methyl (3S,4R,5R)-4-acetamido-3-azido-5-(1-ethylpropoxy)-cyclohex-1-ene-1-carboxylate | 1234466-21-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: methyl (3S,4R,5R)-4-acetamido-3-azido-5-(1-ethylpropoxy)-cyclohex-1-ene-1-carboxylate
• 英文别名: methyl (3S,4R,5R)-4-acetamido-3-azido-5-pentan-3-yloxycyclohexene-1-carboxylate
• CAS: 1234466-21-7
• 化学式: C₁₅H₂₄N₄O₄
• 分子量: 324.38
• InChiKey: QPYGKGIPHWUMGJ-BFHYXJOUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  79
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl (3S,4R,5R)-4-acetamido-3-azido-5-(1-ethylpropoxy)-cyclohex-1-ene-1-carboxylate 在 sodium periodate 、 cerium(III) chloride heptahydrate 、 ruthenium(III) trichloride hydrate 作用下， 以 水 、 乙酸乙酯 、 乙腈 为溶剂， 生成
  参考文献：
  名称：

  开发A型流感病毒神经氨酸酶抑制剂的催化位点和150腔。

  摘要：

  我们在这里报告了甲型流感病毒神经氨酸酶活性位点中的150个腔的利用，用于设计新型的含C-6三唑的达菲衍生物。通过利用高度取代的环状Baylis-Hillman醋酸盐作为通过表面烯丙基叠氮化物[3,3]-σ重排的叠氮化物取代的活性前体，开发了一种通用且便捷的合成路线。这些具有氨基或胍基功能的三唑衍生物的体外病毒复制抑制试验表明，胍化合物对浓度为2×10 –5 M的N2亚型菌株显示出更高的功效，但并未抑制菌株的复制N1亚型，即使浓度为10 –4M.为了探究酶-抑制剂相互作用的性质，对这些化合物与不同神经氨酸酶的复合物进行了分子动力学模拟。结果表明，候选抑制剂同时占据了150个空腔和催化位点，但具有交替的占有率。

  DOI：

  10.1021/jo401854w
• 作为产物：
  描述：

  methyl (3R,4R,5R)-3,4-(acetylepimino)-5-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate 在 sodium azide 、 氯化铵 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 以68%的产率得到methyl (3S,4R,5R)-4-acetamido-3-azido-5-(1-ethylpropoxy)-cyclohex-1-ene-1-carboxylate
  参考文献：
  名称：

  Carbocycles Related to Oseltamivir as Influenza Virus Group-1-Specific Neuraminidase Inhibitors. Binding to N1 Enzymes in the Context of Virus-like Particles

  摘要：

  We report here the exploitation of the 150-cavity in the active sites of group-1 neuraminidases for the design of new triazole-containing carbocycles related to oseltamivir. Inhibition studies with virus-like particles (VLPs) containing the influenza virus neuraminidase-1 (NI) activity indicate that several candidates are inhibitors, with K(i) values in the 10(-5)-10(-8) M range. In contrast, a known candidate that preserves the free amino group and a new candidate containing a guanidine function are better inhibitors, with K(i) values of 1.5 x 10(-9) and 4.6 x 10(-10) M, respectively. The most active inhibitor of the N1 enzyme in the triazole series was selective for the N1 class and showed significantly less inhibition (K(i) = 2.6 mu M vs 0.07 mu M) of the free influenza virus neuraminidase-2 (N2). In addition, saturation transfer difference (STD) NMR spectroscopic studies with this compound and the VLPs show that the entire molecule forms contacts with residues in the active site. These data taken together support our proposed binding mode in which the active site and the adjoining 150-cavity are both occupied.

  DOI：

  10.1021/jm100822f

文献信息

• [EN] COMPOUNDS AND METHODS FOR TREATMENT OF INFLUENZA<br/>[FR] COMPOSÉS ET MÉTHODES POUR LE TRAITEMENT DU VIRUS INFLUENZA
  申请人：UNIV FRASER SIMON

  公开号：WO2010075636A1

  公开（公告）日：2010-07-08

  The present invention provides in part a compound of Formula (I) or a pharmaceutically- acceptable salt or stereoisomer thereof: where R1 is selected from the group consisting of a substituted triazole group, a guanidine group, a urea group, a thiourea group, an amidine group, and N3; and R2 is selected from the group consisting of H, Me, Et and an amino acid, and methods and uses thereof.

  本发明部分提供了一种化合物，其化学式为（I）或其药用盐或立体异构体：其中R1选自以下组：取代三唑基团、胍基团、脲基团、硫脲基团、酰胺基团和N3；R2选自以下组：H、Me、Et和氨基酸，以及其方法和用途。
• Carbocycles Related to Oseltamivir as Influenza Virus Group-1-Specific Neuraminidase Inhibitors. Binding to N1 Enzymes in the Context of Virus-like Particles
  作者：Sankar Mohan、Sarah McAtamney、Thomas Haselhorst、Mark von Itzstein、Brian Mario Pinto

  DOI：10.1021/jm100822f

  日期：2010.10.28

  We report here the exploitation of the 150-cavity in the active sites of group-1 neuraminidases for the design of new triazole-containing carbocycles related to oseltamivir. Inhibition studies with virus-like particles (VLPs) containing the influenza virus neuraminidase-1 (NI) activity indicate that several candidates are inhibitors, with K(i) values in the 10(-5)-10(-8) M range. In contrast, a known candidate that preserves the free amino group and a new candidate containing a guanidine function are better inhibitors, with K(i) values of 1.5 x 10(-9) and 4.6 x 10(-10) M, respectively. The most active inhibitor of the N1 enzyme in the triazole series was selective for the N1 class and showed significantly less inhibition (K(i) = 2.6 mu M vs 0.07 mu M) of the free influenza virus neuraminidase-2 (N2). In addition, saturation transfer difference (STD) NMR spectroscopic studies with this compound and the VLPs show that the entire molecule forms contacts with residues in the active site. These data taken together support our proposed binding mode in which the active site and the adjoining 150-cavity are both occupied.
• Exploitation of the Catalytic Site and 150 Cavity for Design of Influenza A Neuraminidase Inhibitors
  作者：Pal John Pal Adabala、Eric B. LeGresley、Nicole Bance、Masahiro Niikura、B. Mario Pinto

  DOI：10.1021/jo401854w

  日期：2013.11.1

  exploitation of the 150 cavity in the active site of influenza A viral neuraminidases for the design of novel C-6 triazole-containing Tamiflu derivatives. A general and convenient synthetic route was developed by utilizing a highly substituted cyclic Baylis–Hillman acetate as an active precursor for azide substitution via suprafacial allylic azide [3,3]-sigmatropic rearrangement. Virus replication inhibitory assays

  我们在这里报告了甲型流感病毒神经氨酸酶活性位点中的150个腔的利用，用于设计新型的含C-6三唑的达菲衍生物。通过利用高度取代的环状Baylis-Hillman醋酸盐作为通过表面烯丙基叠氮化物[3,3]-σ重排的叠氮化物取代的活性前体，开发了一种通用且便捷的合成路线。这些具有氨基或胍基功能的三唑衍生物的体外病毒复制抑制试验表明，胍化合物对浓度为2×10 –5 M的N2亚型菌株显示出更高的功效，但并未抑制菌株的复制N1亚型，即使浓度为10 –4M.为了探究酶-抑制剂相互作用的性质，对这些化合物与不同神经氨酸酶的复合物进行了分子动力学模拟。结果表明，候选抑制剂同时占据了150个空腔和催化位点，但具有交替的占有率。