5-ethynyl-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole-4-carbonitrile | 182494-73-1

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 咪唑核糖核苷和核糖核苷酸
• 英文名称: 5-ethynyl-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole-4-carbonitrile
• 英文别名: 1-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-5-ethynylimidazole-4-carbonitrile
• CAS: 182494-73-1
• 化学式: C₁₄H₁₅N₃O₄
• 分子量: 289.291
• InChiKey: BFYZOBGJHWBZSI-FDYHWXHSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  89.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-ethynyl-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole-4-carbonitrile 在 二氯乙酸 、 ammonium hydroxide 、 sodium tetrahydroborate 、 DIAION PK₂₁₂ 、 水 、 双氧水 、 草酸 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 甲醇 、 水 、 二甲基亚砜 为溶剂， 反应 10.17h， 生成 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide
  参考文献：
  名称：

  Syntheses of [2-2H]-5-ethynyl-1-(β-D-ribofuranosyl)imidazole-4-carboxamide and 5-ethynyl-1-([5-3H]-β-D-ribofuranosyl)imidazole-4-carboxamide (EICAR)

  摘要：

  DOI：

  10.1002/(sici)1099-1344(199609)38:9<809::aid-jlcr899>3.0.co;2-0
• 作为产物：
  描述：

  Acetic acid (3aR,4R,6R,6aR)-6-(4-cyano-5-trimethylsilanylethynyl-imidazol-1-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethyl ester 在 氨 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以98%的产率得到5-ethynyl-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)imidazole-4-carbonitrile
  参考文献：
  名称：

  Syntheses of [2-2H]-5-ethynyl-1-(β-D-ribofuranosyl)imidazole-4-carboxamide and 5-ethynyl-1-([5-3H]-β-D-ribofuranosyl)imidazole-4-carboxamide (EICAR)

  摘要：

  DOI：

  10.1002/(sici)1099-1344(199609)38:9<809::aid-jlcr899>3.0.co;2-0

文献信息

• Synthesis and Anti-dengue Virus Activity of 5-Ethynylimidazole-4-carboxamide (EICA) Nucleotide Prodrugs
  作者：Motoki Nakamura、Kentaro Uemura、Noriko Saito-Tarashima、Akihiko Sato、Yasuko Orba、Hirofumi Sawa、Akira Matsuda、Katsumi Maenaka、Noriaki Minakawa

  DOI：10.1248/cpb.c21-01038

  日期：2022.3.1

  We previously showed that 5-ethynyl-(1-β-D-ribofuranosyl)imidazole-4-carboxamide (1; EICAR) is a potent anti-dengue virus (DENV) compound but is cytotoxic to some cell lines, while its 4-thio derivative, 5-ethynyl-(4-thio-1-β-D-ribofuranosyl)imidazole-4-carboxamide (2; 4′-thioEICAR), has less cytotoxicity but also less anti-DENV activity. Based on the hypothesis that the lower anti-DENV activity of 2 is due to reduced susceptibility to phosphorylation by cellular kinase(s), we investigated whether a monophosphate prodrug of 2 can improve its activity. Here, we first prepared two types of prodrug of 1, which revealed that the S-acyl-2-thioethyl (SATE) prodrug had stronger anti-DENV activity than the aryloxyphosphoramidate (so-called ProTide) prodrug. Based on these findings, we next prepared the SATE prodrug of 4′-thioEICAR 18. As expected, the resulting 18 showed potent anti-DENV activity, which was comparable to that of 1; however, its cytotoxicity was also increased relative to 2. Our findings suggest that prodrugs of 4′-thioribonucleoside derivatives such as EICAR (1) represent an effective approach to developing potent biologically active compounds; however, the balance between antiviral activity and cytotoxicity remains to be addressed.

  我们之前表明，5-乙炔基-(1-β-D-呋喃核糖基)咪唑-4-甲酰胺 (1; EICAR) 是一种有效的抗登革热病毒 (DENV) 化合物，但对某些细胞系具有细胞毒性，而其 4-硫代衍生物 5-乙炔基-(4-硫代-1-β-D-呋喃核糖基)咪唑-4-甲酰胺 (2; 4'-thioEICAR) 具有较低的细胞毒性，但抗 DENV 活性也较低。基于2的较低抗DENV活性是由于对细胞激酶磷酸化的敏感性降低所致的假设，我们研究了2的单磷酸前药是否可以提高其活性。在这里，我们首先制备了两种1的前药，结果表明S-酰基-2-硫乙基（SATE）前药比芳氧基氨基磷酸酯（所谓的ProTide）前药具有更强的抗DENV活性。基于这些发现，我们接下来制备了4'-thioEICAR 18的SATE前药。正如预期的那样，所得的18显示出有效的抗DENV活性，与1相当；然而，其细胞毒性相对于 2 也有所增加。我们的研究结果表明 EICAR (1) 等 4'-硫核糖核苷衍生物的前药代表了开发有效生物活性化合物的有效方法；然而，抗病毒活性和细胞毒性之间的平衡仍有待解决。