5-Chloro-6-(4-nitro-imidazol-1-ylmethyl)-1H-pyrimidine-2,4-dione | 183204-68-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-Chloro-6-(4-nitro-imidazol-1-ylmethyl)-1H-pyrimidine-2,4-dione
• 英文别名: 5-chloro-6-[(4-nitroimidazol-1-yl)methyl]-1H-pyrimidine-2,4-dione
• CAS: 183204-68-4
• 化学式: C₈H₆ClN₅O₄
• 分子量: 271.62
• InChiKey: SGTJZAHLXLCQGW-UHFFFAOYSA-N

物化性质

• 熔点：
  155-158 °C
• 密度：
  1.95±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  18
• 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

• 作为反应物：
  描述：

  5-Chloro-6-(4-nitro-imidazol-1-ylmethyl)-1H-pyrimidine-2,4-dione 在 palladium on activated charcoal ammonium hydroxide 、 氢气 作用下， 以 甲醇 为溶剂， 反应 5.0h， 生成 6-[(4'-aminoimidazol-1'-yl)methyl]-5-chlorouracil
  参考文献：
  名称：

  Aminoimidazolylmethyluracil Analogues as Potent Inhibitors of Thymidine Phosphorylase and Their Bioreductive Nitroimidazolyl Prodrugs

  摘要：

  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.

  DOI：

  10.1021/jm049494r
• 作为产物：
  描述：

  6-(氯甲基)脲嘧啶 在 氢氧化钾 、 磺酰氯 、 溶剂黄146 作用下， 以 水 为溶剂， 反应 2.5h， 生成 5-Chloro-6-(4-nitro-imidazol-1-ylmethyl)-1H-pyrimidine-2,4-dione
  参考文献：
  名称：

  6-亚甲基桥接的尿嘧啶衍生物的合成和评价。第1部分：发现人类胸苷磷酸化酶的新型口服活性抑制剂。

  摘要：

  已经制备了一系列新型的6-亚甲基桥接的尿嘧啶衍生物作为人胸苷磷酸化酶（TP）的抑制剂。为了增强氟化嘧啶2'-脱氧核糖核苷如2'-脱氧-5-（三氟甲基）尿苷（F（3）dThd）的体内抗肿瘤活性，一种有效的TP抑制剂可防止其降解为惰性化合物。药物化学的目标。我们在此介绍新型人TP抑制剂的合成和评估。与已知的TP抑制剂6-氨基-5-氯尿嘧啶相比，在5-氯尿嘧啶的6-位引入N-取代的氨基甲基侧链具有改善的水溶性和增强的抑制活性。口服给药后，化合物42在小鼠中被合理地很好地吸收。当与F（3）dThd结合使用时，化合物42通过增加前者的最大血浆浓度来发挥其TP抑制作用，这在猴子实验中得到了证明。与单独使用F（3）dThd相比，在携带人肿瘤异种移植物的小鼠中，药代动力学特征的积极变化伴随着该组合体内抗肿瘤活性的增强。生化和药理作用似乎都符合预期的概念。

  DOI：

  10.1016/j.bmc.2004.04.036

文献信息

• Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 1: Discovery of novel orally active inhibitors of human thymidine phosphorylase
  作者：Shingo Yano、Hideki Kazuno、Norihiko Suzuki、Tomohiro Emura、Konstanty Wierzba、Jun-ichi Yamashita、Yukio Tada、Yuji Yamada、Masakazu Fukushima、Tetsuji Asao

  DOI：10.1016/j.bmc.2004.04.036

  日期：2004.7

  prepared as inhibitors of human thymidine phosphorylase (TP). To enhance the in vivo antitumor activity of fluorinated pyrimidine 2'-deoxyribonucleosides such as 2'-deoxy-5-(trifluoromethyl)uridine (F(3)dThd), a potent TP inhibitor preventing their degradation to an inactive compound, has become a target of medicinal chemistry. We present here the synthesis and evaluation of novel human TP inhibitors. Introduction

  已经制备了一系列新型的6-亚甲基桥接的尿嘧啶衍生物作为人胸苷磷酸化酶（TP）的抑制剂。为了增强氟化嘧啶2'-脱氧核糖核苷如2'-脱氧-5-（三氟甲基）尿苷（F（3）dThd）的体内抗肿瘤活性，一种有效的TP抑制剂可防止其降解为惰性化合物。药物化学的目标。我们在此介绍新型人TP抑制剂的合成和评估。与已知的TP抑制剂6-氨基-5-氯尿嘧啶相比，在5-氯尿嘧啶的6-位引入N-取代的氨基甲基侧链具有改善的水溶性和增强的抑制活性。口服给药后，化合物42在小鼠中被合理地很好地吸收。当与F（3）dThd结合使用时，化合物42通过增加前者的最大血浆浓度来发挥其TP抑制作用，这在猴子实验中得到了证明。与单独使用F（3）dThd相比，在携带人肿瘤异种移植物的小鼠中，药代动力学特征的积极变化伴随着该组合体内抗肿瘤活性的增强。生化和药理作用似乎都符合预期的概念。
• 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.