4-N-heptadecylcarbonyl-3',5'-O-bis(tert-butoxycarbonyl) gemcitabine | 1373522-93-0

• 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-heptadecylcarbonyl-3',5'-O-bis(tert-butoxycarbonyl) gemcitabine
• 英文别名: 3',5'-O-bis(tert-butoxycarbonyl)-4-N-stearoylgemcitabine
• CAS: 1373522-93-0
• 化学式: C₃₇H₆₁F₂N₃O₉
• 分子量: 729.903
• InChiKey: GJXGJCAMPAPVSX-VEIFUORISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.25
• 重原子数：
  51.0
• 可旋转键数：
  21.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  144.28
• 氢给体数：
  1.0
• 氢受体数：
  11.0

反应信息

• 作为反应物：
  描述：

  4-N-heptadecylcarbonyl-3',5'-O-bis(tert-butoxycarbonyl) gemcitabine 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以70%的产率得到4-(N)-stearoyl gemcitabine
  参考文献：
  名称：

  LIPOPHILIC MONOPHOSPHORYLATED DERIVATIVES AND NANOPARTICLES

  摘要：

  其中提供了伊立替宾的亲脂性单磷酸化衍生物，还提供了包含伊立替宾的亲脂性单磷酸化衍生物的纳米粒子组合物、相应的药物组合物，以及一种治疗癌症或病毒感染的方法，该方法包括给需要的受试者使用本文披露的药物组合物。

  公开号：

  US20130131008A1
• 作为产物：
  描述：

  盐酸吉西他滨 在 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 potassium hydroxide 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 42.0h， 生成 4-N-heptadecylcarbonyl-3',5'-O-bis(tert-butoxycarbonyl) gemcitabine
  参考文献：
  名称：

  Synthesis and in vitro evaluation of novel lipophilic monophosphorylated gemcitabine derivatives and their nanoparticles

  摘要：

  Gemcitabine hydrochloride (HCl) is approved for the treatment of a wide spectrum of solid tumors. However, the rapid development of resistance often makes gemcitabine less efficacious. In the present study, we synthesized several novel lipophilic monophosphorylated gemcitabine derivatives, incorporated them into solid lipid nanoparticles, and then evaluated their ability to overcome major known gemcitabine resistance mechanisms by evaluating their in vitro cytotoxicities in cancer cells that are deficient in deoxycytidine kinase (dCK), deficient in human equilibrative nucleoside transporter (hENT1), over-expressing ribonucleotide reductase M1 subunit (RRM1), or over-expressing RRM2. In dCK deficient cells, the monophosphorylated gemcitabine derivatives and their nanoparticles were up to 86-fold more cytotoxic than gemcitabine HCl. The majority of the gemcitabine derivatives and their nanoparticles were more cytotoxic than gemcitabine HCl in cells that over-expressing RRM1 or RRM2, and the gemcitabine derivatives in nanoparticles were also resistant to deamination by deoxycytidine deaminase. The gemcitabine derivatives (in nanoparticles) hold a great potential in overcoming gemcitabine resistance. (c) 2012 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ijpharm.2012.03.014

文献信息

• Enhanced Tumor Delivery of Gemcitabine via PEG-DSPE/TPGS Mixed Micelles
  作者：Yingzhe Wang、Wei Fan、Xin Dai、Usha Katragadda、DeAngelo Mckinley、Quincy Teng、Chalet Tan

  DOI：10.1021/mp4005904

  日期：2014.4.7

  Gemcitabine is a potent anticancer drug approved for the treatment of pancreatic, non-small-cell lung, breast, and ovarian cancers. The major deficiencies of current gemcitabine therapy, however, are its rapid metabolic inactivation and narrow therapeutic window. Herein, we employed polyethylene glycol-b-distearoylphosphatidylethanolamine (PEG-DSPE)/tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles as a delivery system, to improve the pharmacokinetic characteristics of gemcitabine and enhance its antitumor efficacy. By conjugating stearic acid to gemcitabine and subsequently encapsulating stearoyl gemcitabine (GemC18) within PEG-DSPE/TPGS mixed micelles, the deamination of gemcitabine was delayed in vitro and in vivo. Importantly, compared to free gemcitabine, GemC18-loaded micelles pronouncedly prolonged the circulation time of gemcitabine and elevated its concentration in the tumor by 3-fold, resulting in superior antitumor efficacy in mice bearing human pancreatic cancer BxPC-3 xenografts. Our findings demonstrate the promise of PEG-DSPE/TPGS mixed micelles as a nanocarrier system for the delivery of gemcitabine to achieve safer and more efficacious therapeutic outcomes.
• Lysosomal Delivery of a Lipophilic Gemcitabine Prodrug Using Novel Acid-Sensitive Micelles Improved Its Antitumor Activity
  作者：Saijie Zhu、Dharmika S. P. Lansakara-P.、Xinran Li、Zhengrong Cui

  DOI：10.1021/bc2005945

  日期：2012.5.16

  Stimulus-sensitive micelles are attractive anticancer drug delivery systems. Herein, we reported a novel strategy to engineer acid-sensitive micelles using a amphiphilic material synthesized by directly conjugating the hydrophilic poly(ethylene glycol) (PEG) with a hydrophobic stearic acid derivative (C18) using an acid-sensitive hydrazone bond (PHC). An acidi-insensitive PEG-amide-C18 (PAC) compound was also synthesized as a control. 4-(N)-Stearoyl gemcitabine (GemC18), a prodrug of the nucleoside analogue gemcitabine, was loaded into the micelles, and they were found to be significantly more cytotoxic to tumor cells than GemC18 solution, likely due to the lysosomal delivery of GemC18 by micelles. Moreover, GemC18 in the acid-sensitive PHC micelles was more cytotoxic than in the acid-insensitive PAC micelles, which may be attributed to the acid-sensitive release of GemC18 from the PHC micelles in lysosomes. In B16-F10 melanoma-bearing mice, GemC18-loaded PHC or PAC micelles showed stronger antitumor activity than GemC18 or gemcitabine solution, likely because of the prolonged circulation time and increased tumor accumulation of the GemC18 by the micelles. Importantly, the in vivo antitumor activity of GemC18-loaded PHC micelles was significantly stronger than that of the PAC micelles, demonstrating the potential of the novel acid-sensitive micelles as an anticancer drug delivery system.