fold) against UV4 cells, while the ortho or para isomers had little selectivity (ca. 2-7-fold). A possible reason may be that the latter compounds, with higher reduction potentials, undergo rapid bioreduction even under aerobic conditions. None showed hypoxic selectivities greater than 2-3-fold against AA8 cells. The 3-[N,N-bis(2-chloroethyl)amino]-2,6-dinitrobenzamide isomer (5b), which showed the highest hypoxic selectivity for UV4 cells in this series, was active against both hypoxic and aerobic cells in KHT tumors in mice at well-tolerated doses, and showed superior in vivo activity to the previously studied 2,4-dinitro isomer 2b.

  DOI：

  10.1021/jm960057p

文献信息

• Effect of methionine and glucosamine conjugation on the anticancer activity of aromatic dinitrobenzamide mustards
  作者：SUBHENDU KARMAKAR、SUDIPTA BHATTACHARYYA、ARINDAM MUKHERJEE

  DOI：10.1007/s12039-015-1019-3

  日期：2016.3

  cancer cells due to higher uptake. To probe this effect, methionine and glucosamine were conjugated to a series of well-known aromatic dinitrobenzamide mustards. The in vitro cytotoxicity studies performed to probe the effect of such conjugation showed that the conjugation of methionine and glucosamine to one of the dinitrobenzamide mustard led to more toxicity selectively in human breast adenocarcinoma

  某些营养素即，葡萄糖和蛋氨酸被癌细胞消耗掉更多。因此，与它们缀合的抗癌剂可能由于较高的摄取而在癌细胞中产生更大的毒性。为了探测这种效果，将蛋氨酸和氨基葡萄糖与一系列众所周知的芳香族二硝基苯甲酰胺芥末结合。在体外细胞毒性研究进行探测这样缀合的显示的效果是蛋氨酸和葡糖胺的缀合在人乳腺腺癌（MCF-7）细胞系导致更多的毒性选择性地将二硝基苯甲酰胺芥之一。但是，功能化的效果不能一概而论。基于低氧的研究表明IC 50值从常氧状态变化不大，这令人鼓舞，因为许多药物在缺氧状态下会失活。在葡糖胺和蛋氨酸结合的二硝基苯甲酰胺芥末中，2-氯苯甲酸的蛋氨酸结合的芳香族二硝基苯甲酰胺芥末是最有效的。它通过G2 / M期阻滞诱导细胞凋亡而发挥作用，令人鼓舞，在体外对非致瘤性人胚肾（HEK-293T）和小鼠胚成纤维细胞（NIH 3T3）的毒性低得多。 体外研究表明，与非致瘤性HEK-293T和小鼠成纤维细胞NIH 3
• Nitroaniline derivatives and their use as anti-tumour agents
  申请人：Cancer Research Campaign Technology Limited

  公开号：US05571845A1

  公开（公告）日：1996-11-05

  The invention provides nitroaniline derivatives represented by general formula (I) 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.

  本发明提供了一种由通式（I）表示的硝基苯胺衍生物，其中硝基基团取代在任何一个可用的苯环位置2-6；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，并且A取代在任何一个可用的苯环位置2-6；其中B表示N(CH.sub.2 CH.sub.2卤素).sub.2或N(CH.sub.2 CH.sub.2 OSO.sub.2 R.sup.3).sub.2取代在任何一个可用的苯环位置；而R.sup.1，R.sup.2和R.sup.3分别表示H，或者低碳基，可选地取代羟基，醚基，羧基或氨基功能，包括环状结构，或者R.sup.1和R.sup.2与氮一起形成杂环结构，并且其中包含它们的制药制剂。这些化合物具有作为低氧选择性细胞毒素，还原激活的细胞毒素前药，低氧细胞放射增敏剂和抗癌剂的活性。
• Hypoxia-Selective Antitumor Agents. 14. Synthesis and Hypoxic Cell Cytotoxicity of Regioisomers of the Hypoxia-Selective Cytotoxin 5-[<i>N</i>,<i>N</i>-Bis(2-chloroethyl)amino]-2,4-dinitrobenzamide
  作者：Brian D. Palmer、William R. Wilson、Robert F. Anderson、Maruta Boyd、William A. Denny

  DOI：10.1021/jm960057p

  日期：1996.1.1

  A series of regioisomers of the novel hypoxia-selective cytotoxin (HSC) 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrabepzamide (2a) have been prepared by displacement of the chloro group from methyl chlorodinitrobenzoates or the corresponding carboxamides with diethanolamine, followed by dimesylation and mesylate displacement with LiCl. The compounds fall into two classes, where the two nitro groups have either a meta or an ortho (or para) disposition to each other. The four meta derivatives had one-electron reduction potentials in the range -340 to -375 mV, similar to that of the known isomer 2a, while the other isomers had much higher values (-262 to -285 mV). The meta derivatives were much less cytotoxic to AA8 cells under aerobic conditions (IC(50)s from 75 to 470 mu M) than were the other compounds (IC(50)s from 1.6 to 20 mu M). However, the ratios of IC(50)s Of the compounds in repair-proficient (AA8) and repair-deficient (UV4) cell lines varied, indicating differing contributions of DNA alkylation to aerobic toxicity between the isomers, with no clear relationship between this and nitro group disposition. The hypoxic selectivities of the (dimethylamino)ethylcarboxamide analogues for each isomer were determined by clonogenic assay against both AA8 and UV4 cells. With one exception, the meta derivatives showed excellent hypoxic selectivities (ca. 45-115-fold) against UV4 cells, while the ortho or para isomers had little selectivity (ca. 2-7-fold). A possible reason may be that the latter compounds, with higher reduction potentials, undergo rapid bioreduction even under aerobic conditions. None showed hypoxic selectivities greater than 2-3-fold against AA8 cells. The 3-[N,N-bis(2-chloroethyl)amino]-2,6-dinitrobenzamide isomer (5b), which showed the highest hypoxic selectivity for UV4 cells in this series, was active against both hypoxic and aerobic cells in KHT tumors in mice at well-tolerated doses, and showed superior in vivo activity to the previously studied 2,4-dinitro isomer 2b.