4-N-5'-O-bis(tert-butoxycarbonyl)gemcitabine | 250698-54-5

• 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: 4-N-5'-O-bis(tert-butoxycarbonyl)gemcitabine
• 英文别名: 4-N-BOC-5'-O-BOC-gemcitabine；tert-butyl [(2R,3R,5R)-4,4-difluoro-3-hydroxy-5-[4-[(2-methylpropan-2-yl)oxycarbonylamino]-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl carbonate
• CAS: 250698-54-5
• 化学式: C₁₉H₂₇F₂N₃O₈
• 分子量: 463.435
• InChiKey: HQTIWXWTJKKSCU-RAIGVLPGSA-N

物化性质

• 密度：
  1.39±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  136
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  4-N-5'-O-bis(tert-butoxycarbonyl)gemcitabine 在 4-二甲氨基吡啶 、 N,N'-羰基二咪唑 作用下， 以 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 33.0h， 生成 bis(4-N-BOC-5'-O-BOC-gemcitabine-3'-succinate)phosphatidylcholine
  参考文献：
  名称：

  一种亲水性药物的磷脂化合物、其药物组合物 及应用

  摘要：

  本发明公开了一种亲水性药物的磷脂化合物、其药物组合物及应用。药物组合物为亲水性药物的磷脂化合物或亲水性药物的磷脂化合物和药效学上可接受的载体的组合药物组合物，是液体制剂、固体制剂、半固体制剂、胶囊剂、颗粒剂、凝胶剂、注射剂。该药物组合物是亲水性药物的磷脂化合物或亲水性药物的磷脂化合物和助剂制成的脂质体纳米颗粒，粒径10‑1000纳米。该亲水性药物的磷脂化合物及其脂质体纳米颗粒可用作液体制剂、固体制剂、半固体制剂、灭菌制剂和无菌制剂，毒性低，可用于各种肿瘤等的高效治疗。

  公开号：

  CN105288648B
• 作为产物：
  描述：

  3',5'-O-bis(tert-butoxycarbonyl)gemcitabine 在 4-二甲氨基吡啶 、 TEA 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 反应 26.0h， 生成 4-N-5'-O-bis(tert-butoxycarbonyl)gemcitabine
  参考文献：
  名称：

  Selective Protection of 2‘,2‘-Difluorodeoxycytidine (Gemcitabine)

  摘要：

  Gemcitabine (1) is a promising new anticancer agent used in pancreatic cancer. Improvement in the selective targeting of compound 1 and other cytotoxic agents to solid tumors may be enhanced by conjugation to ligands that target peripheral benzodiazepine receptors (PBRs) located on mitochondria and known to be overexpressed in human brain tumors. Development of such chemical conjugates requires selective protection on 4-NH2, 5'-OH, and 5'-OH of compound 1. All three monoprotected and three diprotected gemcitabine derivatives (2 to 7) were synthesized in good yield by employing a single commonly used protecting reagent, di-tert-butyl dicarbonate, under different conditions. Consequently, the three mono-ligand-gemcitabine conjugates coupled at 4-NH2, 3'-OH, and 5'-OH respectively (14 to 16) were synthesized in high yield using the PER ligand PK11195. This selective protection/deprotection strategy offers a relatively straightforward means to modify other nucleosides.

  DOI：

  10.1021/jo9911140

文献信息

• Development of bioactive gemcitabine-D-Lys6-GnRH prodrugs with linker-controllable drug release rate and enhanced biopharmaceutical profile
  作者：Nisar Sayyad、Eirinaios I. Vrettos、Theodoros Karampelas、Christos M. Chatzigiannis、Katerina Spyridaki、George Liapakis、Constantin Tamvakopoulos、Andreas G. Tzakos

  DOI：10.1016/j.ejmech.2019.01.041

  日期：2019.3

  GnRH receptor, we examined the peptide-drug conjugation approach. Our design hypothesis was driven by the impact that the linker unit could have on the peptide-drug conjugate efficacy. Along these lines, in order to exploit the potential to manipulate the potency of gemcitabine through altering the linker unit we constructed three different novel peptide-drug conjugates assembled of gemcitabine, the

  肽-药物缀合物已经作为增强药物的靶向和药代动力学特征的有效方法而出现。但是，尚未深入探讨/利用链接器单元的影响。吉西他滨（dFdC）是用于抗多种实体瘤的抗癌药。尽管吉西他滨具有强效功效，但其主要受其非特异性毒性，缺乏靶向性和快速代谢失活的影响。为了最小化这些限制并使其靶向过表达GnRH受体的肿瘤，我们研究了肽-药物结合方法。我们的设计假设是由接头单元可能对肽-药物偶联物功效产生的影响所驱动的。沿着这些思路，6 -GnRH和修饰的接头构建基块。具体而言，对连接基进行了雕刻，以允许缓慢释放药物（利用氨基甲酸酯键）或允许快速解离（使用酰胺键和酯键）。值得注意的是，与天然肽配体D-Lys 6 -GnRH相比，新的类似物对GnRH受体（GnRH-R）具有高达95.5倍的增强结合亲和力。另外，在四种不同的癌细胞系中评估了它们的体外细胞毒性。在代表性细胞系中研究了它们的细胞摄取，吉西他滨的释放以及吉西他
• Development of programmable gemcitabine-GnRH pro-drugs bearing linker controllable “click” oxime bond tethers and preclinical evaluation against prostate cancer
  作者：Eirinaios I. Vrettos、Theodoros Karampelas、Nisar Sayyad、Anastasia Kougioumtzi、Nelofer Syed、Timothy Crook、Carol Murphy、Constantin Tamvakopoulos、Andreas G. Tzakos

  DOI：10.1016/j.ejmech.2020.113018

  日期：2021.2

  metabolites. The major metabolite at low pH emanated from the cleavage of the pH-labile oxime bond, validating our design approach. NMR spectroscopy and in vitro radioligand binding assays were exploited for GOXG1 to validate that upon conjugating the drug to the peptide, the peptide microenvironment responsible for its GnRH-R binding is not perturbed and to confirm its high binding potency to the

  肽-药物缀合物（PDC）作为抗肿瘤剂正获得相当大的关注。然而，它们的开发通常是费力且费时的。在这里，我们已经开发并临床前评估了三个吉西他滨作为抗癌细胞毒性单位和D-Lys 6的PDC。-GnRH（促性腺激素释放激素； GnRH）作为癌症靶向单位。这些单元通过对酸不敏感的可编程接头进行束缚，通过酯或酰胺与“咔嗒”型肟连接的组合来指导药物从PDC释放的差异速率。前药被设计成能够以接头引导的差异药物释放速率选择性靶向恶性肿瘤细胞。我们通过在癌细胞上过度表达的GnRH-R GPCR，利用肟键对肿瘤微环境的酸性pH和GnRH内吞作用的响应。在PDC设计过程中解决了吉西他滨具有挑战性的代谢特性。我们开发了一种快速（1小时）且经济高效的“点击”肟键连接平台，以一锅的方式组装了3个所需的不需要纯化的PDC，超越了传统的时间无效且产量低的方法。首先通过共聚焦激光显微镜和流式细胞术分析验证了过表达GnRH-R
• 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.
• [EN] NUCLEOSIDE-LIPID CONJUGATES, THEIR METHOD OF PREPARATION AND USES THEREOF<br/>[FR] CONJUGUES NUCLEOSIDE-LIPIDE, LEUR PROCEDE DE PREPARATION, ET LEURS UTILISATIONS
  申请人：NEOPHARM INC

  公开号：WO2006029081A3

  公开（公告）日：2009-04-23
• 一种亲水性药物的磷脂化合物、其药物组合物 及应用
  申请人：东南大学

  公开号：CN105288648B

  公开（公告）日：2018-11-06

  本发明公开了一种亲水性药物的磷脂化合物、其药物组合物及应用。药物组合物为亲水性药物的磷脂化合物或亲水性药物的磷脂化合物和药效学上可接受的载体的组合药物组合物，是液体制剂、固体制剂、半固体制剂、胶囊剂、颗粒剂、凝胶剂、注射剂。该药物组合物是亲水性药物的磷脂化合物或亲水性药物的磷脂化合物和助剂制成的脂质体纳米颗粒，粒径10‑1000纳米。该亲水性药物的磷脂化合物及其脂质体纳米颗粒可用作液体制剂、固体制剂、半固体制剂、灭菌制剂和无菌制剂，毒性低，可用于各种肿瘤等的高效治疗。