5-(((2R,3R,5R)-5-(4-((tert-butoxycarbonyl)amino)-2-oxopyrimidin-1(2H)-yl)-3-((tert-butoxycarbonyl)oxy)-4,4-difluorotetrahydrofuran-2-yl)methoxy)-5-oxopentanoic acid | 1415749-34-6

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: 5-(((2R,3R,5R)-5-(4-((tert-butoxycarbonyl)amino)-2-oxopyrimidin-1(2H)-yl)-3-((tert-butoxycarbonyl)oxy)-4,4-difluorotetrahydrofuran-2-yl)methoxy)-5-oxopentanoic acid
• 英文别名: 5-[[(2R,3R,5R)-4,4-difluoro-5-[4-[(2-methylpropan-2-yl)oxycarbonylamino]-2-oxopyrimidin-1-yl]-3-[(2-methylpropan-2-yl)oxycarbonyloxy]oxolan-2-yl]methoxy]-5-oxopentanoic acid
• CAS: 1415749-34-6
• 化学式: C₂₄H₃₃F₂N₃O₁₁
• 分子量: 577.536
• InChiKey: DYVNLCOYFJSURJ-FSPWUOQZSA-N

物化性质

• 密度：
  1.39±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.24
• 重原子数：
  40.0
• 可旋转键数：
  9.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  181.58
• 氢给体数：
  2.0
• 氢受体数：
  12.0

反应信息

• 作为产物：
  描述：

  3'-O-(tert-butoxycarbonyl)gemcitabine 在 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 24.0h， 生成 5-(((2R,3R,5R)-5-(4-((tert-butoxycarbonyl)amino)-2-oxopyrimidin-1(2H)-yl)-3-((tert-butoxycarbonyl)oxy)-4,4-difluorotetrahydrofuran-2-yl)methoxy)-5-oxopentanoic acid
  参考文献：
  名称：

  开发源自抗 ROR1 抗体的肽互补位模拟物和长效肽-药物缀合物，用于靶向癌症治疗

  摘要：

  由于实体瘤中抗体分布不均匀，阻碍了有效的药物输送，基于抗体的癌症靶向治疗面临着挑战。我们通过使用计算方法开发对受体酪氨酸激酶样孤儿受体 1 (ROR1) 具有纳摩尔范围亲和力的肽模拟物来解决这个问题。这些肽在体外和体内均表现出特异性靶向和深度渗透。此外，我们通过各种连接体将靶向肽与毒素药物连接起来，并通过脂肪侧链与白蛋白结合来延长其体内半衰期，从而创建了肽-药物缀合物（PDC）。抗肿瘤候选药物II-3显示出卓越的亲和力 ( K D = 1.72 × 10 –9 M)、内化效率、抗癌效力 (IC 50 = 0.015 ± 0.002 μM) 和药代动力学 ( t 1/2 = 2.6 h)，展示了设计具有良好组织分布和强肿瘤渗透力的 PDC 的合理方法。

  DOI：

  10.1021/acs.jmedchem.4c00511

文献信息

• Macromolecules
  申请人：Owen David

  公开号：US09744246B2

  公开（公告）日：2017-08-29

  The present invention relates to a macromolecule comprising a dendrimer having surface amino groups to which at least two different terminal groups are attached including a pharmaceutically active agent and a pharmacokinetic modifying agent, the pharmaceutically active agent comprising a hydroxyl group and being attached to the surface amino group of the dendrimer through a diacid linker. Pharmaceutical compositions comprising the macromolecules and methods of treatment using the macromolecules are also described.

  本发明涉及一种大分子，包括具有表面氨基团的树枝状聚合物，至少连接有两种不同末端基团，包括药用活性剂和药代动力学修饰剂，所述药用活性剂包括一个羟基，并通过二酸链连接剂连接到树枝状聚合物的表面氨基团上。还描述了包含这种大分子的药物组合物和使用这种大分子进行治疗的方法。
• GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery
  作者：Theodoros Karampelas、Orestis Argyros、Nisar Sayyad、Katerina Spyridaki、Charalampos Pappas、Kevin Morgan、George Kolios、Robert P Millar、George Liapakis、Andreas G. Tzakos、Demosthenes Fokas、Constantin Tamvakopoulos

  DOI：10.1021/bc500081g

  日期：2014.4.16

  Gemcitabine, a drug with established efficacy against a number of solid tumors, has therapeutic limitations due to its rapid metabolic inactivation. The aim of this study was the development of an innovative strategy to produce a metabolically stable analogue of gemcitabine that could also be selectively delivered to prostate cancer (CaP) cells based on cell surface expression of the Gonadotropin Releasing Hormone-Receptor (GnRH-R). The synthesis and evaluation of conjugated molecules, consisting of gemcitabine linked to a GnRH agonist, is presented along with results in androgen-independent prostate cancer models. NMR and ligand binding assays were employed to verify conservation of microenvironments responsible for binding of novel GnRH-gemcitabine conjugates to the GnRH-R. In vitro cytotoxicity, cellular uptake, and metabolite formation of the conjugates were examined in CaP cell lines. Selected conjugates were efficacious in the in vitro assays with one of them, namely, GSG, displaying high antiproliferative activity in CaP cell lines along with significant metabolic and pharmacokinetic advantages in comparison to gemcitabine. Finally, treatment of GnRH-R positive xenografted mice with GSG showed a significant advantage in tumor growth inhibition when compared to gemcitabine.