4-[4-(8-cyclopentyl-6-iodo-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl]-piperazine-1-carboxylic acid tert-butyl ester | 850628-98-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-[4-(8-cyclopentyl-6-iodo-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl]-piperazine-1-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl 4-(4-(8-cyclopentyl-6-iodo-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)phenyl)piperazine-1-carboxylate；Tert-butyl 4-[4-[(8-cyclopentyl-6-iodo-5-methyl-7-oxopyrido[2,3-d]pyrimidin-2-yl)amino]phenyl]piperazine-1-carboxylate
• CAS: 850628-98-7
• 化学式: C₂₈H₃₅IN₆O₃
• 分子量: 630.529
• InChiKey: PQTCWIZAPDGSMI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  38
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  90.9
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-[4-(8-cyclopentyl-6-iodo-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl]-piperazine-1-carboxylic acid tert-butyl ester 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 以79%的产率得到8-cyclopentyl-6-iodo-5-methyl-2-(4-piperazin-1-ylphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one dihydrochloride
  参考文献：
  名称：

  Pyrido [2,3-d] pyrimidin-7-ones作为细胞周期蛋白依赖性激酶4的特异性抑制剂。

  摘要：

  预期细胞周期激酶，细胞周期蛋白依赖性激酶4（Cdk4）的抑制将为治疗增生性疾病（例如癌症）提供有效的方法。以前已经鉴定了吡啶并[2,3-d]嘧啶-7-模板作为抑制ATP依赖性激酶的优先结构，并且已经报道了代表性实例对Cdks的良好效力。获得对单个Cdk酶，特别是Cdk4的选择性一直具有挑战性。在这里，我们报道在吡啶基[2,3-d]嘧啶-7-一个模板的C-5位置处引入甲基取代基足以赋予Cdk4相对于其他Cdks和代表性酪氨酸激酶优异的选择性。进一步的优化导致鉴定出在体外对人肿瘤细胞表现出有效抗增殖活性的高效Cdk4抑制剂。评估了选择性最强的Cdk4抑制剂对小鼠中MDA-MB-435人乳腺癌异种移植物的抗肿瘤活性。

  DOI：

  10.1021/jm049355+
• 作为产物：
  描述：

  对氟硝基苯 在 Ra-Ni 氢气 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二甲基亚砜 、 乙腈 为溶剂， 20.0~100.0 ℃ 、344.74 kPa 条件下， 反应 19.0h， 生成 4-[4-(8-cyclopentyl-6-iodo-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)phenyl]-piperazine-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Pyrido [2,3-d] pyrimidin-7-ones作为细胞周期蛋白依赖性激酶4的特异性抑制剂。

  摘要：

  预期细胞周期激酶，细胞周期蛋白依赖性激酶4（Cdk4）的抑制将为治疗增生性疾病（例如癌症）提供有效的方法。以前已经鉴定了吡啶并[2,3-d]嘧啶-7-模板作为抑制ATP依赖性激酶的优先结构，并且已经报道了代表性实例对Cdks的良好效力。获得对单个Cdk酶，特别是Cdk4的选择性一直具有挑战性。在这里，我们报道在吡啶基[2,3-d]嘧啶-7-一个模板的C-5位置处引入甲基取代基足以赋予Cdk4相对于其他Cdks和代表性酪氨酸激酶优异的选择性。进一步的优化导致鉴定出在体外对人肿瘤细胞表现出有效抗增殖活性的高效Cdk4抑制剂。评估了选择性最强的Cdk4抑制剂对小鼠中MDA-MB-435人乳腺癌异种移植物的抗肿瘤活性。

  DOI：

  10.1021/jm049355+

文献信息

• Radiosynthesis and radiopharmacological evaluation of cyclin-dependent kinase 4 (Cdk4) inhibitors
  作者：Lena Koehler、Franziska Graf、Ralf Bergmann、Jörg Steinbach、Jens Pietzsch、Frank Wuest

  DOI：10.1016/j.ejmech.2009.11.020

  日期：2010.2

  Tumor cells are characterized by their loss of growth control resulting from alterations in regulating pathways of the cell cycle, such as a deregulated cyclin-dependent kinase (Cdk) activity and/or Cdk expression. Appropriately radiolabeled Cdk4 inhibitors are discussed as promising molecular probes for imaging cell proliferation processes and tumor visualization by PET. This work describes the design, synthesis and radiopharmacological evaluation of two I-124-labeled Cdk4 inhibitors as potential radio-tracers for imaging of Cdk4 in vivo. Treatment of a solution containing labeling precursors with [I-124]NaI gave radiolabeled Cdk4 inhibitors [I-124]CKIA and [I-124]CKIB in radiochemical yields of up to 35%. I-124- labeled radiotracers [I-124]CKIA and [I-124]CKIB were used in cell uptake studies as well as biodistribution studies in Wistar rats and small-animal PET in tumor-bearing mice. In vitro radiotracer uptake studies in adherent tumor cells using [I-124]CKIA showed substantial uptake in HT-29 and FaDu cells (750-850% ID/mg protein [I-124]CKIA and 900-1000 %ID/mg protein [I-124]CKIB) after 1 h at 37 degrees C. Biodistribution of [I-124]CKIA and [I-124]CKIB showed rapid blood clearance of radioactivity and an accumulation as well as metabolization in the liver. Both radiotracers were administered intravenously to mouse FaDu xenograft tumor model and imaging studies were performed on a small-animal PET scanner. Both imaging techniques showed only little uptake of both radiotracers in the FaDu tumor xenografts. (C) 2009 Elsevier Masson SAS. All rights reserved.