(R,E)-ethyl 5-(N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-N-(methoxymethyl)sulfamoyl)pent-2-enoate | 1380335-98-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (R,E)-ethyl 5-(N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-N-(methoxymethyl)sulfamoyl)pent-2-enoate
• CAS: 1380335-98-7
• 化学式: C₂₁H₃₁NO₆S
• 分子量: 425.546
• InChiKey: FULWQGIUSYQMIX-JSNVTFDYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.28
• 重原子数：
  29.0
• 可旋转键数：
  13.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  82.14
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (R,E)-ethyl 5-(N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-N-(methoxymethyl)sulfamoyl)pent-2-enoate 在 二异丁基氢化铝 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 生成 (R,E)-5-(3-benzoyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-N-(methoxymethyl)pent-3-ene-1-sulfonamide
  参考文献：
  名称：

  Discovery of Highly Potent Human Deoxyuridine Triphosphatase Inhibitors Based on the Conformation Restriction Strategy

  摘要：

  Human deoxyuridine triphosphatase (dUTPase) inhibition is a promising approach to enhance the efficacy of thymidylate synthase (TS) inhibitor based chemotherapy. In this study, we describe the discovery of a novel class of human dUTPase inhibitors based on the conformation restriction strategy. On the basis of the X-ray cocrystal structure of dUTPase and its inhibitor compound 7, we designed and synthesized two conformation restricted analogues, i.e., compounds 8 and 9. These compounds exhibited increased in vitro potency compared with the parent compound 7. Further structure activity relationship (SAR) studies identified a compound 43 with the highest in vitro potency (IC50 = 39 nM, EC50 = 66 nM). Furthermore, compound 43 had a favorable oral PK profile and exhibited potent antitumor activity in combination with 5-fluorouracil (5-FU) in the MX-1 breast cancer xenograft model. These results suggested that a dUTPase inhibitor may have potential for clinical usage.

  DOI：

  10.1021/jm300416h
• 作为产物：
  描述：

  (R)-3-chloro-N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-N-(methoxymethyl)propane-1-sulfonamide 在 sodium hydride 、 戴斯-马丁氧化剂 、 甲胺 、 sodium iodide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 11.0h， 生成 (R,E)-ethyl 5-(N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-N-(methoxymethyl)sulfamoyl)pent-2-enoate
  参考文献：
  名称：

  Discovery of Highly Potent Human Deoxyuridine Triphosphatase Inhibitors Based on the Conformation Restriction Strategy

  摘要：

  Human deoxyuridine triphosphatase (dUTPase) inhibition is a promising approach to enhance the efficacy of thymidylate synthase (TS) inhibitor based chemotherapy. In this study, we describe the discovery of a novel class of human dUTPase inhibitors based on the conformation restriction strategy. On the basis of the X-ray cocrystal structure of dUTPase and its inhibitor compound 7, we designed and synthesized two conformation restricted analogues, i.e., compounds 8 and 9. These compounds exhibited increased in vitro potency compared with the parent compound 7. Further structure activity relationship (SAR) studies identified a compound 43 with the highest in vitro potency (IC50 = 39 nM, EC50 = 66 nM). Furthermore, compound 43 had a favorable oral PK profile and exhibited potent antitumor activity in combination with 5-fluorouracil (5-FU) in the MX-1 breast cancer xenograft model. These results suggested that a dUTPase inhibitor may have potential for clinical usage.

  DOI：

  10.1021/jm300416h