3-(cyanomethoxy)-2-((3aS,6R,6aR)-2,2,3a-trimethyl-6-(trityloxymethyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acrylonitrile

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: 3-(cyanomethoxy)-2-((3aS,6R,6aR)-2,2,3a-trimethyl-6-(trityloxymethyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acrylonitrile
• 英文别名: 2-[(3aS,6R,6aR)-2,2,3a-trimethyl-6-(trityloxymethyl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]-3-(cyanomethoxy)prop-2-enenitrile
• 化学式: C₃₃H₃₂N₂O₅
• 分子量: 536.627
• InChiKey: IAWOICYCYIUKCG-FVPIIGGMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  40
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  93.7
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-(cyanomethoxy)-2-((3aS,6R,6aR)-2,2,3a-trimethyl-6-(trityloxymethyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acrylonitrile 在 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 乙醇 、 正庚烷 、 乙基苯 为溶剂， 反应 187.0h， 生成 (1S)-1-(4-aminofuro[3,2-d]pyrimidin-7-yl)-1,4-anhydro-2-C-methyl-2,3-O-(1-methylethylidene)-5-O-trityl-D-ribitol
  参考文献：
  名称：

  Ribo 7-N/O/S 嘧啶 9-脱氮 C-核苷类似物作为抑制 HCV RNA 依赖性 RNA 聚合酶的新型抗病毒药物的合成和生物学评价

  摘要：

  丙型肝炎感染是由血源性病原体丙型肝炎病毒 (HCV) 引起的，如果治疗无效，可导致严重的肝脏疾病，并最终导致死亡。本工作报道了7种新型9-O/N/S嘧啶核苷的合成和临床前评价，其中包括化合物12 ，即已知化合物7b的三磷酸酯。核苷是腺苷和鸟苷的 9-脱氮修饰，核糖上带有 β-2'-C-甲基取代基。在该系列化合物中，腺苷的9-脱氮呋喃嘧啶类似物化合物7b在体外表现出高抗HCV活性，在低剂量给药时表现出良好的稳定性、低毒性和低遗传毒性，以及足够的药代动力学特征。与之前的研究相比，还报道了化合物7b的合成改进。合成化合物12作为对照以验证7b在体内发生的磷酸化。

  DOI：

  10.1016/j.ejmech.2023.115991
• 作为产物：
  描述：

  2-[(3aS,6R,6aR)-2,2,3a-trimethyl-6-(trityloxymethyl)-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]-3-hydroxyprop-2-enenitrile 、 氯乙腈 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以222 mg的产率得到3-(cyanomethoxy)-2-((3aS,6R,6aR)-2,2,3a-trimethyl-6-(trityloxymethyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acrylonitrile
  参考文献：
  名称：

  Synthesis and HCV inhibitory properties of 9-deaza- and 7,9-dideaza-7-oxa-2′-C-methyladenosine

  摘要：

  As a part of an ongoing medicinal chemistry effort to identify inhibitors of the Hepatitis C Virus RNA replication, we report here the synthesis and biological evaluation of 9-deaza- and 7,9-dideaza-7-oxa-2'-C-methyladenosine. The parent 2'-C-methyladenosine shows excellent intracellular inhibitory activity but poor pharmacokinetic profile. Replacement of the nucleoside-defining 9-N of 2'-C-methyladenosine with a carbon atom was designed to yield metabolically more stable C-nucleosides. Modifications at position 7 were designed to exploit the importance of the hydrogen bond accepting properties of this heteroatom in modulating the adenosine deaminase (ADA) mediated 6-N deamination. 7-Oxa-7,9-dideaza-2'-C-methyladenosine was found to be a moderately active inhibitor of intracellular HCV RNA replication, whereas 9-deaza- 2'-C-methyladenosine showed only weak activity despite excellent overlap of both of the synthesized target compounds with T-C-methyladenosine's three dimensional structure. Position 7 of the nucleobase proved to be an effective handle for modulating ADA-mediated degradation, with the rate of degradation correlating with the hydrogen-bonding properties at this position. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.05.020

文献信息

• Synthesis and HCV inhibitory properties of 9-deaza- and 7,9-dideaza-7-oxa-2′-C-methyladenosine
  作者：Gabor Butora、David B. Olsen、Steven S. Carroll、Daniel R. McMasters、Christoph Schmitt、Joseph F. Leone、Mark Stahlhut、Christine Burlein、Malcolm MacCoss

  DOI：10.1016/j.bmc.2007.05.020

  日期：2007.8

  As a part of an ongoing medicinal chemistry effort to identify inhibitors of the Hepatitis C Virus RNA replication, we report here the synthesis and biological evaluation of 9-deaza- and 7,9-dideaza-7-oxa-2'-C-methyladenosine. The parent 2'-C-methyladenosine shows excellent intracellular inhibitory activity but poor pharmacokinetic profile. Replacement of the nucleoside-defining 9-N of 2'-C-methyladenosine with a carbon atom was designed to yield metabolically more stable C-nucleosides. Modifications at position 7 were designed to exploit the importance of the hydrogen bond accepting properties of this heteroatom in modulating the adenosine deaminase (ADA) mediated 6-N deamination. 7-Oxa-7,9-dideaza-2'-C-methyladenosine was found to be a moderately active inhibitor of intracellular HCV RNA replication, whereas 9-deaza- 2'-C-methyladenosine showed only weak activity despite excellent overlap of both of the synthesized target compounds with T-C-methyladenosine's three dimensional structure. Position 7 of the nucleobase proved to be an effective handle for modulating ADA-mediated degradation, with the rate of degradation correlating with the hydrogen-bonding properties at this position. (c) 2007 Elsevier Ltd. All rights reserved.
• Synthesis and biological evaluation of Ribo 7-N/O/S pyrimidine 9-deaza C-nucleoside analogs as new antiviral agents for inhibiting HCV RNA-dependent RNA polymerases
  作者：Minwan Wu、Satish Vadlakonda、Yahya El-Kattan、Ajit Ghosh、Tsu-Hsing Lin、Ramanda Chambers-Wilson、Xiaogang Cheng、Shanta Bantia、Debra Kellogg-Yelder、Pooran Chand、Y.S. Babu、Pravin L. Kotian

  DOI：10.1016/j.ejmech.2023.115991

  日期：2024.1

  ineffective. This work reports the synthesis and preclinical evaluation of 7 novel 9-O/N/S pyrimidine nucleosides, including compound 12, the triphosphate of compound of known compound 7b. The nucleosides are 9-deaza modifications of adenosine and guanosine with β-2′-C-methyl substituent on the ribose. Within this series of compounds, a 9-deaza furopyrimidine analog of adenosine, compound 7b, showed

  丙型肝炎感染是由血源性病原体丙型肝炎病毒 (HCV) 引起的，如果治疗无效，可导致严重的肝脏疾病，并最终导致死亡。本工作报道了7种新型9-O/N/S嘧啶核苷的合成和临床前评价，其中包括化合物12 ，即已知化合物7b的三磷酸酯。核苷是腺苷和鸟苷的 9-脱氮修饰，核糖上带有 β-2'-C-甲基取代基。在该系列化合物中，腺苷的9-脱氮呋喃嘧啶类似物化合物7b在体外表现出高抗HCV活性，在低剂量给药时表现出良好的稳定性、低毒性和低遗传毒性，以及足够的药代动力学特征。与之前的研究相比，还报道了化合物7b的合成改进。合成化合物12作为对照以验证7b在体内发生的磷酸化。