(S)-3-amino-6-aziridinyl-2,3-dihydro-7-methyl-1H-pyrrolo[1,2-a]benzimidazole-5,8-dione | 244152-25-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (S)-3-amino-6-aziridinyl-2,3-dihydro-7-methyl-1H-pyrrolo[1,2-a]benzimidazole-5,8-dione
• 英文别名: (3S)-3-amino-6-(aziridin-1-yl)-7-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole-5,8-dione
• CAS: 244152-25-8
• 化学式: C₁₃H₁₄N₄O₂
• 分子量: 258.28
• InChiKey: RBVOHIFWPYOHQO-ZETCQYMHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  81
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  异烟酸 、 (S)-3-amino-6-aziridinyl-2,3-dihydro-7-methyl-1H-pyrrolo[1,2-a]benzimidazole-5,8-dione 在 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 以22%的产率得到(S)-6-aziridinyl-2,3-dihydro-3-isonicotinamido-7-methyl-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
• 作为产物：
  描述：

  乙烯亚胺 、 以 甲醇 为溶剂， 反应 5.0h， 以6.0 mg的产率得到(S)-3-amino-6-aziridinyl-2,3-dihydro-7-methyl-1H-pyrrolo[1,2-a]benzimidazole-5,8-dione
  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

• A Comprehensive Study of the Active Site Residues of DT-Diaphorase:  Rational Design of Benzimidazolediones as DT-Diaphorase Substrates
  作者：Ali Suleman、Edward B. Skibo

  DOI：10.1021/jm0104365

  日期：2002.3.1

  A series of quinone substrates were modeled into the active site of human DT-diaphorase and minimized. Correlation of these models with the substrate specificity k(cat)/K-m provided insights into the structural requirements of quinone substrates. The W105, F106, and H194 residues can influence the position of the quinone substrate in the active site resulting in formation of one of the two possible Michael anions resulting from hydride transfer from FADH(2). Electron withdrawing groups on the substrate can stabilize these anions resulting in excellent substrate specificity. Inspection of models indicated that the W-105 and F-106 residues form parallel walls that will accommodate large polycyclic substrates. Thus excellent polycyclic substrates of DT-diaphorase were designed. However, the placement of tetrahedral centers on these polycyclic substrates interfered with the W-105 and the F-106 residues resulting in their exclusion from the active site. The histidine (H194) residue permits recognition of substrate enantiomers as a result of hydrogen bonding interactions. As a result of this study, it will be possible to design poor to excellent substrates of DT-diaphorase and take advantage of varying levels of this enzyme in histologically different cancers.
• 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.