4-(N)-stearoyl gemcitabine | 849139-20-4

• 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)-stearoyl gemcitabine
• 英文别名: stearoyl gemcitabine；Cytidine, 2'-deoxy-2',2'-difluoro-N-(1-oxooctadecyl)-；N-[1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]octadecanamide
• CAS: 849139-20-4
• 化学式: C₂₇H₄₅F₂N₃O₅
• 分子量: 529.668
• InChiKey: VFWBLJXGULTVOF-NQHRYMMQSA-N

物化性质

• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  37
• 可旋转键数：
  19
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  112
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-(N)-stearoyl gemcitabine 在 三乙胺 、 三氯氧磷 、 碳酸氢钠 、 盐酸 、 水 作用下， 以 二氯甲烷 、 甲醇 、 氯仿 为溶剂， 反应 18.0h， 以12%的产率得到4-N-octadecanoyl-2'-2'-difluoro-2'-deoxycytidine 5'-sodium phosphate
  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
• 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 、 三氟乙酸 、 potassium hydroxide 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 43.0h， 生成 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

文献信息

• pH响应电荷翻转及缺氧响应药物释放的胶束递药系统及其制备方法
  申请人：复旦大学

  公开号：CN115429755A

  公开（公告）日：2022-12-06

  本发明属于生物技术领域，涉及一种pH响应电荷翻转及缺氧响应药物释放的胶束递药系统及其制备方法。本发明制剂由HJC0152缺氧响应前药、吉西他滨前药和合成的聚乙二醇‑聚赖氨酸‑2，3‑二甲基马来酸‑聚苯丙氨酸嵌段聚合物以及注射溶媒等制成装载HJC0152和吉西他滨的胶束递药系统。本发明的载药纳米胶束递药系统，粒径小、分布均一、包封率高，载药胶束在肿瘤微酸环境下发生电荷由负到正的翻转，能促进胶束递药系统向肿瘤深部进行穿透。同时，通过缺氧响应前药策略，能保证药物在体循环中的稳定性，以及定点精准释放，具有良好的生物安全性。
• 一种调控肿瘤免疫抑制微环境和逆转耐药的药物递释系统
  申请人：复旦大学

  公开号：CN116350793A

  公开（公告）日：2023-06-30

  本发明属生物技术领域，涉及药物递释系统，具体涉及一种调控肿瘤免疫抑制微环境和逆转耐药的药物递释系统。该药物递释系统由聚乙二醇‑聚赖氨酸‑聚苯丙氨酸(PEG‑Plys‑Pphe)三嵌段聚合物为构筑基元制成，其可响应于肿瘤微酸微环境，表面电荷由负变正，可增加穿透；其负载的两种前药可进一步在肿瘤微环境下进行释药，分别可通过抑制STAT3，调控肿瘤免疫微环境和逆转肿瘤耐药。本发明有望为纳米药物的临床转化领域起到启示作用。
• 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.
• Enhancing efficacy of gemcitabine in pancreatic patient-derived xenograft mouse models
  作者：Andriana Inkoom、Nkafu Ndemazie、Kevin Affram、Taylor Smith、Xue Zhu、Patrick Underwood、Sunil Krishnan、Edward Ofori、Bo Han、Jose Trevino、Edward Agyare

  DOI：10.1016/j.ijpx.2020.100056

  日期：2020.12

  Gemcitabine (Gem), a nucleoside analog, is a preferred choice of treatment for pancreatic cancer (PCa) and often used in combination therapy against wide range of solid tumors. It is known to be rapidly inactivated in blood by cytidine deaminase. The objective of the study was to improve the systemic stability and anticancer activity of modified Gem termed 4-N-stearoylGem (4NSG) In this study, the IC₅₀ values of 4NSG treated MiaPaCa-2 and primary pancreatic cancer (PPCL-46) cultures were significantly lower when compared with gemcitabine hydrochloride (GemHCl) treated cultures. In acute toxicity study, liver enzyme level of aspartate aminotransferase (AST) of the control mice was not significantly different from AST levels of 4NSG and GemHCl treated mice. However, alanine aminotransferase (ALT) level of control mice (67 ± 5 mUnits/mL) was significantly lower compared with ALT levels of GemHCl (232 ± 28 mUnits/mL) and that of 4NSG (172 ± 22 mUnits/mL) (p < 0.0001). More importantly, ALT level of 4NSG was lower than ALT level of GemHCl (p < 0.05). Although ALT levels were elevated, pathological images of liver and kidney tissues of control, GemHCl and 4NSG treated mice revealed no architectural changes and no significant change in mice weight was observed during treatment. The bioavailability (AUC) of 4NSG was 3-fold high and significantly inhibited the tumor growth as compared with equivalent dose of GemHCl. Immunohistochemical staining revealed that 4NSG significantly inhibited the expression vascular endothelial growth factor (VEGF) receptor. The study is unique because it established, for the first time, enhanced anticancer activity of 4NSG against pancreatic patient-derived xenograft (PDX) mouse model and PPCL-46 cells compared with Gem. 4SGN enhanced pharmacokinetic profile and improved the therapeutic efficacy of the standard-of-care Gem. Lastly, 4GSN showed a remarkable tumor growth inhibition and revealed significant antiangiogenic activity in 4GSN treated pancreatic PDX tumor.
• 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.