1-(3-deoxy-3-fluoro-4,6-O-isopropylidene-β-D-glucopyranosyl)-N⁴-benzoyl cytosine | 924279-87-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-(3-deoxy-3-fluoro-4,6-O-isopropylidene-β-D-glucopyranosyl)-N⁴-benzoyl cytosine
• 英文别名: 1-(3-deoxy-3-fluoro-4,6-O-isopropylidene-β-D-glucopyranosyl)-N⁴-benzoylcytosine；N-[1-[(4aR,6R,7S,8R,8aR)-8-fluoro-7-hydroxy-2,2-dimethyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]-2-oxopyrimidin-4-yl]benzamide
• CAS: 924279-87-8
• 化学式: C₂₀H₂₂FN₃O₆
• 分子量: 419.41
• InChiKey: JNOLDXOSTUDTSO-JOCABOTCSA-N

物化性质

• 密度：
  1.50±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  110
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-(3-deoxy-3-fluoro-4,6-O-isopropylidene-β-D-glucopyranosyl)-N⁴-benzoyl cytosine 在 吡啶 、 重铬酸吡啶 、 乙酸酐 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 4.17h， 生成 1-(6-O-acetyl-3,4-dideoxy-3-fluoro-β-D-glycerohex-3-enopyranosyl-2-ulose)-N⁴-benzoylcytosine
  参考文献：
  名称：

  Fluoro-ketopyranosyl nucleosides: Synthesis and biological evaluation of 3-fluoro-2-keto-β-d-glucopyranosyl derivatives of N4-benzoyl cytosine

  摘要：

  1,2:5,6-Di-O-isopropylidene-ot-D-glucofuranose on mild oxidation, reduction, fluorination, and deisopropylidenation followed by acetylation gave peracetylated 3-deoxy-3-fluoro-D-glueopyranose. This was coupled with silylated N-4-benzoyl cytosine. The nucleoside was deacetylated and after several subsequent protection and deprotection steps afforded the desired 3-fluoro-2-keto-beta-D-glucopyranosyl derivatives. These novel synthesized compounds were evaluated for antiviral and cytotoxic activities against rotavirus, vesicular stomatitis virus, and the human colon adenocarcinoma cell line Caco-2, and have a promising potential in combating the rotaviral infections and in the treatment of colon cancer. As compared to AZT, a nucleoside analogue of reverse transcriptase inhibitor, the novel synthesized 1-(3,4-dideoxy-3-tluoro-beta-D-glycero-hex-3-enopyranosyl-2-ulose)-N-4-benzoyl cytosine showed to be more effective at lower concentrations in inhibition of rotavirus infection as well as in the same range of antitumor activity. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.10.033
• 作为产物：
  描述：

  N4-苯甲酰基胞嘧啶 在 吡啶 、 sodium hydroxide 、 三氟甲磺酸三甲基硅酯 、 对甲苯磺酸 、 六甲基二硅氮烷 、 糖精 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 6.5h， 生成 1-(3-deoxy-3-fluoro-4,6-O-isopropylidene-β-D-glucopyranosyl)-N⁴-benzoyl cytosine
  参考文献：
  名称：

  Fluoro-ketopyranosyl nucleosides: Synthesis and biological evaluation of 3-fluoro-2-keto-β-d-glucopyranosyl derivatives of N4-benzoyl cytosine

  摘要：

  1,2:5,6-Di-O-isopropylidene-ot-D-glucofuranose on mild oxidation, reduction, fluorination, and deisopropylidenation followed by acetylation gave peracetylated 3-deoxy-3-fluoro-D-glueopyranose. This was coupled with silylated N-4-benzoyl cytosine. The nucleoside was deacetylated and after several subsequent protection and deprotection steps afforded the desired 3-fluoro-2-keto-beta-D-glucopyranosyl derivatives. These novel synthesized compounds were evaluated for antiviral and cytotoxic activities against rotavirus, vesicular stomatitis virus, and the human colon adenocarcinoma cell line Caco-2, and have a promising potential in combating the rotaviral infections and in the treatment of colon cancer. As compared to AZT, a nucleoside analogue of reverse transcriptase inhibitor, the novel synthesized 1-(3,4-dideoxy-3-tluoro-beta-D-glycero-hex-3-enopyranosyl-2-ulose)-N-4-benzoyl cytosine showed to be more effective at lower concentrations in inhibition of rotavirus infection as well as in the same range of antitumor activity. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.10.033

文献信息

• Unsaturated dideoxy fluoro-ketopyranosyl nucleosides as new cytostatic agents: A convenient synthesis of 2,6-dideoxy-3-fluoro-4-keto-β-d-glucopyranosyl analogues of uracil, 5-fluorouracil, thymine, N4-benzoyl cytosine and N6-benzoyl adenine
  作者：Stella Manta、Niki Tzioumaki、Evangelia Tsoukala、Aggeliki Panagiotopoulou、Maria Pelecanou、Jan Balzarini、Dimitri Komiotis

  DOI：10.1016/j.ejmech.2009.06.013

  日期：2009.11

  acetylated dideoxy analogues of uracil (8a), 5-fluorouracil (8b), thymine (8c), N4-benzoyl cytosine (8d) and N6-benzoyl adenine (8e), respectively. Finally, direct oxidation of the free hydroxyl group at the 4′-position of 8a–e, and simultaneous elimination reaction of the β-acetoxyl group, afforded the desired unsaturated 2,6-dideoxy-3-fluoro-4-keto-β-d-glucopyranosyl derivatives 9a–e. The new analogues were

  通过过乙酰化的3-脱氧的缩合反应合成了尿嘧啶（2a），5-氟尿嘧啶（2b），胸腺嘧啶（2c），N 4-苯甲酰基胞嘧啶（2d）和N 6-苯甲酰基腺嘌呤（2e）的β-保护核苷。-3-氟- d -glucopyranose（1）与相应的甲硅烷基化碱基。核苷被脱乙酰基化，随后的几个保护和脱保护步骤提供了部分乙酰化的类似物6a - e。选择性碘化然后氢化得到尿嘧啶的乙酰化双脱氧类似物（8a），5-氟尿嘧啶（8b），胸腺嘧啶（8c），N 4-苯甲酰基胞嘧啶（8d）和N 6-苯甲酰基腺嘌呤（8e）。最后，在8a - e的4'位置上直接氧化游离羟基，同时消除β-乙酰氧基的反应，得到所需的不饱和2,6-二脱氧-3-氟-4-酮-β - d吡喃葡萄糖基衍生物9A - ë。评价了新的类似物的抗病毒和细胞抑制活性。化合物9a – e在亚毒性浓度下对广泛的DNA和RNA病毒没有活性。然而，它们对多种肿瘤细胞系具有明显
• Unsaturated fluoro-ketopyranosyl nucleosides: Synthesis and biological evaluation of 3-fluoro-4-keto-β-d-glucopyranosyl derivatives of N4-benzoyl cytosine and N6-benzoyl adenine
  作者：Stella Manta、George Agelis、Tanja Botić、Avrelija Cencič、Dimitri Komiotis

  DOI：10.1016/j.ejmech.2007.04.001

  日期：2008.2

  adenine, respectively. The nucleosides were deacetylated and several subsequent protection and deprotection steps afforded the partially acetylated nucleosides of cytosine 7a and adenine 7b, respectively. Finally, direct oxidation of the free hydroxyl group at 4'-position of 7a and 7b, and simultaneous elimination reaction of the beta-acetoxyl group, afforded the desired unsaturated 3-fluoro-4-keto-beta-d-glucopyranosyl

  受保护的β-核苷1-（2,4,6-三-O-乙酰基3-脱氧-3-氟-β-d-吡喃葡萄糖基）-N（4）-苯甲酰基胞嘧啶（2a）和9-（2通过过乙酰化的3-脱氧-3-偶联反应合成了（4,6-三-O-乙酰基-3-脱氧-3-氟-β-d-吡喃葡萄糖基）-N（6）-苯甲酰基腺嘌呤（2b）。氟-d-吡喃葡萄糖（1）分别被甲硅烷基化的N（4）-苯甲酰基胞嘧啶和N（6）-苯甲酰基腺嘌呤所取代。核苷被脱乙酰，随后的几个保护和脱保护步骤分别提供了胞嘧啶7a和腺嘌呤7b的部分乙酰化的核苷。最后，在7a和7b的4′-位上的游离羟基的直接氧化，和β-乙酰氧基的同时消除反应，得到所需的不饱和3-氟-4-酮-β-d-吡喃葡萄糖基衍生物。对这些新合成的化合物的潜在抗肿瘤和抗病毒活性进行了评估。与5FU相比，新合成的衍生物显示出更有效的抗肿瘤生长抑制剂，并且对轮状病毒表现出直接的抗病毒作用。
• Dideoxy fluoro-ketopyranosyl nucleosides as potent antiviral agents: Synthesis and biological evaluation of 2,3- and 3,4-dideoxy-3-fluoro-4- and -2-keto-β-d-glucopyranosyl derivatives of N4-benzoyl cytosine
  作者：Stella Manta、Evangelia Tsoukala、Niki Tzioumaki、Aleš Goropevšek、Ravi Teja Pamulapati、Avrelija Cencič、Jan Balzarini、Dimitri Komiotis

  DOI：10.1016/j.ejmech.2009.01.020

  日期：2009.6

  The synthesis of the dideoxy fluoro ketopyramonucleoside analogues, 1-(2,3-dideoxy-3-fluoro-6-O-trityl-beta-D-glycero-hexopyranosyl-4-ulose)-N-4-benzoyl cytosine (7a), 1-(3,4-dideoxy-3-fluoro-6-O-trityl-beta-D-glycero-hexopyranosyl-2-ulose)-N-4-benzoyl cytosine (13a) and their detritylated analogues 8a and 14a, respectively, is described. Condensation of peracetylated 3-deoxy-3-fluoro-D-glucopyranose (1) with silylated N-4-benzoyl cytosine, followed by selective deprotection and isopropylidenation afforded compound 2. Routine deoxygenation at position 2', followed by a deprotection-selective reprotection sequence afforded the partially tritylated dideoxy nucleoside of cytosine 6, which upon oxidation of the free hydroxyl group at the 4'-position, furnished the desired tritylated 2,3-dideoxy-3-fluoro ketonucleoside 7a in equilibrium with its hydrated form 7b. Compound 2 was the starting material for the synthesis of the dideoxy fluoro ketopyranonucleoside 13a. Similarly, several subsequent protection and deprotection steps as well as routine cleoxygenation at position 4', followed by oxidation of the free hydroxyl group at the 2'-position of the partially tritylated dideoxy nucleoside 12, yielded the desired carbonyl compound 13a in equilibrium with its hydrated form 13b. Finally, trityl removal from 7ar/b and 13a/b provided the unprotected 2,3-dideoxy-3-fluoro-4-keto and 3,4-dideoxy-3-fluoro-2-ketopyranonucleoside analogues 8a and 14a, in equilibrium with their gem-diol forms 8b and 14b. None of the compounds showed inhibitory activity against a wide variety of DNA and RNA viruses at subtoxic concentrations, except 7a/b that was highly efficient against rotavirus infection. Nucleoside 7a/b also exhibited cytostatic activity against cells of various cancers. BrdU-cell cycle analysis revealed that the mechanism of cytostatic activity may be related to a delay in G1/S phase and initiation of programmed cell death. (C) 2009 Elsevier Masson SAS. All rights reserved.