methyl O-[(5S)-5-[(4-amino-2-oxopyrimidin-1(2H)-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-(tert-butoxycarbonyl)-(L)-tyrosinate

• 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 O-[(5S)-5-[(4-amino-2-oxopyrimidin-1(2H)-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-(tert-butoxycarbonyl)-(L)-tyrosinate
• 英文别名: Boc-(L)-Tyr(cHPMPC)-OMe；methyl (2R)-3-(4-{[(2S,5S)-5-[(4-amino-2-oxo-2H-pyrimidin-1-yl)methyl]-2-oxo-1,4,2λ5-dioxaphosphinan-2-yl]oxy}phenyl)-2-{[(tert-butoxy)carbonyl]amino}propanoate；methyl (2S)-3-[4-[[(2S,5S)-5-[(4-amino-2-oxopyrimidin-1-yl)methyl]-2-oxo-1,4,2lambda5-dioxaphosphinan-2-yl]oxy]phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate；methyl (2S)-3-[4-[[(2S,5S)-5-[(4-amino-2-oxopyrimidin-1-yl)methyl]-2-oxo-1,4,2λ5-dioxaphosphinan-2-yl]oxy]phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate
• 化学式: C₂₃H₃₁N₄O₉P
• 分子量: 538.494
• InChiKey: PPVJMSKUZMXAAX-JLUNXAEMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  37
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  168
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  Boc-L-酪氨酸甲酯 、 西多福韦 在 N,N-二异丙基乙胺 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 methyl O-[(5S)-5-[(4-amino-2-oxopyrimidin-1(2H)-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-(tert-butoxycarbonyl)-(L)-tyrosinate 、 methyl O-[(5S)-5-[(4-amino-2-oxopyrimidin-1(2H)-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-(tert-butoxycarbonyl)-(L)-tyrosinate
  参考文献：
  名称：

  Tyrosine-Based 1-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) Prodrugs: Synthesis, Stability, Antiviral Activity, and in Vivo Transport Studies

  摘要：

  Eight novel single amino acid (6-11) and dipeptide (12, 13) tyrosine P-O esters of cyclic cidofovir ((S)-cHPMPC, 4) and its cyclic adenine analogue ((S)-cHPMPA, 3) were synthesized and evaluated as prodrugs. In vitro IC50 values for the prodrugs (<0.1-50 mu M) vs vaccinia, cowpox, human cytomegalovirus, and herpes simplex type 1 virus were compared to those for the parent drugs ((S)-HPMPC, 2; (S)HPMPA, 1; IC50 0.3-35 mu M); there was no cytoxicity with KB or HFF cells at <= 100 mu M. The prodrugs exhibited a wide range of half-lives in rat intestinal homogenate at pH 6.5 (<30-1732 min) with differences of 3-10x between phostonate diastereomers. The tyrosine allcylamide derivatives of 3 and 4 were the most stable. (L)-Tyr-NH-i-Bu cHPMPA (11) was converted in rat or mouse plasma solely to two active metabolites and had significantly enhanced oral bioavailability vs parent drug 1 in a mouse model (39% vs <5%).

  DOI：

  10.1021/jm2001426

文献信息

• Tyrosine-Based 1-(<i>S</i>)-[3-Hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((<i>S</i>)-HPMPC and (<i>S</i>)-HPMPA) Prodrugs: Synthesis, Stability, Antiviral Activity, and in Vivo Transport Studies
  作者：Valeria M. Zakharova、Michaela Serpi、Ivan S. Krylov、Larryn W. Peterson、Julie M. Breitenbach、Katherine Z. Borysko、John C. Drach、Mindy Collins、John M. Hilfinger、Boris A. Kashemirov、Charles E. McKenna

  DOI：10.1021/jm2001426

  日期：2011.8.25

  Eight novel single amino acid (6-11) and dipeptide (12, 13) tyrosine P-O esters of cyclic cidofovir ((S)-cHPMPC, 4) and its cyclic adenine analogue ((S)-cHPMPA, 3) were synthesized and evaluated as prodrugs. In vitro IC50 values for the prodrugs (<0.1-50 mu M) vs vaccinia, cowpox, human cytomegalovirus, and herpes simplex type 1 virus were compared to those for the parent drugs ((S)-HPMPC, 2; (S)HPMPA, 1; IC50 0.3-35 mu M); there was no cytoxicity with KB or HFF cells at <= 100 mu M. The prodrugs exhibited a wide range of half-lives in rat intestinal homogenate at pH 6.5 (<30-1732 min) with differences of 3-10x between phostonate diastereomers. The tyrosine allcylamide derivatives of 3 and 4 were the most stable. (L)-Tyr-NH-i-Bu cHPMPA (11) was converted in rat or mouse plasma solely to two active metabolites and had significantly enhanced oral bioavailability vs parent drug 1 in a mouse model (39% vs <5%).