TGX-D1 | 1308384-65-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: TGX-D1
• 英文别名: 9-[1-[N-(2-hydroxyethyl)anilino]ethyl]-7-methyl-2-morpholin-4-ylpyrido[1,2-a]pyrimidin-4-one
• CAS: 1308384-65-7
• 化学式: C₂₃H₂₈N₄O₃
• 分子量: 408.5
• InChiKey: VNYXTYFKPUGCCT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  68.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  TGX-D1 在 哌啶 、 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 NH2-SL-TGX
  参考文献：
  名称：

  Development of a Peptide–Drug Conjugate for Prostate Cancer Therapy

  摘要：

  TGX-221 is a highly potent phosphoinositide 3-kinase beta (PI3K beta) inhibitor that holds great promise as a novel chemotherapeutic agent to treat prostate cancer. However, poor solubility and lack of targetability limit its therapeutic applications. The objective of this present study is to develop a peptide-drug conjugate to specifically deliver TGX-221 to HER2 overexpressing prostate cancer cells. Four TGX-221 derivatives with added hydroxyl groups were synthesized for peptide conjugation. Among them, TGX-D1 exhibited a similar bioactivity to TGX-221, and it was selected for conjugation with a peptide promoiety containing a HER2-targeting ligand and a prostate specific antigen (PSA) substrate linkage. From this selection, the peptide-drug conjugate was proven to be gradually cleaved by PSA to release TGX-D1. Cellular uptake of the peptide-drug conjugate was significantly higher in prostate cancer cells compared to the parent drug. Moreover, both the peptide-drug conjugate and its cleaved products demonstrated comparable activities as the parent drug TGX-D1. Our results suggest that this peptide-drug conjugate may provide a promising chemotherapy for prostate cancer patients.

  DOI：

  10.1021/mp200007b
• 作为产物：
  描述：

  9-(1-butoxyvinyl)-7-methyl-2-(4-morpholinyl)-4H-pyrido[1,2-a]pyrimidin-4-one 在 盐酸 、 sodium tetrahydroborate 、 水 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 TGX-D1
  参考文献：
  名称：

  Prodrug Strategy for PSMA-Targeted Delivery of TGX-221 to Prostate Cancer Cells

  摘要：

  TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110 beta catalytic subunit. Recent studies showed that TGX-221 has anti-proliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles was significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than that of the naked drug, and the drug clearance rate was 6.16-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment.

  DOI：

  10.1021/mp3000309

文献信息

• Development of a Peptide–Drug Conjugate for Prostate Cancer Therapy
  作者：Wanyi Tai、Ravi S. Shukla、Bin Qin、Benyi Li、Kun Cheng

  DOI：10.1021/mp200007b

  日期：2011.6.6

  TGX-221 is a highly potent phosphoinositide 3-kinase beta (PI3K beta) inhibitor that holds great promise as a novel chemotherapeutic agent to treat prostate cancer. However, poor solubility and lack of targetability limit its therapeutic applications. The objective of this present study is to develop a peptide-drug conjugate to specifically deliver TGX-221 to HER2 overexpressing prostate cancer cells. Four TGX-221 derivatives with added hydroxyl groups were synthesized for peptide conjugation. Among them, TGX-D1 exhibited a similar bioactivity to TGX-221, and it was selected for conjugation with a peptide promoiety containing a HER2-targeting ligand and a prostate specific antigen (PSA) substrate linkage. From this selection, the peptide-drug conjugate was proven to be gradually cleaved by PSA to release TGX-D1. Cellular uptake of the peptide-drug conjugate was significantly higher in prostate cancer cells compared to the parent drug. Moreover, both the peptide-drug conjugate and its cleaved products demonstrated comparable activities as the parent drug TGX-D1. Our results suggest that this peptide-drug conjugate may provide a promising chemotherapy for prostate cancer patients.
• Prodrug Strategy for PSMA-Targeted Delivery of TGX-221 to Prostate Cancer Cells
  作者：Yunqi Zhao、Shaofeng Duan、Xing Zeng、Chunjing Liu、Neal M. Davies、Benyi Li、M. Laird Forrest

  DOI：10.1021/mp3000309

  日期：2012.6.4

  TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110 beta catalytic subunit. Recent studies showed that TGX-221 has anti-proliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles was significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than that of the naked drug, and the drug clearance rate was 6.16-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment.