1-(3,5-di-O-acetyl-β-D-2-deoxyribofuranosyl)-4-(1,2,4-triazol-1-yl)-5-fluoropyrimidin-2(1H)-one | 161179-94-8

• 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-(3,5-di-O-acetyl-β-D-2-deoxyribofuranosyl)-4-(1,2,4-triazol-1-yl)-5-fluoropyrimidin-2(1H)-one
• 英文别名: 5-fluoro-4-(1,2,4-triazol-1-yl)-1-(3,5-di-O-acetyl-2-deoxy-β-D-ribofuranosyl)-pyrimidine-2(1H)-one；5-fluoro-4-(1,2,4-triazol-1-yl)-1-(β-D-3',5'-di-O-acetyl-2'-deoxy-ribofuranosyl)-pyrimidine-2(1H)-on；[(2R,3S,5R)-3-acetyloxy-5-[5-fluoro-2-oxo-4-(1,2,4-triazol-1-yl)pyrimidin-1-yl]oxolan-2-yl]methyl acetate
• CAS: 161179-94-8
• 化学式: C₁₅H₁₆FN₅O₆
• 分子量: 381.32
• InChiKey: MATDJXWSWVWIKL-YNEHKIRRSA-N

物化性质

• 沸点：
  558.8±60.0 °C(Predicted)
• 密度：
  1.61±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.25
• 重原子数：
  27.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  127.43
• 氢给体数：
  0.0
• 氢受体数：
  11.0

反应信息

• 作为反应物：
  描述：

  1-(3,5-di-O-acetyl-β-D-2-deoxyribofuranosyl)-4-(1,2,4-triazol-1-yl)-5-fluoropyrimidin-2(1H)-one 在 盐酸羟胺 、 氨 、 sodium methylate 作用下， 以 甲醇 为溶剂， 反应 13.0h， 生成 5-fluoro-2'-deoxy-N⁴-hydroxycytidine
  参考文献：
  名称：

  5位取代的N（4）-羟基-2'-脱氧胞苷及其5'-单磷酸酯：合成，构象，与肿瘤胸苷酸合酶的相互作用以及体外抗肿瘤活性。

  摘要：

  描述了通过转化各自的5-取代的3'，5'-二-O-乙酰基-2'-来合成5-取代的N（4）-羟基-2'-脱氧胞苷5a，b，dh的简便方法。脱氧尿苷1a-c，eh。这些程序包括在位置C（4）上进行位点特异性三唑基化或N-甲基咪唑基化，然后进行羟胺化并用MeOH-NH（3）进行解封。借助于麦芽磷酸转移酶系统，将核苷5a，b，dh选择性地转化为相应的5′-单磷酸酯6a，b，dh。由（1）H NMR光谱推导并通过分子力学计算证实的D（2）O溶液中每个核苷的构象表明，戊糖环主要存在于构象S（C-2'-endo）和N（ 4）-OH基为顺式旋转异构体。研究了两种L5178Y鼠白血病细胞系对亲本和5-氟-2'-脱氧尿苷（FdUrd）的耐药性对细胞生长的抑制作用，后者对FdUrd的敏感性比前者低70倍。对于耐FdUrd的L5178Y细胞，5-氟-N（4）-羟基-2'-脱氧胞苷（5e）引起的生长抑制作用几乎是F

  DOI：

  10.1021/jm000975u
• 作为产物：
  描述：

  5-氟-2'-脱氧脲核苷 在 4-二甲氨基吡啶 、 三氯氧磷 作用下， 以 吡啶 为溶剂， 生成 1-(3,5-di-O-acetyl-β-D-2-deoxyribofuranosyl)-4-(1,2,4-triazol-1-yl)-5-fluoropyrimidin-2(1H)-one
  参考文献：
  名称：

  Synthesis of an oligonucleotide suicide substrate for DNA methyltransferases

  摘要：

  The large-scale chemical synthesis of an oligodeoxynucleotide containing 5-fluoro-2'-deoxycytidine (FdC) and its characterization are described. The FdC residue is introduced via the corresponding 4-O-(2,4,6-trimethylphenyl)-2'-deoxyuridine derivative, which undergoes clean conversion to FdC during removal of the oligonucleotide protecting groups with ammonia. A double-stranded oligodeoxynucleotide containing FdC inactivated the DNA methyltransferase enzyme M.Hae III by irreversible formation of a covalent protein-DNA complex.

  DOI：

  10.1021/jo00037a006

文献信息

• Synthesis and In Vitro Antitumor Activity of 2′-Deoxy-5-fluorouridylyl-(3′→5′)-2′-deoxy-5-fluoro-N4-octadecylcytidine: A New Amphiphilic Dinucleoside Phosphate
  作者：Herbert Schott、Peter S. Ludwig、Frank Gansauge、Susanne Gansauge、Reto A. Schwendener

  DOI：10.1002/jlac.199719970220

  日期：1997.2

  The new amphiphilic dinucleoside phosphate, 2′-deoxy-5-fluorouridylyl-(3′5′)-2′-deoxy-5-fluoro-N4-octadecylcytidine (4) was synthesized on a gram scale, using the phosphotriester method, starting from the cytostatic drug 2′-deoxy-5-fluorouridine (5FdU) and 2′-deoxy-5-fluoro-N4-octadecylcytidine (1d). In in vitro clonogenic growth assays using the human pancreatic adenocarcinoma cell line MIA PaCa 2

  使用磷酸三酯法以克级合成了新的两亲性磷酸二核苷2'-脱氧-5-氟尿嘧啶-（3'5'）-2'-脱氧-5-氟-N 4-十八烷基胞嘧啶核苷（4），从细胞抑制药物2'-脱氧-5-氟尿苷（5FdU）和2'-脱氧-5-氟-N 4-十八烷基胞苷（1d）开始。在使用人胰腺腺癌细胞系MIA PaCa 2进行的体外克隆形成生长测定中，两亲性二聚体比母体单体5FdU显着更有效。当以水溶液形式使用时，二聚体的IC 50为10μg/ ml，当以脂质体分散体形式给予时为12μg/ ml，而使用5FdU时，IC 50 在使用的浓度范围内未达到最大浓度。
• [EN] BONE-TARGETING BISPHOSPHONATE DUPLEX DRUGS<br/>[FR] MÉDICAMENTS EN DUPLEX À BASE DE BISPHOSPHONATE À CIBLAGE OSSEUX
  申请人：SCHOTT HERBERT

  公开号：WO2012016994A1

  公开（公告）日：2012-02-09

  The present invention relates to novel bisphosphonate duplex drugs, methods for preparing said compound; pharmaceutical compositions containing the same; as well as the use of said compounds in human and veterinary medicine, and, in particular, for treating tumors, viral infections; or dental disorders.

  本发明涉及新型双膦酸二聚体药物，制备该化合物的方法；含有该化合物的药物组合物；以及在人类和兽医学中使用该化合物，特别是用于治疗肿瘤、病毒感染或口腔疾病。
• Synthesis of 4-alkoxy-5-fluoro-2'-deoxyuridine and its incorporation
  申请人：City of Hope

  公开号：US05663323A1

  公开（公告）日：1997-09-02

  A synthesis of 5-fluoro-2'-ideoxycytidine, of oligonucleotides containing 5-fluoro-2'-deoxycytidine and of certain novel 4-alkoxy-5-fluoro-2'-deoxyuridines is disclosed. These 4-alkoxy compounds are useful intermediates for the preparation of other 4-substituted, 5-fluoro pyrimidine deoxynucleosides, and spontaneously hydrolyze in target cells to form FdU and derivatives thereof.

  揭示了5-氟-2'-脱氧胞苷的合成，含有5-氟-2'-脱氧胞苷的寡核苷酸以及某些新型的4-烷氧基-5-氟-2'-脱氧尿嘧啶。这些4-烷氧基化合物是制备其他4-取代的5-氟嘧啶脱氧核苷的有用中间体，并在靶细胞中自发水解形成FdU及其衍生物。
• N4-[Alkyl-(hydroxyphosphono)phosphonate]-cytidine—New drugs covalently linking antimetabolites (5-FdU, araU or AZT) with bone-targeting bisphosphonates (alendronate or pamidronate)
  作者：Herbert Schott、Daniel Goltz、Timm C. Schott、Claudia Jauch、Reto A. Schwendener

  DOI：10.1016/j.bmc.2011.04.015

  日期：2011.6

  Amino-bisphosphonates (alendronate, pamidronate) were covalently linked in a three step synthesis, with protected and triazolylated derivatives of therapeutically used nucleoside analogs (5-FdU, araC, AZT) by substitution of their triazolyl residue. From the deprotected and chromatographically purified reaction mixtures N-4-[alkyl-(hydroxyphosphono) phosphonate]-cytidine combining two differently cytotoxic functions were obtained. This new family of bisphosphonates (BPs) contains as novelty an alkyl side chain with a cytotoxic nucleoside. The BPs moiety allows for a high binding to hydroxyapatite which is a prerequisite for bone targeting of the drugs. In vitro binding of 5-FdU-alendronate (5-FdU-ale) to hydroxyapatite showed a sixfold increased binding of these BPs as compared to 5-FdU.Exploratory cytotoxic properties of 5-FdU-ale were tested on a panel of human tumor cell lines resulting in growth inhibition ranging between 5% and 38%. The determination of IC50-concentrations of the conjugate in Lewis lung carcinoma and murine macrophages showed an incubation time dependent growth inhibition with higher sensitivity towards the tumor cells. We assume that the antimetabolite-BPs can be cleaved into different active metabolites that may exert cytotoxic and other therapeutic effects. However, the underlying mechanisms of these promising new antimetabolite-BPs conjugates remain to be evaluated in future experiments. (C) 2011 Elsevier Ltd. All rights reserved.