6-acetamido-3-hydroxy-7-methyl-5-nitro-2,3-dihydro-1H-pyrrolo<1,2-a>benzimidazole | 135513-49-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 6-acetamido-3-hydroxy-7-methyl-5-nitro-2,3-dihydro-1H-pyrrolo<1,2-a>benzimidazole
• 英文别名: N-(3-hydroxy-7-methyl-5-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-6-yl)acetamide
• CAS: 135513-49-4
• 化学式: C₁₃H₁₄N₄O₄
• 分子量: 290.279
• InChiKey: LGKWVDAZPAPNBO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  113
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-acetamido-3-hydroxy-7-methyl-5-nitro-2,3-dihydro-1H-pyrrolo<1,2-a>benzimidazole 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 反应 18.0h， 生成 N-(5-Amino-3-hydroxy-7-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)-acetamide
  参考文献：
  名称：

  Pyrrolo[1,2-a]benzimidazole-Based Quinones and Iminoquinones. The Role of the 3-Substituent on Cytotoxicity

  摘要：

  The influence of the 3-substituent on the cytotoxicity of the 6-aziridinylpyrrolo[1,2-a]benzimidazole quinones (PBIs), the 6-acetamidopyrrolo[1,2-a]benzimidazole quinones (APBIs), and the 6-acetamidopyrrolo[1,2-a]benzimidazole iminoquinones (imino-APBIs) was investigated by comparing LC(50) mean graphs consisting of 60 cancer lines. Increasing lipophilicity of the 3-substituent of PBIs and APBIs increased the cytotoxicity specifically in melanoma cell lines. The 3-substituent does not influence DNA cleavage by reduced PBIs, except for the S-carbamate derivative which shows enhanced cleavage. This property of the 3-carbamate is rationalized in terms of the PBI major groove binding model. The imino-APBIs show enhanced cytotoxicity in melanoma and renal cancer cell lines; the correlation coefficient for log LC(50) VS log lipophilicity is 0.8 to 0.9. COMPARE correlations revealed that the PBIs are activated by DT-diaphorase but that the APBIs and imino-APBIs are inactivated by this enzyme. Thus the latter two agents are cytotoxic only as quinones. It was noted that APBIs possess a similar cytotoxic profile to three anthracycline analogues. This observation suggests mechanistic similarities between both types of cytotoxic agents. Major conclusions of this study pertain to the design of agents displaying cytotoxicity specifically against melanoma and renal cancers and to the use of 60-cell line mean graphs and COMPARE in cancer drug QSAR.

  DOI：

  10.1021/jm00001a016
• 作为产物：
  描述：

  6-acetamido-7-methyl-5-nitro-2,3-dihydro-1H-pyrrolo<1,2-a>benzimidazole 3-acetate 在 potassium carbonate 作用下， 以 甲醇 为溶剂， 反应 0.33h， 以78%的产率得到6-acetamido-3-hydroxy-7-methyl-5-nitro-2,3-dihydro-1H-pyrrolo<1,2-a>benzimidazole
  参考文献：
  名称：

  基于吡咯并[1,2-a]苯并咪唑类抗肿瘤剂的结构活性研究：新型还原烷基化DNA裂解剂。

  摘要：

  本文描述了基于吡咯并[1,2-a]苯并咪唑（PBI）环系统的新型抗肿瘤药的结构活性研究。这些化合物被设计为模仿丝裂霉素抗肿瘤剂的新的DNA交联剂。实际上，发现PBI衍生物具有类似蒽环类的特征：（i）在人骨髓瘤细胞系中与阿霉素共有交叉耐药性，（ii）心脏毒性，以及（iii）优异的DNA链切割能力。DNA链的断裂被认为是由于DNA的还原性烷基化，随后是活性氧自由基的产生。研究的最佳抗肿瘤药物是6-N-叠氮基-3-羟基-7-甲基-2,3-二氢-1H-吡咯并-[1,2-a]苯并咪唑-5,8-二酮3-乙酸盐（PBI- A），其具有针对各种人类卵巢癌和结肠癌细胞系的纳摩尔IC50值。

  DOI：

  10.1021/jm00114a003

文献信息

• Structure-activity studies of antitumor agents based on pyrrolo[1,2-a]benzimidazoles: new reductive alkylating DNA cleaving agents
  作者：Imadul Islam、Edward B. Skibo、Robert T. Dorr、David S. Alberts

  DOI：10.1021/jm00114a003

  日期：1991.10

  Described herein are structure-activity studies of new antitumor agents based on the pyrrolo[1,2-a]benzimidazole (PBI) ring system. These compounds were designed as new DNA cross-linkers mimicking the mitomycin antitumor agents. Actually, the PBI derivatives were found to have anthracycline-like features: (i) shared cross resistance with doxorubicin in a human myeloma line, (ii) cardiotoxicity, and

  本文描述了基于吡咯并[1,2-a]苯并咪唑（PBI）环系统的新型抗肿瘤药的结构活性研究。这些化合物被设计为模仿丝裂霉素抗肿瘤剂的新的DNA交联剂。实际上，发现PBI衍生物具有类似蒽环类的特征：（i）在人骨髓瘤细胞系中与阿霉素共有交叉耐药性，（ii）心脏毒性，以及（iii）优异的DNA链切割能力。DNA链的断裂被认为是由于DNA的还原性烷基化，随后是活性氧自由基的产生。研究的最佳抗肿瘤药物是6-N-叠氮基-3-羟基-7-甲基-2,3-二氢-1H-吡咯并-[1,2-a]苯并咪唑-5,8-二酮3-乙酸盐（PBI- A），其具有针对各种人类卵巢癌和结肠癌细胞系的纳摩尔IC50值。
• Synthesis and elucidation of azamitosene and iminoazamitosene
  申请人：Arizona Board of Regents

  公开号：US05015742A1

  公开（公告）日：1991-05-14

  The synthesis of 2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole-5,8-diones (azamitosenes was carried out in conjunction with the design of potential DNA crosslinkers activated by reduction (reductive alkylation). These quinones resemble mitosene antitumor agents, but are based on the benzimidazole nucleus rather than the indole nucleus. Preliminary results indicate the azamitosenes are potent antitumor agents. Iminoquinone derivatives of azamitosenes (iminoazamitosenes) were synthesized as reductive alkylating agents exhibiting low oxygen toxicity. The iminoazamitosenes are hydrolytically stable in neutral buffers and undergo buffer catalyzed syn/anti isomerization at the imino center. Electrochemical and oxygen reactivity studies in aqueous buffers indicate the change from quinone to iminoquinone is accompanied by an increase in reduction potential and a decrease in oxygen reactivity of the corresponding reduced species.

  2,3-二氢-1H-吡咯并[1,2-a]苯并咪唑-5,8-二酮（azamitosenes）的合成与潜在DNA交联剂的设计同时进行，通过还原（还原烷基化）活化。这些醌类似于抗肿瘤剂mitosene，但基于苯并咪唑核而非吲哚核。初步结果表明，azamitosenes是有效的抗肿瘤剂。azamitosenes的亚胺醌衍生物（iminoazamitosenes）作为低氧毒性的还原烷基化剂被合成。在中性缓冲液中，iminoazamitosenes是水解稳定的，且在亚胺中心经历缓冲液催化的syn/anti异构化。在水性缓冲液中的电化学和氧反应性研究表明，从醌到亚胺醌的转变伴随着还原物种的还原势增加和相应还原物种的氧反应性降低。
• US5015742A
  申请人：——

  公开号：US5015742A

  公开（公告）日：1991-05-14
• Pyrrolo[1,2-a]benzimidazole-Based Quinones and Iminoquinones. The Role of the 3-Substituent on Cytotoxicity
  作者：William G. Schulz、Imadul Islam、Edward B. Skibo

  DOI：10.1021/jm00001a016

  日期：1995.1

  The influence of the 3-substituent on the cytotoxicity of the 6-aziridinylpyrrolo[1,2-a]benzimidazole quinones (PBIs), the 6-acetamidopyrrolo[1,2-a]benzimidazole quinones (APBIs), and the 6-acetamidopyrrolo[1,2-a]benzimidazole iminoquinones (imino-APBIs) was investigated by comparing LC(50) mean graphs consisting of 60 cancer lines. Increasing lipophilicity of the 3-substituent of PBIs and APBIs increased the cytotoxicity specifically in melanoma cell lines. The 3-substituent does not influence DNA cleavage by reduced PBIs, except for the S-carbamate derivative which shows enhanced cleavage. This property of the 3-carbamate is rationalized in terms of the PBI major groove binding model. The imino-APBIs show enhanced cytotoxicity in melanoma and renal cancer cell lines; the correlation coefficient for log LC(50) VS log lipophilicity is 0.8 to 0.9. COMPARE correlations revealed that the PBIs are activated by DT-diaphorase but that the APBIs and imino-APBIs are inactivated by this enzyme. Thus the latter two agents are cytotoxic only as quinones. It was noted that APBIs possess a similar cytotoxic profile to three anthracycline analogues. This observation suggests mechanistic similarities between both types of cytotoxic agents. Major conclusions of this study pertain to the design of agents displaying cytotoxicity specifically against melanoma and renal cancers and to the use of 60-cell line mean graphs and COMPARE in cancer drug QSAR.