palbociclib

• 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: palbociclib
• 英文别名: 6-Acetyl-8-cyclopentyl-5-methyl-2-(4-piperazin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one；6-acetyl-8-cyclopentyl-5-methyl-2-(4-piperazin-1-ylanilino)pyrido[2,3-d]pyrimidin-7-one
• 化学式: C₂₅H₃₀N₆O₂
• 分子量: 446.552
• InChiKey: QJWIKMKAGFNAJH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  90.5
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  palbociclib 、 2,3,5,6-tetrafluorophenyl 4-isocyanobutanoate 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.17h， 以49%的产率得到6-acetyl-8-cyclopentyl-2-((5-(4-(4-isocyanobutanoyl)piperazin-1-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one
  参考文献：
  名称：

  Synthesis and Biological Evaluation of Novel ^99mTc-Labeled Palbociclib Derivatives Targeting Cyclin-Dependent Kinase 4/6 (CDK4/6) as Potential Cancer Imaging Agents

  摘要：

  Cancer results from cell proliferation that exceeds normal growth control. There are various specific proteins that control and regulate the cell cycle, such as cyclin-dependent kinases (CDKs), cyclins, and retinoblastoma protein (pRb). The aberration of the cyclin D-CDK4/6-INK4-pRb pathway occurs frequently in cancers; thus, CDK4/6 is an attractive target for the development of radiopharmaceuticals for tumor imaging. In this study, we chose palbociclib, which was approved by the FDA for treating ER+/HER2- advanced breast cancer as the target vector and the isonitrile group, which can coordinate strongly with the [Tc-99(m)(CO)(3)](+) core as the bifunctional chelator, to develop four novel Tc-99(m)-labeled radiotracers for tumor imaging. The ligands (L2, L3, L4, and L5) were synthesized by reacting palbociclib with isocyanide-containing active esters and then radiolabeling with a [Tc-99(m)(CO)(3)](+) core to produce radiotracers (Tc-99(m)-L2, Tc-99(m)-L3, Tc-99(m)-L4, and Tc-99(m)-L5) with high radiochemical purity (>95%) and good stability in vitro. The structures of the Tc-99(m) complexes were identified by preparation and characterization of the corresponding stable rhenium complexes. Partition coefficient results indicated that these complexes were lipophilic. A kinase inhibition assay demonstrated the high affinity of the stable Re complexes for CDK4. A cell study showed that all four complexes had substantial uptake by MCF-7 cells and could be significantly inhibited by palbociclib and nonradiolabeled ligand, indicating a CDK4/6-specific uptake mechanism. Biodistribution studies in nude mice bearing MCF-7 tumors showed that the complexes had obvious accumulation in tumors at 2 h postinjection. Tc-99(m)-L2 exhibited the highest tumor uptake and tumor/blood ratio, whereas Tc-99(m)-L4 showed the highest tumor/muscle ratio. The micro-SPECT/CT study showed that complex Tc-99(m)-L4 had visible uptake at the tumor site, and the accumulation was clearly reduced in the image after pretreatment with palbociclib, further indicating CDK4/6 specificity. All the results showed that the Tc-99(m)-labeled complexes in this work have the potential for tumor imaging.

  DOI：

  10.1021/acs.molpharmaceut.9b00540

文献信息

• PYRIMIDINE-BASED COMPOUNDS FOR THE TREATMENT OF CANCER
  申请人：G1 Therapeutics, Inc.

  公开号：US20200239486A1

  公开（公告）日：2020-07-30

  This invention is in the area of pyrimidine-based compounds for the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.
• CYCLIN-DEPENDENT KINASE INHIBITORS
  申请人：SPV THERAPEUTICS INC.

  公开号：US20220220103A1

  公开（公告）日：2022-07-14

  Described herein are compounds and their pharmaceutically acceptable salts, pharmaceutical compositions thereof, methods of treatment, and medical uses. The compounds described herein are modulators of cyclin-dependent kinases, and are useful in the treatment or alleviation of protein kinase associated disorders, including cancer, infectious diseases, autoimmune diseases, or cardiovascular diseases.
• Synthesis and Biological Evaluation of Novel ^99mTc-Labeled Palbociclib Derivatives Targeting Cyclin-Dependent Kinase 4/6 (CDK4/6) as Potential Cancer Imaging Agents
  作者：Xiaoqing Song、Qianqian Gan、Xuran Zhang、Junbo Zhang

  DOI：10.1021/acs.molpharmaceut.9b00540

  日期：2019.10.7

  Cancer results from cell proliferation that exceeds normal growth control. There are various specific proteins that control and regulate the cell cycle, such as cyclin-dependent kinases (CDKs), cyclins, and retinoblastoma protein (pRb). The aberration of the cyclin D-CDK4/6-INK4-pRb pathway occurs frequently in cancers; thus, CDK4/6 is an attractive target for the development of radiopharmaceuticals for tumor imaging. In this study, we chose palbociclib, which was approved by the FDA for treating ER+/HER2- advanced breast cancer as the target vector and the isonitrile group, which can coordinate strongly with the [Tc-99(m)(CO)(3)](+) core as the bifunctional chelator, to develop four novel Tc-99(m)-labeled radiotracers for tumor imaging. The ligands (L2, L3, L4, and L5) were synthesized by reacting palbociclib with isocyanide-containing active esters and then radiolabeling with a [Tc-99(m)(CO)(3)](+) core to produce radiotracers (Tc-99(m)-L2, Tc-99(m)-L3, Tc-99(m)-L4, and Tc-99(m)-L5) with high radiochemical purity (>95%) and good stability in vitro. The structures of the Tc-99(m) complexes were identified by preparation and characterization of the corresponding stable rhenium complexes. Partition coefficient results indicated that these complexes were lipophilic. A kinase inhibition assay demonstrated the high affinity of the stable Re complexes for CDK4. A cell study showed that all four complexes had substantial uptake by MCF-7 cells and could be significantly inhibited by palbociclib and nonradiolabeled ligand, indicating a CDK4/6-specific uptake mechanism. Biodistribution studies in nude mice bearing MCF-7 tumors showed that the complexes had obvious accumulation in tumors at 2 h postinjection. Tc-99(m)-L2 exhibited the highest tumor uptake and tumor/blood ratio, whereas Tc-99(m)-L4 showed the highest tumor/muscle ratio. The micro-SPECT/CT study showed that complex Tc-99(m)-L4 had visible uptake at the tumor site, and the accumulation was clearly reduced in the image after pretreatment with palbociclib, further indicating CDK4/6 specificity. All the results showed that the Tc-99(m)-labeled complexes in this work have the potential for tumor imaging.