(S)-(+)-3-amino-6-bromo-2,3-dihydro-7-methyl-5-nitro-1H-pyrrolo[1,2-a]benzimidazole | 244152-11-2

• 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: (S)-(+)-3-amino-6-bromo-2,3-dihydro-7-methyl-5-nitro-1H-pyrrolo[1,2-a]benzimidazole
• 英文别名: (3S)-6-bromo-7-methyl-5-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-amine
• CAS: 244152-11-2
• 化学式: C₁₁H₁₁BrN₄O₂
• 分子量: 311.138
• InChiKey: UROHJZFUKHEJAG-LURJTMIESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  18
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  89.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-(+)-3-amino-6-bromo-2,3-dihydro-7-methyl-5-nitro-1H-pyrrolo[1,2-a]benzimidazole 在 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.2h， 生成 2-Amino-N-((S)-6-bromo-7-methyl-5-nitro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)-acetamide
  参考文献：
  名称：

  Pyrrolobenzimidazoles Linked to Heterocycles and Peptides. Design of DNA Base Pair Specific Phosphate Hydrolyzing Agents and Novel Cytotoxic Agents

  摘要：

  Work in this laboratory has been involved with the design of aziridinyl quinone-based cancer drugs (PBIs) capable of both recognizing the DNA major groove and cleaving the phosphate backbone upon reduction to the hydroquinone. The hydroquinone species recognizes the major groove of DNA at single base pairs by Hoogsteen-type hydrogen bonding. The present study extends recognition beyond a single base pair by adding amino acid residues to the 3-amino center of the PBI system. Thus, extension with proline or proline-glycine results in phosphate cleavage at 5'-AA-3' with insignificant N(7) guanine alkylation. Molecular models were used to validate the observed sequence specificity. This report also describes the design of PBIs not capable of DNA alkylation. Removal of major groove interactions by methylation or the presence of steric bulk prevented DNA alkylation reactions upon reductive activation. From these studies it was concluded that DNA alkyation was not necessary for PBI cytostatic and cytotoxic activity. For example, linkage of two phenylalanines to the PBI results in highly selective cytostatic and cytotoxic activity against melanoma, although this compound is a weak DNA alkylator.

  DOI：

  10.1021/jm0302750
• 作为产物：
  描述：

  (S)-(-)-6-bromo-3-trifluoroacetamido-2,3-dihydro-7-methyl-5-nitro-1H-pyrrolo[1,2-a]benzimidazole 在 氨 作用下， 反应 48.0h， 以66%的产率得到(S)-(+)-3-amino-6-bromo-2,3-dihydro-7-methyl-5-nitro-1H-pyrrolo[1,2-a]benzimidazole
  参考文献：
  名称：

  Design of Highly Active Analogues of the Pyrrolo[1,2-a]benzimidazole Antitumor Agents

  摘要：

  The pyrrolo[1,2-a]benzimidazole (PBI) reductive alkylating agents have been investigated in this laboratory since their discovery in the late 1980s. Of all the structural modifications of the PBIs investigated so far, the variation of the 3-substituent has the greatest influence on cytotoxicity, toxicity, and in vivo antitumor activity. In the present study, we prepared both the R and S enantiomers of nitrogen-containing 3-substituents possessing hydrogen-bonding capability as well as varying basicity. The rationale was to take advantage of stereoselective DT-diaphorase reductive activation as well as hydrogen bonding in the DNA major groove. As a result of these studies, analogues were discovered possessing among the highest hollow fiber tumor assay scores observed in hundreds of natural and synthetic antitumor agents. Our findings indicate that a relatively basic 3-substituent is required for outstanding PBI cytotoxicity but that the importance of using pure enantiomers is still open to study.

  DOI：

  10.1021/jm990029h

文献信息

• Triple molecular target approach to selective melanoma cytotoxicity
  作者：Edward B. Skibo、Akmal Jamil、Brittany Austin、Douglas Hansen、Armand Ghodousi

  DOI：10.1039/b920260a

  日期：——

  Phenylalanine-linked pyrrolo[1,2-a]benzimidazoles were successfully designed to target melanoma cells in vitro. Our design utilised three molecular targets: a phenylalanine pump, the reducing enzyme DT-diaphorase, and IMP dehydrogenase. We describe the synthesis of these compounds as well as the results of in vitro, in vivo, and QSAR studies.

  苯丙氨酸连接吡咯并[1,2-a]苯并咪唑成功地被设计用于靶向黑色素瘤细胞体外。我们的设计利用了三个分子靶点：苯丙氨酸泵、还原酶DT-diaphorase和IMP脱氢酶。我们描述了这些化合物的合成以及体外、体内和QSAR研究的结果。
• Pyrrolobenzimidazoles Linked to Heterocycles and Peptides. Design of DNA Base Pair Specific Phosphate Hydrolyzing Agents and Novel Cytotoxic Agents
  作者：Arman Ghodousi、Xiaofen Huang、Zheng Cheng、Edward B. Skibo

  DOI：10.1021/jm0302750

  日期：2004.1.1

  Work in this laboratory has been involved with the design of aziridinyl quinone-based cancer drugs (PBIs) capable of both recognizing the DNA major groove and cleaving the phosphate backbone upon reduction to the hydroquinone. The hydroquinone species recognizes the major groove of DNA at single base pairs by Hoogsteen-type hydrogen bonding. The present study extends recognition beyond a single base pair by adding amino acid residues to the 3-amino center of the PBI system. Thus, extension with proline or proline-glycine results in phosphate cleavage at 5'-AA-3' with insignificant N(7) guanine alkylation. Molecular models were used to validate the observed sequence specificity. This report also describes the design of PBIs not capable of DNA alkylation. Removal of major groove interactions by methylation or the presence of steric bulk prevented DNA alkylation reactions upon reductive activation. From these studies it was concluded that DNA alkyation was not necessary for PBI cytostatic and cytotoxic activity. For example, linkage of two phenylalanines to the PBI results in highly selective cytostatic and cytotoxic activity against melanoma, although this compound is a weak DNA alkylator.
• Design of Highly Active Analogues of the Pyrrolo[1,2-<i>a</i>]benzimidazole Antitumor Agents
  作者：William A. Craigo、Benjamin W. LeSueur、Edward B. Skibo

  DOI：10.1021/jm990029h

  日期：1999.8.1

  The pyrrolo[1,2-a]benzimidazole (PBI) reductive alkylating agents have been investigated in this laboratory since their discovery in the late 1980s. Of all the structural modifications of the PBIs investigated so far, the variation of the 3-substituent has the greatest influence on cytotoxicity, toxicity, and in vivo antitumor activity. In the present study, we prepared both the R and S enantiomers of nitrogen-containing 3-substituents possessing hydrogen-bonding capability as well as varying basicity. The rationale was to take advantage of stereoselective DT-diaphorase reductive activation as well as hydrogen bonding in the DNA major groove. As a result of these studies, analogues were discovered possessing among the highest hollow fiber tumor assay scores observed in hundreds of natural and synthetic antitumor agents. Our findings indicate that a relatively basic 3-substituent is required for outstanding PBI cytotoxicity but that the importance of using pure enantiomers is still open to study.