(2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate | 849813-94-1

• 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: (2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate
• CAS: 849813-94-1
• 化学式: C₁₉H₂₈F₂N₄O₇
• 分子量: 462.451
• InChiKey: BASBHTZGYGUENN-CQROYNQRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.81
• 重原子数：
  32.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  155.0
• 氢给体数：
  3.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  (2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate 、 三氟乙酸 以 二氯甲烷 为溶剂， 反应 4.0h， 生成
  参考文献：
  名称：

  靶向肿瘤的口服抗癌前药的潜在发展：吉西他滨的氨基酸和二肽单酯前药。

  摘要：

  癌症治疗的主要障碍之一是将药物有效地输送到目标部位。由于基质细胞在肿瘤周围发育，因此化学治疗剂必须穿过基质细胞才能到达肿瘤。作为改善药物向肿瘤部位递送的方法，采用吉西他滨的前药方法。合成了吉西他滨的氨基酸和二肽单酯前药，并确定了它们在缓冲液中的化学稳定性，对胸苷磷酸化酶和胞苷脱氨酶的抗性，抗增殖活性以及作为基质细胞替代物的HFF细胞的吸收/通透性，并将其与母体药物进行比较，吉西他滨。在胰腺细胞匀浆中，所有吉西他滨前药的活化要快于其在缓冲液中的水解，这表明存在酶促作用。与它们的母体药物相比，所有前药在HFF细胞匀浆中均表现出极大的稳定性，对胸苷磷酸化酶对糖苷键代谢的抵抗力增强，以及对胞苷脱氨酶的脱氨作用。与吉西他滨相比，所有吉西他滨前药在HFF细胞中的吸收都更高，并且在HFF单层中的通透性更高，表明向肿瘤部位的递送更好。Panc-1和Capan-2胰腺导管细胞系中的细胞抗增殖试验表明，吉西他

  DOI：

  10.3390/molecules22081322
• 作为产物：
  描述：

  N-Boc-L-缬氨酸 、 吉西他滨 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 (2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate 、 5'-(Boc-L-Val)-cytarabine 、 (2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((((tert-butoxycarbonyl)-L-valyl)oxy)methyl)-4,4-difluorotetrahydrofuran-3-yl (tert-butoxycarbonyl)-L-valinate
  参考文献：
  名称：

  靶向肿瘤的口服抗癌前药的潜在发展：吉西他滨的氨基酸和二肽单酯前药。

  摘要：

  癌症治疗的主要障碍之一是将药物有效地输送到目标部位。由于基质细胞在肿瘤周围发育，因此化学治疗剂必须穿过基质细胞才能到达肿瘤。作为改善药物向肿瘤部位递送的方法，采用吉西他滨的前药方法。合成了吉西他滨的氨基酸和二肽单酯前药，并确定了它们在缓冲液中的化学稳定性，对胸苷磷酸化酶和胞苷脱氨酶的抗性，抗增殖活性以及作为基质细胞替代物的HFF细胞的吸收/通透性，并将其与母体药物进行比较，吉西他滨。在胰腺细胞匀浆中，所有吉西他滨前药的活化要快于其在缓冲液中的水解，这表明存在酶促作用。与它们的母体药物相比，所有前药在HFF细胞匀浆中均表现出极大的稳定性，对胸苷磷酸化酶对糖苷键代谢的抵抗力增强，以及对胞苷脱氨酶的脱氨作用。与吉西他滨相比，所有吉西他滨前药在HFF细胞中的吸收都更高，并且在HFF单层中的通透性更高，表明向肿瘤部位的递送更好。Panc-1和Capan-2胰腺导管细胞系中的细胞抗增殖试验表明，吉西他

  DOI：

  10.3390/molecules22081322

文献信息

• Prodrug composition
  申请人：Hilfinger John

  公开号：US20050137141A1

  公开（公告）日：2005-06-23

  A prodrug composition is provided which includes a pharmaceutical species and an amino acid having a covalent bond to the pharmaceutical species. The pharmaceutical species is characterized by bioavailability of 30% or less and a molecular weight in the range of 100-1000 Daltons. The composition is characterized further in that the pharmaceutical species is not acyclovir, ganciclovir, BRL44385, or penciclovir. Also described is an inventive method of delivering a pharmaceutical species to an individual including the step of orally administering an inventive prodrug to an individual. In one embodiment the prodrug includes a pharmaceutical species characterized by bioavailability of 30% or less, wherein the pharmaceutical species has a molecular weight in the range of 100-1000 Daltons. The inventive prodrug is transported from the gastrointestinal lumen by a specific transporter and is enzymatically cleaved to yield the pharmaceutical species, such that the pharmaceutical species is delivered to the individual.

  提供了一种前药组合物，其中包括一种药用物种和与该药用物种具有共价键的氨基酸。该药用物种的生物利用度为30%或更低，分子量在100-1000道尔顿的范围内。该组合物的特征进一步在于，该药用物种不是阿昔洛韦、甘氨鸟苷、BRL44385或者喷昔洛韦。还描述了一种将药用物种传递给个体的创新方法，其中包括口服给个体一种创新前药的步骤。在一个实施例中，前药包括一种生物利用度为30%或更低的药用物种，该药用物种的分子量在100-1000道尔顿的范围内。该创新前药通过特定转运体从胃肠腔转运，并经酶解裂解以产生药用物种，从而将药用物种传递给个体。
• The development of orally administrable gemcitabine prodrugs with d-enantiomer amino acids: Enhanced membrane permeability and enzymatic stability
  作者：Yasuhiro Tsume、Tuba Incecayir、Xueqin Song、John M. Hilfinger、Gordon L. Amidon

  DOI：10.1016/j.ejpb.2013.12.009

  日期：2014.4

  Gemcitabine prodrugs with D- and L-configuration amino acids were synthesized and their chemical stability in buffers, resistance to glycosidic bond metabolism, enzymatic activation, permeability in Caco-2 cells and mouse intestinal membrane, anti-proliferation activity in cancer cell were determined and compared to that of parent drug, gemcitabine. Prodrugs containing D-configuration amino acids were enzymatically more stable than ones with L-configuration amino acids. The activation of all gemcitabine prodrugs was 1.3-17.6-fold faster in cancer cell homogenate than their hydrolysis in buffer, suggesting enzymatic action. The enzymatic activation of amino acid monoester prodrugs containing D-configuration amino acids in cell homogenates was 2.2-10.9-fold slower than one of amino acid monoester prodrugs with L-configuration amino acids. All prodrugs exhibited enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase compared to parent gemcitabine. Gemcitabine prodrugs showed superior the effective permeability in mouse jejunum to gemcitabine. More importantly, the high plasma concentration of d-amino acid gemcitabine prodrugs was observed more than one of L-amino acid gemcitabine prodrugs. In general, the 5'-mono-amino acid monoester gemcitabine prodrugs exhibited higher permeability and uptake than their parent drug, gemcitabine. Cell proliferation assays in AsPC-1 pancreatic ductal cell line indicated that gemcitabine prodrugs were more potent than their parent drug, gemcitabine. The transport and enzymatic profiles of 5'-D-valyl-gemcitabine and 5'-D-phenylalanyl-gemcitabine suggest their potential for increased oral uptake and delayed enzymatic bioconversion as well as enhanced uptake and cytotoxic activity in cancer cells, would facilitate the development of oral dosage form for anti-cancer agents and, hence, improve the quality of life for the cancer patients.