4-(2-Bromo-acryloylamino)-1-methyl-1H-pyrrole-2-carboxylic acid phenylamide | 287734-05-8

• 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-(2-Bromo-acryloylamino)-1-methyl-1H-pyrrole-2-carboxylic acid phenylamide
• 英文别名: 4-(2-bromoprop-2-enoylamino)-1-methyl-N-phenylpyrrole-2-carboxamide
• CAS: 287734-05-8
• 化学式: C₁₅H₁₄BrN₃O₂
• 分子量: 348.199
• InChiKey: XZOSRZKQBDRKBI-UHFFFAOYSA-N

物化性质

• 沸点：
  474.8±45.0 °C(Predicted)
• 密度：
  1.43±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  63.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  腺嘌呤 、 4-(2-Bromo-acryloylamino)-1-methyl-1H-pyrrole-2-carboxylic acid phenylamide 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 生成 4-[(E)-3-(6-Amino-purin-9-yl)-acryloylamino]-1-methyl-1H-pyrrole-2-carboxylic acid phenylamide
  参考文献：
  名称：

  一种新的潜在抗癌药的发现：案例历史。

  摘要：

  DNA小沟结合剂（MGB）代表一类抗癌药物，据推测其DNA序列特异性可导致较高的作用选择性。他莫司汀A（DST）的苯甲酰氮芥子气衍生物塔利莫司（TAM）在临床前测试中显示出优异的抗肿瘤活性，但同时也具有严重的骨髓毒性。最近发现了DST的新型氮芥，氮半芥末和硫芥末衍生物，它们显示出优异的活性，并报道了SAR。特别地，作为单臂烷基化剂的氮半芥末和硫芥末衍生物代表了令人感兴趣的结构新颖性。另一类新的细胞毒性抗癌药是DST样寡肽的α-卤代丙烯酰胺衍生物，与TAM相比，其活性明显提高。特别地，以胍基部分结束的α-溴-丙烯酰胺基四吡咯衍生物brostallicin（PNU-166196）与TAM和其他MGB相比，显示出高的细胞毒性和骨髓毒性。Brostallicin与小沟结合，但在经典的体外DNA烷基化测定中似乎无反应。关于明显缺乏DNA烷基化的现象，我们推测细胞内亲核试剂（例如谷胱甘肽（GSH））可

  DOI：

  10.1016/s0014-827x(03)00014-4
• 作为产物：
  描述：

  α-bromoacrylic acid chloride 、 4-amino-1-methyl-N-phenyl-1H-pyrrole-2-carboxamide hydrochloride 在 三乙胺 作用下， 以 乙腈 为溶剂， 生成 4-(2-Bromo-acryloylamino)-1-methyl-1H-pyrrole-2-carboxylic acid phenylamide
  参考文献：
  名称：

  Cytotoxic alpha-Bromoacrylic derivatives of low molecular weight

  摘要：

  In vitro and in vivo activities of a small series of alpha-bromoacrylic derivatives of low molecular weight (MW) are described and compared with those of alpha-bromoacrylic derivatives of distamycin-like frames. Low MW compounds, when lacking of a strong basic moiety, are potent cytotoxics, while analogues bearing a strong basic moiety are not. This suggests the existence of an active transport mechanism for distamycin-derived cytotoxics characterized by strong basic amidino or guanidino moieties. Low MW compounds are inactive in vivo, possibly because of the metabolic lability of alpha-bromoacrylic moiety. The same moiety is however present in a series of potent anticancer distamycin-like minor groove binders, for example, PNU-166196 (brostallicin), a fact that underlines the features of the latter. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)00177-4

文献信息

• The discovery of a new potential anticancer drug: a case history
  作者：Paolo Cozzi

  DOI：10.1016/s0014-827x(03)00014-4

  日期：2003.3

  represent a class of anticancer agents whose DNA sequence specificity was hypothesized to lead to high selectivity of action. Tallimustine (TAM), a benzoyl nitrogen mustard derivative of distamycin A (DST), showed excellent antitumor activity in preclinical tests, but also a severe myelotoxicity. Novel nitrogen mustard, nitrogen half-mustard and sulfur mustard derivatives of DST showing excellent activity

  DNA小沟结合剂（MGB）代表一类抗癌药物，据推测其DNA序列特异性可导致较高的作用选择性。他莫司汀A（DST）的苯甲酰氮芥子气衍生物塔利莫司（TAM）在临床前测试中显示出优异的抗肿瘤活性，但同时也具有严重的骨髓毒性。最近发现了DST的新型氮芥，氮半芥末和硫芥末衍生物，它们显示出优异的活性，并报道了SAR。特别地，作为单臂烷基化剂的氮半芥末和硫芥末衍生物代表了令人感兴趣的结构新颖性。另一类新的细胞毒性抗癌药是DST样寡肽的α-卤代丙烯酰胺衍生物，与TAM相比，其活性明显提高。特别地，以胍基部分结束的α-溴-丙烯酰胺基四吡咯衍生物brostallicin（PNU-166196）与TAM和其他MGB相比，显示出高的细胞毒性和骨髓毒性。Brostallicin与小沟结合，但在经典的体外DNA烷基化测定中似乎无反应。关于明显缺乏DNA烷基化的现象，我们推测细胞内亲核试剂（例如谷胱甘肽（GSH））可
• Cytotoxic α-Halogenoacrylic Derivatives of Distamycin A and Congeners
  作者：Italo Beria、Pier Giovanni Baraldi、Paolo Cozzi、Marina Caldarelli、Cristina Geroni、Sergio Marchini、Nicola Mongelli、Romeo Romagnoli

  DOI：10.1021/jm031051k

  日期：2004.5.1

  action of many antitumor agents involves DNA damage, either by direct binding of the drug to DNA or to DNA-binding proteins. However, most of the DNA-interacting agents have only a limited degree of sequence specificity, which implies that they may hit all the cellular genes. DNA minor groove binders, among which the derivatives of distamycin A play an important role, could provide significant improvement

  许多抗肿瘤药的作用机制都涉及DNA损伤，这可能是由于药物与DNA或与DNA结合蛋白的直接结合而引起的。但是，大多数DNA相互作用剂仅具有有限程度的序列特异性，这意味着它们可能击中所有细胞基因。DNA小沟结合剂（其中双霉素A的衍生物起着重要作用）由于与富含胸腺嘧啶-腺嘌呤（TA）的序列具有很高的选择性，可以显着改善癌症的治疗，增加基因特异性。我们现在报告和讨论合成的，体外和体内活性以及二霉素A的α-卤代丙烯酰胺基衍生物的一些机理特征。这项工作的最终结果是选择brostallicin 17（PNU-166196）。Brostallicin，目前处于II期临床试验中，与广谱霉素衍生物塔木斯汀相比，它具有广谱的抗肿瘤活性和更高的凋亡作用。与临床测试的DNA小沟结合剂相比，brostallicin的重要体外毒理学特征是对人类造血祖细胞的骨髓毒性与对肿瘤细胞的细胞毒性之间的比率非常高。brostall
• Cytotoxic alpha-Bromoacrylic derivatives of low molecular weight
  作者：Italo Beria、Marina Caldarelli、Cristina Geroni、Nicola Mongelli、Benedetta Reinach、Luisella Vignati、Paolo Cozzi

  DOI：10.1016/s0960-894x(02)00177-4

  日期：2002.6

  In vitro and in vivo activities of a small series of alpha-bromoacrylic derivatives of low molecular weight (MW) are described and compared with those of alpha-bromoacrylic derivatives of distamycin-like frames. Low MW compounds, when lacking of a strong basic moiety, are potent cytotoxics, while analogues bearing a strong basic moiety are not. This suggests the existence of an active transport mechanism for distamycin-derived cytotoxics characterized by strong basic amidino or guanidino moieties. Low MW compounds are inactive in vivo, possibly because of the metabolic lability of alpha-bromoacrylic moiety. The same moiety is however present in a series of potent anticancer distamycin-like minor groove binders, for example, PNU-166196 (brostallicin), a fact that underlines the features of the latter. (C) 2002 Elsevier Science Ltd. All rights reserved.