1'-(2',3',5'-tri-O-tert-butyldimethylsilyl-β-D-arabinofuranosyl)-cytosine | 90362-54-2

• 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: 1'-(2',3',5'-tri-O-tert-butyldimethylsilyl-β-D-arabinofuranosyl)-cytosine
• 英文别名: 2',3',5'-tri-O-tert-butyldimethylsilylcytosine-1-β-D-arabinofuranoside；1-[2',3',5'-tris-O-(tert-butyldimethylsilyl)-β-D-arabinofuranosyl]cytosine；TBDMS(-2)[TBDMS(-3)][TBDMS(-5)]D-Araf(b)-cytosin-1-yl；4-amino-1-[(2R,3S,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-[[tert-butyl(dimethyl)silyl]oxymethyl]oxolan-2-yl]pyrimidin-2-one
• CAS: 90362-54-2
• 化学式: C₂₇H₅₅N₃O₅Si₃
• 分子量: 586.007
• InChiKey: STPFNZPGQPDBNI-XBYSBRQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.53
• 重原子数：
  38
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  95.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1'-(2',3',5'-tri-O-tert-butyldimethylsilyl-β-D-arabinofuranosyl)-cytosine 在 吡啶 、 重铬酸吡啶 、 乙酸酐 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三氟乙酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 二甲基亚砜 、 苯 为溶剂， 反应 12.25h， 生成 diethyl [1'-(5'-keto-2',3'-di-O-tert-butyldimethylsilyl-β-D-arabino-penta-1',4'-furanosyl)-N⁴-acetylcytosyl]-5'-phosphonate
  参考文献：
  名称：

  胞苷和胞嘧啶阿拉伯糖苷的5'-羟基-5'-膦酸酯衍生物的立体选择性合成。

  摘要：

  胞苷和胞嘧啶阿拉伯糖苷（ara-C）的（R）-和（S）-5'-羟基5'-膦酸酯衍生物均通过亚磷酸酯加成或路易斯酸介导的适当保护的5'-核苷醛进行氢膦酰化而制得。亚磷酸酯被添加到作为2'，3'-丙酮化物保护的胞嘧啶醛中，主要生成5'R异构体，而亚磷酸酯添加到相应的2'，3'-bis TBS衍生物则有利于5'S立体化学。相反，亚磷酸酯加到由ara-C衍生的2'，3'-双TBS保护的醛中仅得到5'R加合物。但是，相同的ara-C醛的TiCl（4）介导的氢膦酰化作用以2：1的比例有利于5'S立体异构体。一旦所有四个非对映异构体都存在，这些化合物的立体化学可根据其光谱数据或从其O-甲基扁桃酸酯衍生物获得。在膦酸酯和各种保护基水解后，测试了四种α-羟基膦酸作为核苷单磷酸激酶底物的能力以及对K562细胞的毒性。

  DOI：

  10.1021/jo020483k
• 作为产物：
  描述：

  叔丁基二甲基氯硅烷 、 阿糖胞苷 在 咪唑 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以85%的产率得到1'-(2',3',5'-tri-O-tert-butyldimethylsilyl-β-D-arabinofuranosyl)-cytosine
  参考文献：
  名称：

  一系列细胞色素 P4503A 激活的前药（HepDirect 前药）的设计、合成和表征，可用于将基于磷（上）酸盐的药物靶向肝脏§

  摘要：

  描述了一类新的磷酸盐和膦酸盐前药，称为 HepDirect 前药，它结合了快速肝脏裂解的特性与高血浆和组织稳定性，以实现肝脏中药物水平的增加。前药是取代的环状 1,3-丙酸酯，设计用于经历由主要在肝脏中表达的细胞色素 P(450) (CYP) 催化的氧化裂解反应。本文报道了在 C4 上含有芳基取代基的前药系列的发现及其用于将基于核苷的药物递送至肝脏的用途。阿糖腺苷、拉米夫定 (3TC) 和阿糖胞苷的 5'-单磷酸酯前药以及膦酸阿德福韦在暴露于肝脏匀浆后显示出裂解，并在血液和其他组织中表现出良好的稳定性。前药裂解需要在顺式构型中存在芳基，但相对独立于 C4 的核苷和绝对立体化学。机理研究表明，前药裂解通过初始 CYP3A 催化氧化为中间体开环一元酸，随后通过 β-消除反应转化为磷酸（on）酸酯和芳基乙烯基酮。在原代大鼠肝细胞和正常大鼠中比较 3TC 和相应的 HepDirect 前药的研究表

  DOI：

  10.1021/ja031818y

文献信息

• Synthesis of phosphonate derivatives of uridine, cytidine, and cytosine arabinoside
  作者：Kang-Yeoun Jung、Raymond J. Hohl、Andrew J. Wiemer、David F. Wiemer

  DOI：10.1016/s0968-0896(00)00183-8

  日期：2000.10

  The vinyl phosphonate derivatives of uridine, cytidine, and cytosine arabinoside (ara-C) have been prepared through oxidation of appropriately protected nucleosides to the 5' aldehydes and Wittig condensation with [(diethoxyphosphinyl)methylidine]triphenylphosphorane. Dihydroxylation of these vinyl phosphonates with an AD-mix reagent generated the new 5',6'-dihydroxy-6'-phosphonates. After hydrolysis

  尿苷，胞苷和胞嘧啶阿拉伯糖苷（ara-C）的乙烯基膦酸酯衍生物是通过将适当保护的核苷氧化成5'醛并与[（二乙氧基膦基）亚甲基]三苯基磷烷进行Wittig缩合反应制得的。用AD-mix试剂将这些乙烯基膦酸酯二羟基化，生成新的5'，6'-二羟基-6'-膦酸酯。在膦酸酯和各种保护基水解后，测试了六种膦酸作为核苷酸单磷酸激酶底物的能力以及对K562细胞的毒性。
• Enhanced cellular uptake of Ara-C via a peptidomimetic prodrug, L-valyl-ara-C in Caco-2 cells
  作者：Eun-Pa Cheon、Joon Hee Hong、Hyo-Kyung Han

  DOI：10.1211/jpp.58.7.0007

  日期：2010.2.18

  This study aimed to investigate the gastrointestinal stability and the cellular uptake characteristics of l-valyl-ara-C, a peptidomimetic prodrug of ara-C (cytarabine). After the synthesis of l-valyl-ara-C via the incorporation of l-valine into the N4-amino group of the cytosine ring in ara-C, the gastrointestinal stability of l-valyl-ara-C was examined using artificial gastric juice and artificial intestinal fluids. The cellular uptake characteristics of l-valyl-ara-C were also examined in Caco-2 cells. The disappearance half-life of l-valyl-ara-C was 2.2 h in artificial gastric juice, while the degradation of l-valyl-ara-C was negligible in artificial intestinal fluid and also in the supernatant above the Caco-2 cell monolayer during the 2-h incubation. The cellular accumulation of l-valyl-ara-C was 5-fold higher than that of ara-C in Caco-2 cells. Furthermore, the cellular uptake of l-valyl-ara-C did not increase proportionally to the increase in drug concentration. The cellular accumulation of l-valyl-ara-C was significantly reduced in the presence of uridine, p-aminohippurate, tetraethylammonium and small dipeptides, while it was not changed in the presence of l-valine and benzoic acid, suggesting that l-valyl-ara-C could interact with multiple uptake transporters, including peptide transporters, organic anion and cation transporters and nucleoside transporters, but might not interact with amino acid transporters. In conclusion, l-valyl-ara-C could be effective to improve the oral absorption of ara-C via the carrier-mediated transport pathway.

  本研究旨在探讨l-缬氨酰-阿糖胞苷（ara-C）的类肽前药在胃肠道稳定性和细胞摄取特性方面的表现。通过将l-缬氨酸引入ara-C 的胞嘧啶环的N4-氨基基团中，合成了l-缬氨酰-ara-C。使用人工胃液和人工肠液检测了l-缬氨酰-ara-C的胃肠道稳定性。在Caco-2细胞中，也检测了l-缬氨酰-ara-C的细胞摄取特性。在人工胃液中，l-缬氨酰-ara-C的消失半衰期为2.2小时，而在人工肠液和Caco-2细胞单层上方的上清液中，l-缬氨酰-ara-C的降解可以忽略不计。在Caco-2细胞中，l-缬氨酰-ara-C的细胞积累量比ara-C高5倍。此外，l-缬氨酰-ara-C的细胞摄取量并未与药物浓度成比例增加。在脲、对氨基苯甲酸、四乙基铵和小肽存在时，l-缬氨酰-ara-C的细胞积累量显著降低，而在l-缬氨酸和苯甲酸存在时则未发生变化，这表明l-缬氨酰-ara-C可能与多种摄取转运体相互作用，包括肽转运体、有机阴离子和阳离子转运体以及核苷转运体，但可能不与氨基酸转运体相互作用。总之，通过载体介导的转运途径，l-缬氨酰-ara-C可能有效提高ara-C的口服吸收。

• Synthesis of chemoreversible prodrugs of ara-C with variable time-release profiles. Biological evaluation of their apoptotic activity
  作者：Peter Wipf、Wenjie Li、Christianah M. Adeyeye、James M. Rusnak、John S. Lazo

  DOI：10.1016/0968-0896(96)00153-8

  日期：1996.10

  N-4-Dipeptidyl slow-release forms of the anticancer drug ara-C were prepared by acylation of the lithiated nucleotide with 4,4-dialkyloxazolinones. An azapeptide prodrug of am-C was obtained by condensation of an amino acid hydrazide with an activated nucleotide urea. The use of unnatural amino acid residues at N-4 prevented nonspecific proteolytic cleavage in biological medium. Aln-C prodrugs 10, 15, 17, and 19 released active drug with half-lives from a few minutes to several days, respectively. Activation via intramolecular N-4-deacylation did not require enzymatic intervention but was strictly dependent on the structure of the peptide chain. The prodrugs 10, 15, and 17 produced similar growth inhibition as ara-C in cultured murine leukemia cells while the azapeptide prodrug 19 was less potent reflecting the slow release of active drug with this compound. All four prodrugs retained the ability to induce apoptosis in human HL-60 leukemia cells with kinetics dictated by the rate of intramolecular N-4-deacylation. This the first demonstration for the control of apoptotic cell death by the modulation of drug release from prodrugs. Copyright (C) 1996 Elsevier Science Ltd
• Synthetic Approaches to a Mononucleotide Prodrug of Cytarabine
  作者：R. Bazzanini、M. -H. Gouy、S. Peyrottes、G. Gosselin、C. Périgaud、S. Manfredini

  DOI：10.1080/15257770500267006

  日期：2005.9.1

  Synthetic pathways to a mononucleotide prodrug of cytarabine (Ara-C) bearing S-pivaloyl-2-thioethyl (tBuSATE) groups, as biolabile phosphate protections, are reported. Using a common phosphoramidite approach, two different kinds of nucleoside protecting groups have been investigated. During this study, we observed an intermolecular migration of the Boc protecting group in the course of the tert-butyldimethylsilyl ether cleavage using tetrabutyl ammonium fluoride.
• EP3730504
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  公开号：——

  公开（公告）日：——