1-methyl-2-(hydroxymethyl)-4,7-dimethoxybenzimidazole | 99922-28-8

• 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: 1-methyl-2-(hydroxymethyl)-4,7-dimethoxybenzimidazole
• 英文别名: 4,7-dimethoxy-2-hydroxymethyl-1-methylbenzimidazole；NoName_3877；(4,7-dimethoxy-1-methylbenzimidazol-2-yl)methanol
• CAS: 99922-28-8
• 化学式: C₁₁H₁₄N₂O₃
• 分子量: 222.244
• InChiKey: VZHBPLBQXJCXCQ-UHFFFAOYSA-N

物化性质

• 熔点：
  153-155 °C
• 沸点：
  430.4±35.0 °C(Predicted)
• 密度：
  1.26±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  56.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-methyl-2-(hydroxymethyl)-4,7-dimethoxybenzimidazole 在 氨 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 1.83h， 生成 2-(4,7-dimethoxy-1-methylbenzimidazolyl)methyl N,N-bis(2-bromoethyl)phosphorodiamidate
  参考文献：
  名称：

  Development of Novel Quinone Phosphorodiamidate Prodrugs Targeted to DT-Diaphorase

  摘要：

  A series of naphthoquinone and benzimidazolequinone phosphorodiamidates has been synthesized and studied as potential cytotoxic prodrugs activated by DT-diaphorase. Reduction of the quinone moiety in the target compounds was expected to provide a pathway for expulsion of the phosphoramide mustard alkylating agent. All of the compounds synthesized were excellent substrates for purified human DT-diaphorase (k(cat)/K-m = 3 x 10(7) - 3 x 10(8) M-1 s(-1)). The naphthoquinones were toxic to both HT-29 and BE human colon cancer cell lines in a clonogenic assay; however, cytotoxicity did not correlate with DT-diaphorase activity in these cell lines. The benzimidazolequinone analogues were 1-2 orders of magnitude less cytotoxic than the naphthoquinone analogues. Chemical reduction of the naphthoquinone led to rapid expulsion of the phosphorodiamidate anion; in contrast, the benzimidazole reduction product was stable. Michael addition of glutathione and other sulfur nucleophiles provides an alternate mechanism for activation of the naphthoquinone phosphorodiamidates, and this mechanism may contribute to the cytotoxicity of these compounds.

  DOI：

  10.1021/jm000179o
• 作为产物：
  描述：

  对苯二甲醚 在 硝酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 10.33h， 生成 1-methyl-2-(hydroxymethyl)-4,7-dimethoxybenzimidazole
  参考文献：
  名称：

  Development of Novel Quinone Phosphorodiamidate Prodrugs Targeted to DT-Diaphorase

  摘要：

  A series of naphthoquinone and benzimidazolequinone phosphorodiamidates has been synthesized and studied as potential cytotoxic prodrugs activated by DT-diaphorase. Reduction of the quinone moiety in the target compounds was expected to provide a pathway for expulsion of the phosphoramide mustard alkylating agent. All of the compounds synthesized were excellent substrates for purified human DT-diaphorase (k(cat)/K-m = 3 x 10(7) - 3 x 10(8) M-1 s(-1)). The naphthoquinones were toxic to both HT-29 and BE human colon cancer cell lines in a clonogenic assay; however, cytotoxicity did not correlate with DT-diaphorase activity in these cell lines. The benzimidazolequinone analogues were 1-2 orders of magnitude less cytotoxic than the naphthoquinone analogues. Chemical reduction of the naphthoquinone led to rapid expulsion of the phosphorodiamidate anion; in contrast, the benzimidazole reduction product was stable. Michael addition of glutathione and other sulfur nucleophiles provides an alternate mechanism for activation of the naphthoquinone phosphorodiamidates, and this mechanism may contribute to the cytotoxicity of these compounds.

  DOI：

  10.1021/jm000179o

文献信息

• Formation and fate of benzimidazole-based quinone methides. Influence of pH on quinone methide fate
  作者：Edward B. Skibo

  DOI：10.1021/jo00048a020

  日期：1992.10

  The influence of pH on quinone methide fate was assessed from a comparative hydrolytic study of benzimidazole hydroquinones and their O-methylated analogues. Elimination of a leaving group from the hydroquinones affords the carbocation or the quinone methide depending on the pH. The O-methylated analogues, on the other hand, can only afford the carbocation species. Evidence is presented herein that the quinone methide species is reversibly protonated to afford the carbocation species. The acid dissociation constant for this equilibrium is pK(a) 5.5. Above pH 5.5, the quinone methide species traps both nucleophiles and the proton. Below pH 5.5, the quinone methide species is protonated to afford the carbocation species, which exclusively traps nucleophiles. Therefore, the carbocation acid dissociation constant can be used to predict quinone methide fate as a function of pH.
• Development of Novel Quinone Phosphorodiamidate Prodrugs Targeted to DT-Diaphorase
  作者：Carolee Flader、Jiwen Liu、Richard F. Borch

  DOI：10.1021/jm000179o

  日期：2000.8.1

  A series of naphthoquinone and benzimidazolequinone phosphorodiamidates has been synthesized and studied as potential cytotoxic prodrugs activated by DT-diaphorase. Reduction of the quinone moiety in the target compounds was expected to provide a pathway for expulsion of the phosphoramide mustard alkylating agent. All of the compounds synthesized were excellent substrates for purified human DT-diaphorase (k(cat)/K-m = 3 x 10(7) - 3 x 10(8) M-1 s(-1)). The naphthoquinones were toxic to both HT-29 and BE human colon cancer cell lines in a clonogenic assay; however, cytotoxicity did not correlate with DT-diaphorase activity in these cell lines. The benzimidazolequinone analogues were 1-2 orders of magnitude less cytotoxic than the naphthoquinone analogues. Chemical reduction of the naphthoquinone led to rapid expulsion of the phosphorodiamidate anion; in contrast, the benzimidazole reduction product was stable. Michael addition of glutathione and other sulfur nucleophiles provides an alternate mechanism for activation of the naphthoquinone phosphorodiamidates, and this mechanism may contribute to the cytotoxicity of these compounds.