N-羧基苄基吉西他滨 | 138685-83-3

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 中文名称: N-羧基苄基吉西他滨
• 中文别名: 山柰酚-3-O-芸香糖苷,来源于红花
• 英文名称: 4-(benzyloxycarbonylamino)-1-(2-deoxy-2,2-difluoro-β-D-erythro-pentofuranosyl)pyrimidin-2(1H)-one
• 英文别名: 4-N-(benzyloxycarbonyl)-2'-deoxy-2',2'-difluorocytidine；benzyl 1-(3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-ylcarbamate；N-Carboxybenzyl Gemcitabine；benzyl N-[1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]carbamate
• CAS: 138685-83-3
• 化学式: C₁₇H₁₇F₂N₃O₆
• 分子量: 397.335
• InChiKey: KFZMOOGZFANFGH-MRVWCRGKSA-N

物化性质

• 熔点：
  >115°C (dec.)
• 密度：
  1.56±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  121
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-羧基苄基吉西他滨 在 Pd⁰-functionalized resin 作用下， 以 aq. phosphate buffer 为溶剂， 生成 吉西他滨
  参考文献：
  名称：

  Development and Bioorthogonal Activation of Palladium-Labile Prodrugs of Gemcitabine

  摘要：

  Bioorthogonal chemistry has become one of the main driving forces in current chemical biology, inspiring the search for novel biocompatible chemospecific reactions for the past decade. Alongside the well-established labeling strategies that originated the bioorthogonal paradigm, we have recently proposed the use of heterogeneous palladium chemistry and bioorthogonal Pd(0)-labile prodrugs to develop spatially targeted therapies. Herein, we report the generation of biologically inert precursors of cytotoxic gemcitabine by introducing Pd(0)-cleavable groups in positions that are mechanistically relevant for gemcitabine's pharmacological activity. Cell viability studies in pancreatic cancer cells showed that carbamate functionalization of the 4-amino group of gemcitabine significantly reduced (>23-fold) the prodrugs' cytotoxicity. The N-propargyloxycarbonyl (N-Poc) promoiety displayed the highest sensitivity to heterogeneous palladium catalysis under biocompatible conditions, with a reaction half-life of less than 6 h. Zebrafish studies with allyl, propargyl, and benzyl carbamate-protected rhodamines confirmed N-Poc as the most suitable masking group for implementing in vivo bioorthogonal organometallic chemistry.

  DOI：

  10.1021/jm500531z
• 作为产物：
  描述：

  盐酸吉西他滨 在 N-甲基咪唑 、 硫酸氢铵 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 为溶剂， 反应 6.0h， 生成 N-羧基苄基吉西他滨
  参考文献：
  名称：

  CYTIDINE DERIVATIVE DIMERS AND APPLICATIONS THEREOF

  摘要：

  本公开提供胞嘧啶衍生物二聚体、胞嘧啶衍生物二聚体的盐和组合物，以及制备和使用这些胞嘧啶衍生物二聚体的方法，这些方法对于治疗哺乳动物主体中的肿瘤很有用。胞嘧啶衍生物二聚体可能具有以下一般式(I)： 通过分子设计这种基于胞嘧啶的化合物，所公开的胞嘧啶衍生物二聚体/盐对HCT-116人类结肠癌细胞表现出显著的抑制作用，并且对于在裸鼠体内生长的HCT-116人类结肠癌异种移植物表现出强烈的生长抑制作用。所公开的胞嘧啶衍生物二聚体/盐具有高抗肿瘤活性，毒性低，并且适用于治疗癌症。

  公开号：

  US20160137684A1

文献信息

• [EN] TREATMENT OR PROPHYLAXIS OF PROLIFERATIVE CONDITIONS<br/>[FR] TRAITEMENT OU PROPHYLAXIE D'ÉTATS PROLIFÉRATIFS
  申请人：UNIV DUNDEE

  公开号：WO2010125350A1

  公开（公告）日：2010-11-04

  The invention relates to novel compounds for use in the treatment or prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express cytochrome P450 1B1 (CYP1B1) and allelic variants thereof. The invention also provides pharmaceutical compositions comprising one or more such compounds for use in medical therapy, for example in the treatment of prophylaxis of cancers or other proliferative conditions, as well as methods for treating cancers or other conditions in human or non-human animal patients. The invention also provides methods for identifying novel compounds for use in the treatment of prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express CYP1 B1 and allelic variants thereof. The invention also provides a method for determining the efficacy of a compound of the invention in treating cancer.

  该发明涉及用于治疗或预防癌症和其他增殖性疾病的新化合物，例如这些疾病的特征是细胞表达细胞色素P450 1B1（CYP1B1）及其等位基因变体。该发明还提供包含一种或多种此类化合物的药物组合物，用于医学治疗，例如用于治疗或预防癌症或其他增殖性疾病，以及用于治疗人类或非人类动物患者的癌症或其他疾病的方法。该发明还提供用于识别用于治疗或预防癌症和其他增殖性疾病的新化合物的方法，例如这些疾病的特征是细胞表达CYP1B1及其等位基因变体。该发明还提供一种用于确定该发明中化合物治疗癌症的疗效的方法。
• Synthesis and in vitro anticancer activity of new gemcitabine-nucleoside analogue dimers containing methyltriazole or ester-methyltriazole linker
  作者：Roksana Trznadel、Aleksandra Singh、Natalia Kleczewska、Joanna Liberska、Piotr Ruszkowski、Lech Celewicz

  DOI：10.1016/j.bmcl.2019.08.003

  日期：2019.9

  units exhibited the highest activity among dimers 21–30. The activity of compound 29 was higher than that of dFdC in all the studied cancer cell lines. A similar order of activity was observed for compounds 25, 28, and 30. The best activity among all the dimers synthesized was displayed by compound 39, comprising two gemcitabine units with a cleavable linker. The activity of compound 39 was 5 to 9 times

  使用“点击”化学方法合成了两个系列的新型吉西他滨-核苷类似物二聚体。在第一系列二聚体（的21 - 30），该核苷单位用一个稳定的连接methyltriazole 4 Ñ -3'（或5'）ç接头，而第二系列（31 - 40）配有一个可裂解的酯，methyltriazole 4 N -3'（或5'）C接头。Dimers 21 – 40使用磺基罗丹明，对五种人类癌细胞系（例如宫颈癌（HeLa），鼻咽癌（KB），肺脏（A549），脑（U87），肝脏（HepG2）和正常皮肤成纤维细胞系（HDF）的细胞毒性活性进行了评估。 B（SRB）分析。化合物29包括两个吉西他滨（DFDC）单元表现出最高的活性二聚体中21 - 30。在所有研究的癌细胞系中，化合物29的活性均高于dFdC。观察到的化合物活性的类似的命令25，28，和30。化合物39显示出合成的所有二聚体中最好的活性，包括两个具有可裂解接头的吉西他
• [EN] NUCLEOTIDES FOR THE TREATMENT OF CANCER<br/>[FR] NUCLÉOTIDES POUR LE TRAITEMENT DU CANCER
  申请人：IDENIX PHARMACEUTICALS LLC

  公开号：WO2016188943A1

  公开（公告）日：2016-12-01

  The present invention relates to novel nucleoside derivatives of formula (I) as defined in claim 1, pharmaceutical compositions comprising the compounds, processes of preparation thereof, and methods of use thereof for treating cancer.

  本发明涉及公式(I)所定义的新型核苷衍生物，其中，该化合物的制备过程、制药组合物、以及治疗癌症的使用方法。
• A Pharmacokinetic and Pharmacodynamic Evaluation of the Anti-Hepatocellular Carcinoma Compound 4-N-Carbobenzoxy-gemcitabine (Cbz-dFdC)
  作者：Yilin Sun、Jiankun Wang、Kun Hao

  DOI：10.3390/molecules25092218

  日期：——

  Gemcitabine (dFdC) demonstrates significant effectiveness against solid tumors in vitro and in vivo; however, its clinical application is limited because it tends to easily undergo deamination metabolism. Therefore, we synthesized 4-N-carbobenzoxy-gemcitabine (Cbz-dFdC) as a lead prodrug and conducted a detailed pharmacokinetic, metabolic, and pharmacodynamic evaluation. After intragastric Cbz-dFdC administration, the Cmax of Cbz-dFdC and dFdC was 451.1 ± 106.7 and 1656.3 ± 431.5 ng/mL, respectively. The Tmax of Cbz-dFdC and dFdC was 2 and 4 h, respectively. After intragastric administration of Cbz-dFdC, this compound was mainly distributed in the intestine due to low carboxylesterase-1 (CES1) activity. Cbz-dFdC is activated by CES1 in both humans and rats. The enzyme kinetic curves were well fitted by the Michaelis–Menten equation in rats’ blood, plasma, and tissue homogenates and S9 of the liver and kidney, as well as human liver S9 and CES1 recombinase. The pharmacodynamic results showed that the Cbz-dFdC have a good antitumor effect in the HepG2 cell and in tumor-bearing mice, respectively. In general, Cbz-dFdC has good pharmaceutical characteristics and is therefore a good candidate for a potential prodrug.

  Gemcitabine (dFdC)在体外和体内对实体肿瘤表现出显著的有效性，但其临床应用受到限制，因为它容易发生脱氨基代谢。因此，我们合成了4-N-苯甲酰基基西他滨（Cbz-dFdC）作为前体药物，并进行了详细的药代动力学、代谢和药效学评价。经口给予Cbz-dFdC后，Cbz-dFdC和dFdC的Cmax分别为451.1 ± 106.7和1656.3 ± 431.5 ng/mL。Cbz-dFdC和dFdC的Tmax分别为2和4小时。经口给予Cbz-dFdC后，由于低羧酸酯酶-1（CES1）活性，该化合物主要分布在肠道中。Cbz-dFdC在人和大鼠中均通过CES1激活。在大鼠的血液、血浆和组织匀浆以及肝脏和肾脏的S9以及人类肝脏S9和CES1重组酶中，酶动力学曲线都很好地符合Michaelis-Menten方程。药效学结果显示，Cbz-dFdC在HepG2细胞和带瘤小鼠中均具有良好的抗肿瘤效果。总的来说，Cbz-dFdC具有良好的药学特性，因此是潜在的前体药物候选。
• Gemcitabine Prodrugs, Pharmaceutical Compositions and Uses Thereof
  申请人：Gallop A. Mark

  公开号：US20080021208A1

  公开（公告）日：2008-01-24

  The present invention provides gemcitabine prodrugs, methods of making gemcitabine prodrugs, pharmaceutical compositions of gemcitabine prodrugs and methods of using gemcitabine prodrugs and pharmaceutical compositions of using gemcitabine prodrugs to treat or prevent diseases or disorders such as cancer or viral infections.