(3S)-6-aziridinyl-2,3-dihydro-7-methyl-3-(N-L-phenylalanyl-L-phenylalanylamino)-1H-pyrrolo[1,2-a]benzimidazole-5,8-dione

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (3S)-6-aziridinyl-2,3-dihydro-7-methyl-3-(N-L-phenylalanyl-L-phenylalanylamino)-1H-pyrrolo[1,2-a]benzimidazole-5,8-dione
• 英文别名: (3S)-6-aziridinyl-2,3-dihydro-7-methyl-1H-3-(N-L-phenylalanyl-L-phenylalanylamino)-pyrrolo[1,2-a]benzimidazole-5,8-dione；NSC # 723006；(2S)-2-amino-N-[(2S)-1-[[(3S)-6-(aziridin-1-yl)-7-methyl-5,8-dioxo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazol-3-yl]amino]-1-oxo-3-phenylpropan-2-yl]-3-phenylpropanamide
• 化学式: C₃₁H₃₂N₆O₄
• 分子量: 552.633
• InChiKey: CCFWFKFJWPUGDA-VABKMULXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  41
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  139
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  乙烯亚胺 、 (S)-2-Amino-N-[(S)-1-((S)-7-methyl-5,8-dioxo-2,3,5,8-tetrahydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ylcarbamoyl)-2-phenyl-ethyl]-3-phenyl-propionamide 以 甲醇 为溶剂， 反应 3.0h， 生成 (3S)-6-aziridinyl-2,3-dihydro-7-methyl-3-(N-L-phenylalanyl-L-phenylalanylamino)-1H-pyrrolo[1,2-a]benzimidazole-5,8-dione
  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

文献信息

• 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.