[4-[[(2S)-2-[[(2S)-3-phenyl-2-[[(2R)-2-(prop-2-enoxycarbonylamino)propanoyl]amino]propanoyl]amino]-6-(prop-2-enoxycarbonylamino)hexanoyl]amino]phenyl]methyl N-[(2S,3S,4S,6R)-3-hydroxy-2-methyl-6-[[(1S,3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-2,4-dihydro-1H-tetracen-1-yl]oxy]oxan-4-yl]carbamate | 220369-59-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 蒽环类药物
• 英文名称: [4-[[(2S)-2-[[(2S)-3-phenyl-2-[[(2R)-2-(prop-2-enoxycarbonylamino)propanoyl]amino]propanoyl]amino]-6-(prop-2-enoxycarbonylamino)hexanoyl]amino]phenyl]methyl N-[(2S,3S,4S,6R)-3-hydroxy-2-methyl-6-[[(1S,3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-2,4-dihydro-1H-tetracen-1-yl]oxy]oxan-4-yl]carbamate
• CAS: 220369-59-5
• 化学式: C₆₁H₇₀N₆O₂₀
• 分子量: 1207.25
• InChiKey: KXQAPYMBTIMMMR-YWQBGBHNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  87
• 可旋转键数：
  29
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  382
• 氢给体数：
  11
• 氢受体数：
  20

反应信息

• 作为反应物：
  描述：

  [4-[[(2S)-2-[[(2S)-3-phenyl-2-[[(2R)-2-(prop-2-enoxycarbonylamino)propanoyl]amino]propanoyl]amino]-6-(prop-2-enoxycarbonylamino)hexanoyl]amino]phenyl]methyl N-[(2S,3S,4S,6R)-3-hydroxy-2-methyl-6-[[(1S,3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-2,4-dihydro-1H-tetracen-1-yl]oxy]oxan-4-yl]carbamate 在 四(三苯基膦)钯 吗啉 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 N-(N-(D-alanyl-L-phenylalanyl-L-lysyl)-p-aminobenzyloxycarbonyl)doxorubicin
  参考文献：
  名称：

  Synthesis and Biological Evaluation of Novel Prodrugs of Anthracyclines for Selective Activation by the Tumor-Associated Protease Plasmin

  摘要：

  New prodrugs of daunorubicin and doxorubicin designed for selective activation by the serine protease plasmin are described. The low toxic prodrugs 3, 4, and 5 are converted to the corresponding cytotoxic drugs upon proteolysis by the tumor-associated protease plasmin. Application of a self-eliminating spacer was essential for enzyme activation. A prodrug containing a chloro-substituted spacer was synthesized with the aim of enhancing the rate of conversion by plasmin. All prodrugs were highly stable in buffer solution and in serum and on the average 15-fold less cytotoxic than the parent drugs in seven human tumor cell lines. A marked in vitro selectivity was demonstrated by incubation of the doxorubicin prodrugs with a plasmin generating MCF-7 breast cancer cell. line transfected with urokinase-type plasminogen activator (u-PA) in comparison with the nontransfected nonplasmin generating cell line. Prodrugs 4 and 5 showed the same cytotoxic effect as the free parent drug doxorubicin in the u-PA transfected cells, indicating complete conversion of the prodrug by plasmin. Addition of the plasmin inhibitor Trasylol drastically increased the ID50 values in the u-PA transfected MCF-7 cells for both prodrugs 4 and 5.

  DOI：

  10.1021/jm9910472
• 作为产物：
  描述：

  [(1S)-2-[(2,5-二氧代-1-吡咯烷基)氧基]-2-氧代-1-(苯基甲基)乙基]氨基甲酸芴甲基酯 在 N-甲基吗啉 、 吡啶 、 N-甲基吡咯烷酮 、 盐酸 、 sodium hydroxide 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 乙酸乙酯 、 乙腈 为溶剂， 反应 96.0h， 生成 [4-[[(2S)-2-[[(2S)-3-phenyl-2-[[(2R)-2-(prop-2-enoxycarbonylamino)propanoyl]amino]propanoyl]amino]-6-(prop-2-enoxycarbonylamino)hexanoyl]amino]phenyl]methyl N-[(2S,3S,4S,6R)-3-hydroxy-2-methyl-6-[[(1S,3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-2,4-dihydro-1H-tetracen-1-yl]oxy]oxan-4-yl]carbamate
  参考文献：
  名称：

  Synthesis and Biological Evaluation of Novel Prodrugs of Anthracyclines for Selective Activation by the Tumor-Associated Protease Plasmin

  摘要：

  New prodrugs of daunorubicin and doxorubicin designed for selective activation by the serine protease plasmin are described. The low toxic prodrugs 3, 4, and 5 are converted to the corresponding cytotoxic drugs upon proteolysis by the tumor-associated protease plasmin. Application of a self-eliminating spacer was essential for enzyme activation. A prodrug containing a chloro-substituted spacer was synthesized with the aim of enhancing the rate of conversion by plasmin. All prodrugs were highly stable in buffer solution and in serum and on the average 15-fold less cytotoxic than the parent drugs in seven human tumor cell lines. A marked in vitro selectivity was demonstrated by incubation of the doxorubicin prodrugs with a plasmin generating MCF-7 breast cancer cell. line transfected with urokinase-type plasminogen activator (u-PA) in comparison with the nontransfected nonplasmin generating cell line. Prodrugs 4 and 5 showed the same cytotoxic effect as the free parent drug doxorubicin in the u-PA transfected cells, indicating complete conversion of the prodrug by plasmin. Addition of the plasmin inhibitor Trasylol drastically increased the ID50 values in the u-PA transfected MCF-7 cells for both prodrugs 4 and 5.

  DOI：

  10.1021/jm9910472

文献信息

• Synthesis and Biological Characterization of Protease-Activated Prodrugs of Doxazolidine
  作者：Benjamin L. Barthel、Daniel L. Rudnicki、Thomas Price Kirby、Sean M. Colvin、David J. Burkhart、Tad H. Koch

  DOI：10.1021/jm300714p

  日期：2012.7.26

  Doxazolidine (doxaz) is a new anthracycline anticancer agent. While structurally similar to doxorubicin (dox), doxaz acts via a distinct mechanism to selectively enhance anticancer activity over cardiotoxicity, the most significant clinical impediment to successful anthracycline treatment. Here, we describe the synthesis and characterization of a prodrug platform designed for doxaz release mediated by secreted proteolytic activity, a common association with invasiveness and poor prognosis in cancer patients. GaFK-Doxaz is hydrolyzable by the proteases plasmin and cathepsin B, both strongly linked with cancer progression, as well as trypsin. We demonstrate that activation of GaFK-Doxaz releases highly potent doxaz that powerfully inhibits the growth of a wide variety of cancer cells (average IC50 of 8 nM). GaFK-Doxaz is stable in human plasma and is poorly membrane permeable, thereby limiting activation to locally secreted proteolytic activity and reducing the likelihood of severe side effects.
• Synthesis and Biological Evaluation of Novel Prodrugs of Anthracyclines for Selective Activation by the Tumor-Associated Protease Plasmin
  作者：Franciscus M. H. de Groot、Anton C. W. de Bart、Jan H. Verheijen、Hans W. Scheeren

  DOI：10.1021/jm9910472

  日期：1999.12.1

  New prodrugs of daunorubicin and doxorubicin designed for selective activation by the serine protease plasmin are described. The low toxic prodrugs 3, 4, and 5 are converted to the corresponding cytotoxic drugs upon proteolysis by the tumor-associated protease plasmin. Application of a self-eliminating spacer was essential for enzyme activation. A prodrug containing a chloro-substituted spacer was synthesized with the aim of enhancing the rate of conversion by plasmin. All prodrugs were highly stable in buffer solution and in serum and on the average 15-fold less cytotoxic than the parent drugs in seven human tumor cell lines. A marked in vitro selectivity was demonstrated by incubation of the doxorubicin prodrugs with a plasmin generating MCF-7 breast cancer cell. line transfected with urokinase-type plasminogen activator (u-PA) in comparison with the nontransfected nonplasmin generating cell line. Prodrugs 4 and 5 showed the same cytotoxic effect as the free parent drug doxorubicin in the u-PA transfected cells, indicating complete conversion of the prodrug by plasmin. Addition of the plasmin inhibitor Trasylol drastically increased the ID50 values in the u-PA transfected MCF-7 cells for both prodrugs 4 and 5.