Methyl 4-[bis(2-hydroxyethyl)amino]-2,3-dinitrobenzoate | 177035-59-5

• 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: Methyl 4-[bis(2-hydroxyethyl)amino]-2,3-dinitrobenzoate
• CAS: 177035-59-5
• 化学式: C₁₂H₁₅N₃O₈
• 分子量: 329.266
• InChiKey: OVPKQXUNTLRFDO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  162
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  Methyl 4-[bis(2-hydroxyethyl)amino]-2,3-dinitrobenzoate 在 吡啶 、 氢氧化钾 、 氯化亚砜 、 N,N-二甲基甲酰胺 、 lithium chloride 作用下， 以 甲醇 、 水 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 6.42h， 生成 4-[bis(2-chloroethyl)amino]-N-(2,3-dihydroxypropyl)-2,3-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-chloro-2,3-dinitrobenzoate 、 二乙醇胺 以 1,4-二氧六环 为溶剂， 反应 72.0h， 以78%的产率得到Methyl 4-[bis(2-hydroxyethyl)amino]-2,3-dinitrobenzoate
  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

• 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.