6-(4-Nitro-imidazol-1-ylmethyl)-pyrimidine-2,4-diol | 126401-73-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 6-(4-Nitro-imidazol-1-ylmethyl)-pyrimidine-2,4-diol
• 英文别名: 6-[(4-nitroimidazol-1-yl)methyl]-1H-pyrimidine-2,4-dione
• CAS: 126401-73-8
• 化学式: C₈H₇N₅O₄
• 分子量: 237.175
• InChiKey: XUICQRQYPVRQTC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.1
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  122
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  四丁基溴化铵 生成 6-(4-Nitro-imidazol-1-ylmethyl)-pyrimidine-2,4-diol
  参考文献：
  名称：

  摘要：

  DOI：

文献信息

• Searcey, M.; Pye, P. L.; Lee, J. B., Synthetic Communications, 1989, vol. 19, # 7,8, p. 1309 - 1316
  作者：Searcey, M.、Pye, P. L.、Lee, J. B.

  DOI：——

  日期：——
• Aminoimidazolylmethyluracil Analogues as Potent Inhibitors of Thymidine Phosphorylase and Their Bioreductive Nitroimidazolyl Prodrugs
  作者：Philip Reigan、Philip N. Edwards、Abdul Gbaj、Christian Cole、Simon T. Barry、Ken M. Page、Susan E. Ashton、Richard W. A. Luke、Kenneth T. Douglas、Ian J. Stratford、Mohammed Jaffar、Richard A. Bryce、Sally Freeman

  DOI：10.1021/jm049494r

  日期：2005.1.1

  Thymidine phosphorylase (TP) is an important target enzyme for cancer chemotherapy because it is expressed at high levels in the hypoxic regions of many tumors and inhibitors of TP have been shown in animal model studies to inhibit angiogenesis and metastasis, and to promote tumor cell apoptosis. The 5-halo-6-[(2'-aminoimidazol-1'-yl)methyl]uracils (3, X = Cl, Br) are very potent inhibitors of E. coli and human TP with IC(50) values of similar to20 nM when the enzyme concentration is similar to40 nM. Their 4'-aminoimidazol-1'-yl analogues (4, X = Cl, Br) are >350-fold less active with IC50 values of similar to7 muM. The 5-unsubstituted analogues (3 and 4, X = H) were both less active than their 5-halo derivatives. Determination of pK(a) values and molecular modeling studies of these compounds in the active site of human TP was used to rationalize their activities. The finding that 3, X = Br has a poor pharmacokinetic (PK) profile in mice, coupled with the desire for tumor selectivity, led us to design prodrugs. The corresponding 2'-nitrolmidazol-1'-ylmethyluracils (5, X = Cl, Br) are > 1000-fold less active (IC(50) 22-24 muM) than their 2'-amino analogues and are reduced to the 2'-amino inhibitors (3, X = Cl, Br) by xanthine oxidase (XO). As XO is also highly expressed in many tumors, the 2'-nitro prodrugs have the potential to selectively deliver the potent 2'-aminoimidazol-1'-yl TP inhibitors into hypoxic solid tumors.