5-(aziridin-1-yl)-N-(2,3-dihydroxypropyl)-2-(methylsulfonyl)-4-nitrobenzamide

• 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-(aziridin-1-yl)-N-(2,3-dihydroxypropyl)-2-(methylsulfonyl)-4-nitrobenzamide
• 英文别名: 5-(aziridin-1-yl)-N-(2,3-dihydroxypropyl)-2-methylsulfonyl-4-nitrobenzamide
• 化学式: C₁₃H₁₇N₃O₇S
• 分子量: 359.36
• InChiKey: ILQGOGISNAREPA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.1
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  161
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  5-(aziridin-1-yl)-N-(2,3-dihydroxypropyl)-2-(methylsulfonyl)-4-nitrobenzamide 、 5-chloro-2-(methylsulfonyl)-4-nitrobenzoic acid 、 氯化亚砜 、 3-氨基-1,2-丙二醇 在 N,N-二甲基甲酰胺 acid chloride 、 氯化钠 、 乙酸乙酯 、 silica gel 、 ethyl acetate diisopropyl ether 作用下， 以 水 、 乙酸乙酯 为溶剂， 反应 1.25h， 以to give 5-chloro-N-(2,3-dihydroxypropyl)-2-(methylsulfonyl)-4-nitrobenzamide (2.54 g, 91%), mp (EtOAc/iPr2O) 141-142° C的产率得到5-chloro-N-(2,3-dihydroxypropyl)-2-(methylsulfonyl)-4-nitrobenzamide
  参考文献：
  名称：

  Nitrophenylaziridine compounds and their use as prodrugs

  摘要：

  提供一系列的环氧乙烷基-1-基硝基苯酰胺作为前药，与硝基还原酶（NR）酶一起使用。酰胺可能具有1或2个取代基，这些取代基可能是笨重和极性的。例如，公式（A）的5-（环氧乙烷基-1-基）-N-[2-（4-吗啡基）乙基]-2,4-二硝基苯酰胺被发现对所有测试的NR+细胞系都具有高活性。

  公开号：

  US06517836B1
• 作为产物：
  描述：

  5-chloro-2-(methylsulfanyl)benzoic acid 在 氯化亚砜 、 硫酸 、 双氧水 、 硝酸 、 溶剂黄146 、 N,N-二甲基甲酰胺 作用下， 以 水 、 乙酸乙酯 、 丙酮 为溶剂， 反应 23.25h， 生成 5-(aziridin-1-yl)-N-(2,3-dihydroxypropyl)-2-(methylsulfonyl)-4-nitrobenzamide
  参考文献：
  名称：

  Aziridinyldinitrobenzamides:  Synthesis and Structure−Activity Relationships for Activation by E. coli Nitroreductase

  摘要：

  The 5-aziridinyl-2,4-dinitrobenzamide CB 1954 is a substrate for the oxygen-insensitive nitroreductase (NTR) from E. coli and is in clinical trial in combination with NTR-armed adenoviral vectors in a GDEPT protocol; CB 1954 is also of interest for selective deletion of NTR-marked cells in normal tissues. Since little further drug development has been carried out around this lead, we report here the synthesis of more soluble variants and regioisomers and structure-activity relationship (SAR) studies. The compounds were primarily prepared from the corresponding chloro(di)nitroacids through amide side chain elaboration and subsequent aziridine formation. One-electron reduction potentials [E(1)], determined by pulse radiolysis, were around -400 mV, varying little for aziridinyldinitrobenzamide regioisomers. Cytotoxicity in a panel of NTR-transfected cell lines showed that in the CB 1954 series there was considerable tolerance of substituted CONHR side chains. The isomeric 2-aziridinyl-3,5-dinitrobenzamide was also selective toward NTR+ve lines but was approximately 10-fold less potent than CB 1954. Other regioisomers were too insoluble to evaluate. While CB 1954 gave both 2- and 4-hydroxylamine metabolites in NTR+ve cells, related analogues with substituted carboxamides gave only a single hydroxylamine metabolite possibly because the steric bulk in the side chain constrains binding within the active site. CB 1954 is also a substrate for the two-electron reductase DT-diaphorase, but all of the other aziridines (regioisomers and close analogues) were poorer substrates with resulting improved specificity for NTR. Bystander effects were determined in multicellular layer cocultures and showed that the more hydrophilic side chains resulted in a modest reduction in bystander killing efficiency. A limited number of analogues were tested for in vivo activity, using a single ip dose to CD-1 nude mice bearing WiDr-NTRneo tumors. The most active of the CB 1954 analogues was a diol derivative, which showed a substantial median tumor growth delay (59 days compared with >85 days for CB 1954) in WiDr xenografts comprising 50% NTR+ve cells. The diol is much more soluble and can be formulated in saline for administration. The results suggest there may be advantages with carefully selected analogues of CB 1954; the weaker bystander effect of its diol derivative may be an advantage in the selective cell ablation of NTR-tagged cells in normal tissues.

  DOI：

  10.1021/jm0498699

文献信息

• US6517836B1
  申请人：——

  公开号：US6517836B1

  公开（公告）日：2003-02-11
• Aziridinyldinitrobenzamides:  Synthesis and Structure−Activity Relationships for Activation by <i>E. </i><i>coli</i> Nitroreductase
  作者：Nuala A. Helsby、Graham J. Atwell、Shangjin Yang、Brian D. Palmer、Robert F. Anderson、Susan M. Pullen、Dianne M. Ferry、Alison Hogg、William R. Wilson、William A. Denny

  DOI：10.1021/jm0498699

  日期：2004.6.1

  The 5-aziridinyl-2,4-dinitrobenzamide CB 1954 is a substrate for the oxygen-insensitive nitroreductase (NTR) from E. coli and is in clinical trial in combination with NTR-armed adenoviral vectors in a GDEPT protocol; CB 1954 is also of interest for selective deletion of NTR-marked cells in normal tissues. Since little further drug development has been carried out around this lead, we report here the synthesis of more soluble variants and regioisomers and structure-activity relationship (SAR) studies. The compounds were primarily prepared from the corresponding chloro(di)nitroacids through amide side chain elaboration and subsequent aziridine formation. One-electron reduction potentials [E(1)], determined by pulse radiolysis, were around -400 mV, varying little for aziridinyldinitrobenzamide regioisomers. Cytotoxicity in a panel of NTR-transfected cell lines showed that in the CB 1954 series there was considerable tolerance of substituted CONHR side chains. The isomeric 2-aziridinyl-3,5-dinitrobenzamide was also selective toward NTR+ve lines but was approximately 10-fold less potent than CB 1954. Other regioisomers were too insoluble to evaluate. While CB 1954 gave both 2- and 4-hydroxylamine metabolites in NTR+ve cells, related analogues with substituted carboxamides gave only a single hydroxylamine metabolite possibly because the steric bulk in the side chain constrains binding within the active site. CB 1954 is also a substrate for the two-electron reductase DT-diaphorase, but all of the other aziridines (regioisomers and close analogues) were poorer substrates with resulting improved specificity for NTR. Bystander effects were determined in multicellular layer cocultures and showed that the more hydrophilic side chains resulted in a modest reduction in bystander killing efficiency. A limited number of analogues were tested for in vivo activity, using a single ip dose to CD-1 nude mice bearing WiDr-NTRneo tumors. The most active of the CB 1954 analogues was a diol derivative, which showed a substantial median tumor growth delay (59 days compared with >85 days for CB 1954) in WiDr xenografts comprising 50% NTR+ve cells. The diol is much more soluble and can be formulated in saline for administration. The results suggest there may be advantages with carefully selected analogues of CB 1954; the weaker bystander effect of its diol derivative may be an advantage in the selective cell ablation of NTR-tagged cells in normal tissues.
• Nitrophenylaziridine compounds and their use as prodrugs
  申请人：Auckland Uniservices Limited

  公开号：US06517836B1

  公开（公告）日：2003-02-11

  A range of aziridin-1-yl nitrobenzamides are provided for use as prodrugs in conjunction with nitroreductase (NR) enzymes. The amides may have 1 or 2-substituents which may be bulky and polar. For example, 5-(aziridin-1-yl)-N-[2-(4-morpholino)ethyl]-2,4-dinitrobenzamide of Formula (A) was found to be highly active against all NR+ cell lines tested.

  提供了一系列的环氧乙烷-1-基硝基苯酰胺作为前药，与硝基还原酶（NR）酶一起使用。这些酰胺可能具有1个或2个取代基，这些取代基可能是庞大且极性的。例如，发现Formula（A）的5-(环氧乙烷-1-基)-N-[2-(4-吗啉基)乙基]-2,4-二硝基苯酰胺对所有经过测试的NR+细胞系具有很高的活性。