4-[[(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]amino]-2,2,3,3-tetramethyl-4-oxobutanoic acid | 1036961-03-1

• 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,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]amino]-2,2,3,3-tetramethyl-4-oxobutanoic acid
• CAS: 1036961-03-1
• 化学式: C₃₅H₄₁NO₁₄
• 分子量: 699.709
• InChiKey: SQOUMJCYBVOBKK-NGYGTYHKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  50
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.51
• 拓扑面积：
  246
• 氢给体数：
  7
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  3,3,4,4-四甲基四氢呋喃-2,5-二酮 、 阿霉素 以 二甲基亚砜 为溶剂， 反应 6.0h， 生成 4-[[(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]amino]-2,2,3,3-tetramethyl-4-oxobutanoic acid
  参考文献：
  名称：

  Amidization of doxorubicin alleviates doxorubicin-induced contractile dysfunction and reduced survival in murine cardiomyocytes

  摘要：

  Doxorubicin is an effective anthracycline used for cancer therapy. However, the clinical application of doxorubicin has been largely limited by its irreversible cardiotoxicity, which is mainly induced by the primary amine group. In this study, we structurally modified doxorubicin by converting the primary amine into an acid-labile amide before assessing the acute cardiac effect of doxorubicin (pristine or modified) on cardiomyocyte contractile function. Contractile properties of murine cardiomyocytes were analyzed including peak shortening (PS), time-to-PS JPS), time-to-90% relengthening (TR90) and maximal velocity of shortening/relengthening (+/- dL/dt). Cell toxicity and survival rate were evaluated using the MTT assay. The doxorubicin-free base was amidized by reacting with 3,4,5,6-tetrahydophthalic anhydride (THPA) or 3,3,4,4-tetramethylsuccinic anhydride (TMSA) to yield doxorubicin-THPA or -TMSA. Acute exposure of pristine doxorubicin (10(-9)-10(-5) M) for 30 min significantly prolonged TPS and TR90 without affecting PS and +/- dL/dt. Interestingly, doxorubicin-induced prolongation of TPS and TR90 was significantly attenuated or abrogated by amidization of doxorubicin. Neither doxorubicin-THPA nor -TMSA affected PS and +/- dL/dt. RCS and MTT assay revealed significantly reduced ROS production and cardiac cell toxicity from amidized doxorubicin compared with the pristine compound. Comparable cytotoxicity in human ovarian cancer SKOV-3 cells was observed between amidized and pristine doxorubicin compounds. These data provide evidence for the first time that structural modification of doxorubicin alleviates its cardiac toxicity. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

  DOI：

  10.1016/j.toxlet.2008.03.010

文献信息

• Amidization of doxorubicin alleviates doxorubicin-induced contractile dysfunction and reduced survival in murine cardiomyocytes
  作者：Subat Turdi、Peisheng Xu、Qun Li、Youqing Shen、Parhat Kerram、Jun Ren

  DOI：10.1016/j.toxlet.2008.03.010

  日期：2008.5

  Doxorubicin is an effective anthracycline used for cancer therapy. However, the clinical application of doxorubicin has been largely limited by its irreversible cardiotoxicity, which is mainly induced by the primary amine group. In this study, we structurally modified doxorubicin by converting the primary amine into an acid-labile amide before assessing the acute cardiac effect of doxorubicin (pristine or modified) on cardiomyocyte contractile function. Contractile properties of murine cardiomyocytes were analyzed including peak shortening (PS), time-to-PS JPS), time-to-90% relengthening (TR90) and maximal velocity of shortening/relengthening (+/- dL/dt). Cell toxicity and survival rate were evaluated using the MTT assay. The doxorubicin-free base was amidized by reacting with 3,4,5,6-tetrahydophthalic anhydride (THPA) or 3,3,4,4-tetramethylsuccinic anhydride (TMSA) to yield doxorubicin-THPA or -TMSA. Acute exposure of pristine doxorubicin (10(-9)-10(-5) M) for 30 min significantly prolonged TPS and TR90 without affecting PS and +/- dL/dt. Interestingly, doxorubicin-induced prolongation of TPS and TR90 was significantly attenuated or abrogated by amidization of doxorubicin. Neither doxorubicin-THPA nor -TMSA affected PS and +/- dL/dt. RCS and MTT assay revealed significantly reduced ROS production and cardiac cell toxicity from amidized doxorubicin compared with the pristine compound. Comparable cytotoxicity in human ovarian cancer SKOV-3 cells was observed between amidized and pristine doxorubicin compounds. These data provide evidence for the first time that structural modification of doxorubicin alleviates its cardiac toxicity. (c) 2008 Elsevier Ireland Ltd. All rights reserved.