1-((1R,4R,5S)-4,5-dihydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 核苷和核苷酸类似物
• 英文名称: 1-((1R,4R,5S)-4,5-dihydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione
• 英文别名: 2,4(1H,3H)-Pyrimidinedione, 1-[4,5-dihydroxy-3-(hydroxymethyl)-2-cyclopenten-1-yl]-5-fluoro-；1-[(1R,4R,5S)-4,5-dihydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl]-5-fluoropyrimidine-2,4-dione
• 化学式: C₁₀H₁₁FN₂O₅
• 分子量: 258.206
• InChiKey: XLTHQNOMPHFPMV-PRJMDXOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.3
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  110
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-((1R,4R,5S)-4,5-dihydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione 在 Uridine-Cytidine Kinase 2 、 potassium chloride 、 ATP disodium salt 、 cytidine monophosphate kinase 1 、 lactate dehydrogenase from porcine heart 、 pyruvate kinase from rabbit muscle type III 、 phosphoenolpyruvic acid monopotassium salt 、 NADH 、 magnesium chloride 、 4-羟乙基哌嗪乙磺酸 、 1,4-二巯基-2,3-丁二醇 作用下， 以 aq. phosphate buffer 为溶剂， 反应 24.0h， 生成
  参考文献：
  名称：

  通过与嘧啶代谢调节剂组合增强 RNA 依赖性 RNA 聚合酶抑制的抗病毒功效。

  摘要：

  对 GSK983（一种有效的抗病毒剂）作用模式的全基因组分析，确定了二氢乳清酸脱氢酶作为其靶标，并发现嘧啶挽救的基因敲低使细胞对 GSK983 敏感。由于 GSK983 在生理尿苷浓度存在下是一种无效的抗病毒药物，因此我们探索了将 GSK983 与嘧啶补救抑制剂联合使用。我们合成并评估了环戊烯基尿嘧啶 (CPU) 的类似物，它是一种尿苷补救抑制剂。我们发现CPU在细胞内转化为三磷酸盐。当与 GSK983 结合使用时，CPU 导致蜂窝 UTP 和 CTP 池大幅下降。因此，CPU-GSK983 在生理浓度的尿苷存在下抑制登革热病毒复制。此外，CPU-GSK983组合显着增强了RNA依赖性RNA聚合酶（RdRp）对病毒感染的抑制作用。我们的研究结果强调了一种新的宿主靶向策略，可增强 RdRp 抑制剂的抗病毒活性。

  DOI：

  10.1016/j.chembiol.2020.05.002
• 作为产物：
  描述：

  (+/-)-2,2-dimethyl-3αβ,6αβ-dihydro-4H-cyclopenta-1,3-dioxol-4-one 在 4-二甲氨基吡啶 、 双(乙腈)氯化钯(II) 、 potassium tert-butylate 、 氨 、 仲丁基锂 、 三乙胺 、 三苯基膦 、 三氟乙酸 、 对苯醌 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 为溶剂， 反应 79.5h， 生成 1-((1R,4R,5S)-4,5-dihydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  Enantiomeric Synthesis of d- and l-Cyclopentenyl Nucleosides and Their Antiviral Activity Against HIV and West Nile Virus

  摘要：

  Enantiomeric synthesis Of D- and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus are described. The key intermediate (-)- and (+)-cyclopentenyl alcohols (7 and 15) were prepared from D-gamma -ribonolactone and D-ribose, respectively. Coupling of 7 with appropriately blocked purine and pyrimidine bases via the Mitsunobu reaction followed by deprotection afforded the target L-(+)-cyclopentenyl nucleosides (24-28, 31, 33, and 36). D-(-)Cyclopentenyl nucleosides (1, 40, 43, and 52-56) were also prepared by a similar procedure for L-isomers from 15. The synthesized compounds were evaluated for their antiviral activity against two RNA viruses: HIV and West Nile virus. Among the synthesized D-(-)-nucleosides, adenine (1, neplanocin A), cytosine (55, CPE-C), and 5-fluorocytosine (56) analogues exhibited moderate to potent anti-HIV activity (EC50 0.1, 0.06, and 5.34 muM, respectively) with significant cytotoxicity in PBM, Vero, and CEM cells. Also, cytosine (55) and 5-fluorocytosine (56) analogues exhibited the most potent anti-West Nile virus activity (EC50 0.2-3.0 and 15-20 muM, respectively). Among L-(+)-nucleosides, only the cytosine (27) analogue exhibited weak anti-HIV activity (EC50 58.9 muM).

  DOI：

  10.1021/jm010256v

文献信息

• Enantiomeric Synthesis of <scp>d</scp>- and <scp>l</scp>-Cyclopentenyl Nucleosides and Their Antiviral Activity Against HIV and West Nile Virus
  作者：Gyu Y. Song、Vincent Paul、Hyunah Choo、John Morrey、Robert W. Sidwell、Raymond F. Schinazi、Chung K. Chu

  DOI：10.1021/jm010256v

  日期：2001.11.1

  Enantiomeric synthesis Of D- and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus are described. The key intermediate (-)- and (+)-cyclopentenyl alcohols (7 and 15) were prepared from D-gamma -ribonolactone and D-ribose, respectively. Coupling of 7 with appropriately blocked purine and pyrimidine bases via the Mitsunobu reaction followed by deprotection afforded the target L-(+)-cyclopentenyl nucleosides (24-28, 31, 33, and 36). D-(-)Cyclopentenyl nucleosides (1, 40, 43, and 52-56) were also prepared by a similar procedure for L-isomers from 15. The synthesized compounds were evaluated for their antiviral activity against two RNA viruses: HIV and West Nile virus. Among the synthesized D-(-)-nucleosides, adenine (1, neplanocin A), cytosine (55, CPE-C), and 5-fluorocytosine (56) analogues exhibited moderate to potent anti-HIV activity (EC50 0.1, 0.06, and 5.34 muM, respectively) with significant cytotoxicity in PBM, Vero, and CEM cells. Also, cytosine (55) and 5-fluorocytosine (56) analogues exhibited the most potent anti-West Nile virus activity (EC50 0.2-3.0 and 15-20 muM, respectively). Among L-(+)-nucleosides, only the cytosine (27) analogue exhibited weak anti-HIV activity (EC50 58.9 muM).
• Enhancing the Antiviral Efficacy of RNA-Dependent RNA Polymerase Inhibition by Combination with Modulators of Pyrimidine Metabolism
  作者：Qi Liu、Amita Gupta、Ayse Okesli-Armlovich、Wenjie Qiao、Curt R. Fischer、Mark Smith、Jan E. Carette、Michael C. Bassik、Chaitan Khosla

  DOI：10.1016/j.chembiol.2020.05.002

  日期：2020.6

  Genome-wide analysis of the mode of action of GSK983, a potent antiviral agent, led to the identification of dihydroorotate dehydrogenase as its target along with the discovery that genetic knockdown of pyrimidine salvage sensitized cells to GSK983. Because GSK983 is an ineffective antiviral in the presence of physiological uridine concentrations, we explored combining GSK983 with pyrimidine salvage inhibitors

  对 GSK983（一种有效的抗病毒剂）作用模式的全基因组分析，确定了二氢乳清酸脱氢酶作为其靶标，并发现嘧啶挽救的基因敲低使细胞对 GSK983 敏感。由于 GSK983 在生理尿苷浓度存在下是一种无效的抗病毒药物，因此我们探索了将 GSK983 与嘧啶补救抑制剂联合使用。我们合成并评估了环戊烯基尿嘧啶 (CPU) 的类似物，它是一种尿苷补救抑制剂。我们发现CPU在细胞内转化为三磷酸盐。当与 GSK983 结合使用时，CPU 导致蜂窝 UTP 和 CTP 池大幅下降。因此，CPU-GSK983 在生理浓度的尿苷存在下抑制登革热病毒复制。此外，CPU-GSK983组合显着增强了RNA依赖性RNA聚合酶（RdRp）对病毒感染的抑制作用。我们的研究结果强调了一种新的宿主靶向策略，可增强 RdRp 抑制剂的抗病毒活性。