N-(3-(benzo[b]thiophen-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide | 1369967-00-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 双噻吩和低聚噻吩
• 英文名称: N-(3-(benzo[b]thiophen-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide
• 英文别名: N-[3-(1-benzothiophen-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]acetamide
• CAS: 1369967-00-9
• 化学式: C₁₇H₁₆N₂OS₂
• 分子量: 328.459
• InChiKey: ZKVYIGYUDDBTED-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  97.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  6-(叔丁基)-3-乙基-2-氨基-4,7-二氢噻吩[2,3-C]吡啶二甲酸叔丁酯 在 四(三苯基膦)钯 、 溴 、 sodium carbonate 、 N,N-二异丙基乙胺 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 二氯甲烷 、 氯仿 、 N,N-二甲基乙酰胺 、 水 为溶剂， 反应 16.0h， 生成 N-(3-(benzo[b]thiophen-3-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Structure–Activity Relationships of a Novel Class of Apurinic/Apyrimidinic Endonuclease 1 Inhibitors

  摘要：

  APE1 is an essential protein that operates in the base excision repair (BER) pathway and is responsible for >= 95% of the total apurinic/apyrimidinic (AP) endonuclease activity in human cells. BER is a major pathway that copes with DNA damage induced by several anticancer agents, including ionizing radiation and temozolomide. Overexpression of APEI and enhanced AP endonuclease activity have been linked to increased resistance of tumor cells to treatment with monofunctional alkylators, implicating inhibition of APEI as a valid strategy for cancer therapy. We report herein the results of a focused medicinal chemistry effort around a novel APEI inhibitor, N-(3-(benzo[d]thiazol-2-yl)-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide (3). Compound 3 and related analogues exhibit single-digit micromolar activity against the purified APE1 enzyme and comparable activity in HeLa whole cell extract assays and potentiate the cytotoxicity of the alkylating agents methylmethane sulfonate and temozolomide. Moreover, this class of compounds possesses a generally favorable in vitro ADME profile, along with good exposure levels in plasma and brain following intraperitoneal dosing (30 mg/kg body weight) in mice.

  DOI：

  10.1021/jm201537d

文献信息

• [EN] INHIBITORS OF HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE 1<br/>[FR] INHIBITEURS D'ENDONUCLÉASE APURINIQUE/APYRIMIDIQUE 1
  申请人：US HEALTH

  公开号：WO2012148889A1

  公开（公告）日：2012-11-01

  Disclosed are inhibitors of human APE1, for example, of formula (I), wherein A, B, X, R2, and R3 are as defined herein, that are useful in treating an APE1 mediated disease or disorder, e.g., cancer. Also disclosed is a composition comprising a pharmaceutically suitable carrier and at least one compound of the invention, a method of treating cancer in a mammal and a method of potentiating treatment of cancer.

  本文披露了人类APE1的抑制剂，例如公式(I)所示，其中A、B、X、R2和R3的定义如本文所述，这些抑制剂对治疗APE1介导的疾病或紊乱，如癌症，是有用的。还披露了一种包含药学适宜载体和本发明中至少一种化合物的组合物，一种治疗哺乳动物癌症的方法以及一种增强癌症治疗的方法。
• Synthesis, Biological Evaluation, and Structure–Activity Relationships of a Novel Class of Apurinic/Apyrimidinic Endonuclease 1 Inhibitors
  作者：Ganesha Rai、Vaddadi N. Vyjayanti、Dorjbal Dorjsuren、Anton Simeonov、Ajit Jadhav、David M. Wilson、David J. Maloney

  DOI：10.1021/jm201537d

  日期：2012.4.12

  APE1 is an essential protein that operates in the base excision repair (BER) pathway and is responsible for >= 95% of the total apurinic/apyrimidinic (AP) endonuclease activity in human cells. BER is a major pathway that copes with DNA damage induced by several anticancer agents, including ionizing radiation and temozolomide. Overexpression of APEI and enhanced AP endonuclease activity have been linked to increased resistance of tumor cells to treatment with monofunctional alkylators, implicating inhibition of APEI as a valid strategy for cancer therapy. We report herein the results of a focused medicinal chemistry effort around a novel APEI inhibitor, N-(3-(benzo[d]thiazol-2-yl)-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide (3). Compound 3 and related analogues exhibit single-digit micromolar activity against the purified APE1 enzyme and comparable activity in HeLa whole cell extract assays and potentiate the cytotoxicity of the alkylating agents methylmethane sulfonate and temozolomide. Moreover, this class of compounds possesses a generally favorable in vitro ADME profile, along with good exposure levels in plasma and brain following intraperitoneal dosing (30 mg/kg body weight) in mice.