5'-(Boc-L-Val)-cytarabine | 849813-99-6

• 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: 5'-(Boc-L-Val)-cytarabine
• CAS: 849813-99-6
• 化学式: C₁₉H₂₈F₂N₄O₇
• 分子量: 462.451
• InChiKey: SILXNIVCHYGCRE-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：

  5'-(Boc-L-Val)-cytarabine 以 水 、 乙酸乙酯 为溶剂， 反应 4.0h， 以91.8%的产率得到
  参考文献：
  名称：

  核苷类药物5’-位氨基酸酯的区域选择性合成 方法

  摘要：

  本发明涉及结构特征如通式I所示的核苷类药物5'‑位氨基酸酯及其在药学上可接受盐的区域选择性合成方法。其中Base,R，R2，R3如说明书定义，该方法通过利用三芳基甲基(Ar3C‑)选择性地保护核苷类药物5'‑位羟基，然后利用烯丙氧羰基(allyloxycarbonyl,AOC)保护核苷类药物碱基部分及糖结构部分中的其余所有活性位点，再酸性下选择性脱除三芳基甲基，进而与Boc保护的氨基酸缩合、在核苷类药物分子中的5'‑位选择性地成酯，紧接着钯催化脱除AOC，最后于酸性条件下脱除Boc并成相应的盐。本发明的方法具有收率高，所得产物易于分离纯化，更适合于工业化生产的优点。

  公开号：

  CN104231008B
• 作为产物：
  描述：

  吉西他滨 在 盐酸 、 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 甲酸 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 正丁胺 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 吡啶 、 乙二醇二甲醚 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 21.0h， 生成 5'-(Boc-L-Val)-cytarabine
  参考文献：
  名称：

  通过正交保护方案区域选择性合成某些核苷的5'-氨基酸酯

  摘要：

  可以通过肠寡肽转运蛋白1（PepT1）主动转运的拟肽前药5'-位的核苷氨基酸酯具有改善的口服生物利用度。我们在这里通过具有三苯甲基（Tr）和烯丙氧羰基（AOC）保护基团的正交保护方案，确定了一些核苷的5'-酯的区域选择性合成。选择性合成了一系列阿糖胞苷和吉西他滨的5'-酯，总收率超过36.0％。这种有效而稳健的方法将为进一步研究大量抗病毒和抗癌核苷的前药提供例证。

  DOI：

  10.1016/j.tet.2015.01.023

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。
• Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine
  作者：Yasuhiro Tsume、Adam Drelich、David Smith、Gordon Amidon

  DOI：10.3390/molecules22081322

  日期：——

  cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug approach for gemcitabine was adopted. Amino acid and dipeptide monoester prodrugs of gemcitabine were synthesized and their chemical stability in buffers, resistance to thymidine phosphorylase and cytidine deaminase, antiproliferative

  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
• 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.