(-)-N(4)-(4,4'-dimethoxytrityl)-2',3'-dideoxy-3'-thiacytidine | 956897-01-1

• 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: (-)-N(4)-(4,4'-dimethoxytrityl)-2',3'-dideoxy-3'-thiacytidine
• 英文别名: 4-[[bis(4-methoxyphenyl)-phenylmethyl]amino]-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one
• CAS: 956897-01-1
• 化学式: C₂₉H₂₉N₃O₅S
• 分子量: 531.632
• InChiKey: KXXDQYLVHILWRA-RRPNLBNLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  38
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  118
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (-)-N(4)-(4,4'-dimethoxytrityl)-2',3'-dideoxy-3'-thiacytidine 在 哌啶 、 1-辛硫醇 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 (-)-5'-O-(3-aminopropanoyl)-N(4)-(4,4'-dimethoxytrityl)-2',3'-dideoxy-3'-thiacytidine
  参考文献：
  名称：

  Synthesis and Biological Evaluation of Fatty Acyl Ester Derivatives of (−)-2′,3′-Dideoxy-3′-thiacytidine

  摘要：

  A number of fatty acyl derivatives of (-)-2',3'-dideoxy-3'-thiacytidine (lamivudine, 3TC, 1) were synthesized and evaluated for their anti-HIV activity. The monosubstituted 5'-O-fatty acyl derivatives of 3TC (EC50 = 0.2-2.3 mu M) were more potent than the corresponding monosubstituted N-4-fatty acyl (EC50 = 0.4-29.4 mu M) and 5'-O-N-4-disubstituted (EC50 = 72.6 to >154.0 mu M) derivatives of the nucleoside. 5'-O-Myristoyl (16) and 5'-O-12-azidododecanoyl derivatives (17) were found to be the most potent compounds (EC50 = 0.2-0.9 mu M) exhibiting at least 16-36-fold higher anti-HIV activity against cell-free virus than 1 (EC50 = 11.4-32.7 mu M). The EC90 values for 16 against B-subtype and C-subtype clinical isolates were several folds lower than those of 1. The cellular uptake studies confirmed that compound 16 accumulated intracellularly after 1 h of incubation with CCRF-CEM cells and underwent intracellular hydrolysis. 5'-O-Fatty acyl derivatives of 1 showed significantly higher anti-HIV activity than the corresponding physical mixtures against the B-subtype virus.

  DOI：

  10.1021/jm300492q
• 作为产物：
  描述：

  拉米夫定 在 吡啶 、 咪唑 、 四丁基氟化铵 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 (-)-N(4)-(4,4'-dimethoxytrityl)-2',3'-dideoxy-3'-thiacytidine
  参考文献：
  名称：

  双核苷逆转录酶抑制剂的对称二羧酸酯的合成及其抗HIV活性

  摘要：

  三种核苷类似物3'-氟-2'，3'-二脱氧胸苷（FLT），3'-叠氮基2'，3'-二脱氧胸苷（AZT）和2'，3'-二脱氧胸苷3'-硫代胞苷（将3TC）与三种不同的二羧酸缀合以提供核苷的长链二羧酸酯。通常，FLT和3TC与长链二元羧酸的二核苷酯共轭物显示出比其母体核苷更高的抗HIV活性。发现FLT的十二烷酸酯和十四烷酸酯二核苷酯衍生物是针对HIV-1 US / 92/727和HIV-1 IIIB细胞的EC 50值分别为0.8-1.0 nM和3-4 nM的最有效化合物。含有长链二羧酸二酯的3TC偶联物的抗HIV活性（EC 50 = 3-60 nM）与3TC（EC 50  = 90-200 nM）相比提高了1.5-66倍。这项研究表明，二羧酸与许多核苷的对称酯缀合可产生具有改进的抗HIV谱的缀合物。

  DOI：

  10.1016/j.bmcl.2012.07.037

文献信息

• Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly-<i>L</i>-Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors
  作者：Bhanu P. Pemmaraju、Swapnil Malekar、Hitesh K. Agarwal、Rakesh K. Tiwari、Donghoon Oh、Gustavo F. Doncel、David R. Worthen、Keykavous Parang

  DOI：10.1080/15257770.2014.945649

  日期：2015.1.2

  (2015). Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly-L-Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors. Nucleosides, Nucleotides & Nucleic Acids: Vol. 34, No. 1, pp. 1-15.

  （2015）。核苷逆转录酶抑制剂的聚-L-精氨酸脂肪酸衍生物的设计，合成，抗病毒活性和预配制开发。核苷，核苷酸和核酸：第1卷。34，第1号，第1-15页。
• Synthesis and anti-HIV activities of unsymmetrical long chain dicarboxylate esters of dinucleoside reverse transcriptase inhibitors
  作者：Hitesh K. Agarwal、Bhupender S. Chhikara、Gustavo F. Doncel、Keykavous Parang

  DOI：10.1016/j.bmcl.2017.03.031

  日期：2017.5

  dicarboxylic acids, succinic acid, suberic acid and 1,14-tetradecandioc acid, were diesterified with either 3'-azido-2',3'-dideoxythymidine (AZT), 3'-fluoro-2',3'-dideoxythymidine (FLT), 2',3'-dideoxy-3'-thiacytidine (3TC), or 5-fluoro-2',3'-dideoxy-3'-thiacytidine (FTC). The anti-HIV activity of synthesized compounds was evaluated against HIV-1 X4 (IIIB) and R5 (BaL) viral strains in single-round infection

  合成了一系列11种不对称的二核苷逆转录酶抑制剂的二羧酸盐共轭物。用3'-叠氮基2'，3'-二脱氧胸苷（AZT），3'-氟-2'，3'-二脱氧胸苷（3'-叠氮基-2'，3'-二脱氧胸苷（ FLT），2'，3'-二脱氧-3'-硫代胞苷（3TC）或5-氟-2'，3'-二脱氧-3'-硫代胞苷（FTC）。在单轮感染试验中评估了合成化合物对HIV-1 X4（IIIB）和R5（BaL）病毒株的抗HIV活性。结果表明，核苷的十四烷酸酯比相应的母体核苷和核苷结合物具有更强的抗HIV活性。
• Synthesis and Anti-HIV Activities of Glutamate and Peptide Conjugates of Nucleoside Reverse Transcriptase Inhibitors
  作者：Hitesh K. Agarwal、Bhupender S. Chhikara、Megrose Quiterio、Gustavo F. Doncel、Keykavous Parang

  DOI：10.1021/jm201551m

  日期：2012.3.22

  Mono-, di-, and trinucleoside conjugates of glutamate or peptide scaffolds containing nucleoside reverse transcriptase inhibitors were synthesized. Among dinucleoside glutamate ester derivatives, N-myristoylated derivatives showed significantly higher anti-HIV activity than the corresponding N-acetylated conjugates against cell-free virus. Myristoyl-Glu(3TC)-FLT (46, EC50 = 0.3-0.6 mu M) and myristoyl-Glu(FTC)-FLT (47, EC50 = 0.1-0.4 mu M) derivatives were the most active glutamate-dinucleoside conjugates. A trinucleoside glutamate derivative containing AZT, FLT, and 3TC (34, EC50 = 0.9-1.4 mu M) exhibited higher anti-HIV activity than AZT and 3TC against cell-free virus. Compound 34 also exhibited higher anti-HIV activity against multidrug (IC50 = 5.9 nM) and NNRTI (IC50 = 12.9 nM) resistant viruses than parent nucleosides. The physical mixture containing FLT-succinate, AZT, 3TC, and glutamic acid exhibited 115-fold less activity against cell associated virus (EC50 = 91.9 mu M) when compared to 34 (EC50 = 0.8 mu M). Other conjugates showed less or comparable potency to that of the corresponding physical mixtures.
• Synthesis and anti-HIV activities of symmetrical dicarboxylate esters of dinucleoside reverse transcriptase inhibitors
  作者：Hitesh K. Agarwal、Karen W. Buckheit、Robert W. Buckheit、Keykavous Parang

  DOI：10.1016/j.bmcl.2012.07.037

  日期：2012.9

  Three nucleoside analogues, 3′-fluoro-2′,3′-dideoxythymidine (FLT), 3′-azido-2′,3′-dideoxythymidine (AZT), and 2′,3′-dideoxy-3′-thiacytidine (3TC) were conjugated with three different dicarboxylic acids to afford the long chain dicarboxylate esters of nucleosides. In general, dinucleoside ester conjugates of FLT and 3TC with long chain dicarboxylic acids exhibited higher anti-HIV activity than their parent

  三种核苷类似物3'-氟-2'，3'-二脱氧胸苷（FLT），3'-叠氮基2'，3'-二脱氧胸苷（AZT）和2'，3'-二脱氧胸苷3'-硫代胞苷（将3TC）与三种不同的二羧酸缀合以提供核苷的长链二羧酸酯。通常，FLT和3TC与长链二元羧酸的二核苷酯共轭物显示出比其母体核苷更高的抗HIV活性。发现FLT的十二烷酸酯和十四烷酸酯二核苷酯衍生物是针对HIV-1 US / 92/727和HIV-1 IIIB细胞的EC 50值分别为0.8-1.0 nM和3-4 nM的最有效化合物。含有长链二羧酸二酯的3TC偶联物的抗HIV活性（EC 50 = 3-60 nM）与3TC（EC 50  = 90-200 nM）相比提高了1.5-66倍。这项研究表明，二羧酸与许多核苷的对称酯缀合可产生具有改进的抗HIV谱的缀合物。
• Synthesis and Biological Evaluation of Fatty Acyl Ester Derivatives of (−)-2′,3′-Dideoxy-3′-thiacytidine
  作者：Hitesh K. Agarwal、Bhupender S. Chhikara、Michael J. Hanley、Guofeng Ye、Gustavo F. Doncel、Keykavous Parang

  DOI：10.1021/jm300492q

  日期：2012.5.24

  A number of fatty acyl derivatives of (-)-2',3'-dideoxy-3'-thiacytidine (lamivudine, 3TC, 1) were synthesized and evaluated for their anti-HIV activity. The monosubstituted 5'-O-fatty acyl derivatives of 3TC (EC50 = 0.2-2.3 mu M) were more potent than the corresponding monosubstituted N-4-fatty acyl (EC50 = 0.4-29.4 mu M) and 5'-O-N-4-disubstituted (EC50 = 72.6 to >154.0 mu M) derivatives of the nucleoside. 5'-O-Myristoyl (16) and 5'-O-12-azidododecanoyl derivatives (17) were found to be the most potent compounds (EC50 = 0.2-0.9 mu M) exhibiting at least 16-36-fold higher anti-HIV activity against cell-free virus than 1 (EC50 = 11.4-32.7 mu M). The EC90 values for 16 against B-subtype and C-subtype clinical isolates were several folds lower than those of 1. The cellular uptake studies confirmed that compound 16 accumulated intracellularly after 1 h of incubation with CCRF-CEM cells and underwent intracellular hydrolysis. 5'-O-Fatty acyl derivatives of 1 showed significantly higher anti-HIV activity than the corresponding physical mixtures against the B-subtype virus.