1-[2',3'-di-O-(tert-butyldimethylsilyl)-β-D-arabinofuranosyl]cytosine | 87418-91-5

• 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'-di-O-(tert-butyldimethylsilyl)-β-D-arabinofuranosyl]cytosine
• 英文别名: 2',3'-di-O-tert-butyldimethylsilyl-cytosine-β-D-arabinofuranoside；2',3'-di-O-tert-butyldimethylsilylcytosine-1-β-D-arabinofuranoside；2',3'-di-O-TBS-cytarabine；4-amino-1-[(2R,3S,4R,5R)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one
• CAS: 87418-91-5
• 化学式: C₂₁H₄₁N₃O₅Si₂
• 分子量: 471.745
• InChiKey: BUXPAKUSVYSXKP-NRSFXHEJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  107
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-[2',3'-di-O-(tert-butyldimethylsilyl)-β-D-arabinofuranosyl]cytosine 在 吡啶 、 叔丁基氯化镁 、 三氟乙酸 作用下， 以 四氢呋喃 为溶剂， 反应 48.5h， 生成 4-氨基-1-[5-O-[(2R,4S)-2-氧代-4-(4-吡啶基)-1,3,2-二氧磷杂环己烷-2-基]-BETA-D-呋喃阿拉伯糖基]-2(1H)-嘧啶酮
  参考文献：
  名称：

  Synthesis and Characterization of a Novel Liver-Targeted Prodrug of Cytosine-1-β-d-arabinofuranoside Monophosphate for the Treatment of Hepatocellular Carcinoma

  摘要：

  Cytotoxic nucleosides have proven to be ineffective for the treatment of hepatocellular carcinoma (HCC) due, in part, to their inadequate conversion to their active nucleoside triphosphates (NTP) in the liver tumor and high conversion in other tissues. These characteristics lead to poor efficacy, high toxicity, and a drug class associated with an unacceptable therapeutic index. Cyclic 1-aryl-1,3-propanyl phosphate prodrugs selectively release the monophosphate of a nucleoside (NMP) into CYP3A4-expressing cells, such as hepatocytes, while leaving the prodrug intact in plasma and extrahepatic tissues. This prodrug strategy was applied to the monophosphate of the well-known cytotoxic nucleoside cytosine-1-beta-D-arabinofuranoside (cytarabine, araC). Compound 19S (MB07133), in mice, achieves good liver targeting compared to araC, generating > 19-fold higher cytarabine triphosphate (araCTP) levels in the liver than levels of araC in the plasma and > 12-fold higher araCTP levels in the liver than in the bone marrow, representing a > 120-fold and > 28-fold improvement, respectively, over araC administration.

  DOI：

  10.1021/jm0607449
• 作为产物：
  描述：

  阿糖胞苷 在 咪唑 、 三氟乙酸 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 1-[2',3'-di-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

• Stereoselective Synthesis of the 5‘-Hydroxy-5‘-phosphonate Derivatives of Cytidine and Cytosine Arabinoside
  作者：Xuemei Chen、Andrew J. Wiemer、Raymond J. Hohl、David F. Wiemer

  DOI：10.1021/jo020483k

  日期：2002.12.1

  Both the (R)- and (S)-5'-hydroxy 5'-phosphonate derivatives of cytidine and cytosine arabinoside (ara-C) have been prepared via phosphite addition or a Lewis acid mediated hydrophosphonylation of appropriately protected 5'-nucleoside aldehydes. Phosphite addition to a cytosine aldehyde protected as the 2',3'-acetonide gave predominately the 5'R isomer, while phosphite addition to the corresponding

  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。
• Novel cytarabine monophosphate prodrugs
  申请人：——

  公开号：US20040092476A1

  公开（公告）日：2004-05-13

  Compounds of Formula I, their preparation and uses are described: 1 wherein: M and V are cis to one another and MH is cytarabine; the 5′ oxygen of said cytarabine is attached to the phosphorus; V is 4-pyridyl; and pharmaceutically acceptable prodrugs and salts thereof.

  式I的化合物，其制备和用途如下所述： 其中： M和V相对于彼此为顺式，MH为紫杉醇； 所述紫杉醇的5′氧原子连接到磷； V为4-吡啶基； 以及其药用可接受的前药和盐。
• 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。
• Phosphonate Analogues of Cytosine Arabinoside Monophosphate
  作者：Xuemei Chen、Kang-Yeoun Jung、David F. Wiemer、Andrew J. Wiemer、Raymond J. Hohl

  DOI：10.1080/10426500212248

  日期：2002.6.1

  Phosphonate derivatives of cytidine and cytosine arabinoside have been prepared from the corresponding nucleoside aldehydes and tested for their ability to serve as substrates for nucleotide monophosphate kinase and for their toxicity to K562 leukemia cells.
• 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.