2-Amino-5-thio-substituted thiazole 29 | 224435-28-3

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 2-Amino-5-thio-substituted thiazole 29
• 英文别名: N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]-2-methylpropanamide
• CAS: 224435-28-3
• 化学式: C₁₅H₂₁N₃O₂S₂
• 分子量: 339.483
• InChiKey: FETXAWXOSWHGHF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  122
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-Amino-5-thio-substituted thiazole 29 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以34%的产率得到2-Amino-substituted thiazole 51
  参考文献：
  名称：

  Discovery of Aminothiazole Inhibitors of Cyclin-Dependent Kinase 2:  Synthesis, X-ray Crystallographic Analysis, and Biological Activities

  摘要：

  High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC50 values in the 1-10 nM range were rapidly prepared. The X-ray crystallographic data of the inhibitors bound to the active site of CDK2 protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues displayed potent and broad spectrum antiproliferative activity across a panel of tumor cell lines in vitro. In addition, A2780 ovarian carcinoma cells undergo rapid apoptosis following exposure to CDK2 inhibitors of this class. Mechanism of action studies have confirmed that the phosphorylation of CDK2 substrates such as RB, histone H1, and DNA polymerase alpha (p70 subunit) is reduced in the presence of compound 14. Further optimization led to compounds such as water soluble 45, which possesses a favorable pharmacokinetic profile in mice and demonstrates significant antitumor activity in vivo in several murine and human models, including an engineered murine mammary tumor that overexpresses cyclin E, the coactivator of CDK2.

  DOI：

  10.1021/jm0201520
• 作为产物：
  描述：

  1-diazo-3,3-dimethyl-2-butanone 在 吡啶 、 sodium hydroxide 、 三氟化硼乙醚 、 potassium tert-butylate 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， 反应 29.75h， 生成 2-Amino-5-thio-substituted thiazole 29
  参考文献：
  名称：

  Discovery of Aminothiazole Inhibitors of Cyclin-Dependent Kinase 2:  Synthesis, X-ray Crystallographic Analysis, and Biological Activities

  摘要：

  High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC50 values in the 1-10 nM range were rapidly prepared. The X-ray crystallographic data of the inhibitors bound to the active site of CDK2 protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues displayed potent and broad spectrum antiproliferative activity across a panel of tumor cell lines in vitro. In addition, A2780 ovarian carcinoma cells undergo rapid apoptosis following exposure to CDK2 inhibitors of this class. Mechanism of action studies have confirmed that the phosphorylation of CDK2 substrates such as RB, histone H1, and DNA polymerase alpha (p70 subunit) is reduced in the presence of compound 14. Further optimization led to compounds such as water soluble 45, which possesses a favorable pharmacokinetic profile in mice and demonstrates significant antitumor activity in vivo in several murine and human models, including an engineered murine mammary tumor that overexpresses cyclin E, the coactivator of CDK2.

  DOI：

  10.1021/jm0201520

文献信息

• COMBINATION OF IPILIMUMAB AND PACLITAXEL FOR THE TREATMENT OF CANCER
  申请人：Bristol-Myers Squibb Company

  公开号：EP2962731A1

  公开（公告）日：2016-01-06

  Compositions and methods are disclosed which are useful of the treatment and prevention of proliferative disorders.

  本研究公开了有助于治疗和预防增殖性疾病的组合物和方法。
• COMBINATION OF EPOTHILONE ANALOGS AND CHEMOTHERAPEUTIC AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
  申请人：Lee Francis Y.F.

  公开号：US20100015149A1

  公开（公告）日：2010-01-21

  Compositions and methods are disclosed which are useful of the treatment and prevention of proliferative disorders.
• COMBINATION OF ANTI-CTLA4 ANTIBODY WITH TUBULIN MODULATING AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
  申请人：Jure-Kunkel Maria

  公开号：US20100278828A1

  公开（公告）日：2010-11-04

  Compositions and methods are disclosed which are useful for the treatment and prevention of proliferative disorders, and which comprise an anti-CTLA4 antagonist with a tubulin modulating agent.
• METHODS FOR TREATING CANCER IN PATIENTS HAVING BREAST CANCER RESISTANCE PROTEIN OVEREXPRESSION
  申请人：Lee Francis Y

  公开号：US20110112155A1

  公开（公告）日：2011-05-12

  A method for treating cancer comprising identifying a mammal that overexpresses breast cancer resistance protein; and administering to said mammal a pharmaceutical composition comprising a therapeutically effective amount of ixabepilone. In one aspect, the mammal is not administered an agent that is susceptible to breast cancer resistance protein overexpression resistance. In another aspect, the cancer is breast and/or lung cancer.
• COMBINATION OF ANTI-CTLA4 ANTIBODY WITH TUBULIN MODULATING AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US20140323533A1

  公开（公告）日：2014-10-30

  Compositions and methods are disclosed which are useful of the treatment and prevention of proliferative disorders.