7-[3-[4-(4-hydroxybutyl)-[1,2,3]triazol-1-yl]-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl]daunorubicinone

• 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: 7-[3-[4-(4-hydroxybutyl)-[1,2,3]triazol-1-yl]-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl]daunorubicinone
• 英文别名: (7S,9S)-9-acetyl-6,9,11-trihydroxy-7-[(2R,4S,5S,6S)-5-hydroxy-4-[4-(4-hydroxybutyl)triazol-1-yl]-6-methyloxan-2-yl]oxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
• 化学式: C₃₃H₃₇N₃O₁₁
• 分子量: 651.67
• InChiKey: FFRFOMGYGVQECY-PLCAQZSNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  47
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  211
• 氢给体数：
  5
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  柔红霉素 盐酸盐 在 triethylphosphite copper(I) iodide complex 、 triflic azide 、 potassium carbonate 、 copper(II) sulfate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 48.0h， 生成 7-[3-[4-(4-hydroxybutyl)-[1,2,3]triazol-1-yl]-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl]daunorubicinone
  参考文献：
  名称：

  Discovery of a Daunorubicin Analogue That Exhibits Potent Antitumor Activity and Overcomes P-gp-Mediated Drug Resistance

  摘要：

  Anthracyclines are considered to be some of the most effective anticancer drugs for cancer therapy. However, drug resistance and cardiotoxicity of anthracyclines limit their clinical application. We hypothesize that direct modifications of the sugar moiety of anthracyclines avert P-glycoprotein (P-gp) recognition and efflux, increase drug intracellular concentration in cancer cells, and thus overcome P-gp-mediated drug resistance. Daunorubicin (DNR) analogues with sugar modifications were synthesized by directly transforming the amino group of DNR to an azido group or triazole group. Molecular docking showed that the lead compound (3'-azidodaunorubicin, ADNR) averts P-gp binding, while daunorubicin (DNR) extensively interacts with multidrug-resistance (MDR) protein through H-bonds and electrostatic interactions. FACS assay demonstrated that these new compounds abolished P-gp drug efflux and accumulated high intracellular concentration in the drug-resistant leukemia K562/Dox. P-gp inhibition by CsA confirmed that these new analogues are no longer P-gp substrates. ADNR exhibited potent anticancer activity in both drug-sensitive (K562) and drug-resistant leukemia cells (K562/Dox), with a 25-fold lower drug resistance index than DNR. An in vivo xenograft model demonstrated that ADNR showed more than 2.5-fold higher maximum growth inhibition rate against drug-resistant cancers and significant improvement for animal survival rate versus DNR. No significant body weight reduction in mice was observed for ADNR at the maximum tolerable dose, as compared to more than 70% body weight reduction for DNR. These data suggest that sugar modifications of anthracyclines avert P-gp binding, abolish P-gp-mediated drug efflux, increase intracellular drug concentration, and thus overcome P-gp-mediated drug resistance in cancer therapy.

  DOI：

  10.1021/jm050800q

文献信息

• Discovery of a Daunorubicin Analogue That Exhibits Potent Antitumor Activity and Overcomes P-gp-Mediated Drug Resistance
  作者：Lanyan Fang、Guisheng Zhang、Chenglong Li、Xincheng Zheng、Lizhi Zhu、Jim J. Xiao、Gergely Szakacs、Janos Nadas、Kenneth K. Chan、Peng George Wang、Duxin Sun

  DOI：10.1021/jm050800q

  日期：2006.2.1

  Anthracyclines are considered to be some of the most effective anticancer drugs for cancer therapy. However, drug resistance and cardiotoxicity of anthracyclines limit their clinical application. We hypothesize that direct modifications of the sugar moiety of anthracyclines avert P-glycoprotein (P-gp) recognition and efflux, increase drug intracellular concentration in cancer cells, and thus overcome P-gp-mediated drug resistance. Daunorubicin (DNR) analogues with sugar modifications were synthesized by directly transforming the amino group of DNR to an azido group or triazole group. Molecular docking showed that the lead compound (3'-azidodaunorubicin, ADNR) averts P-gp binding, while daunorubicin (DNR) extensively interacts with multidrug-resistance (MDR) protein through H-bonds and electrostatic interactions. FACS assay demonstrated that these new compounds abolished P-gp drug efflux and accumulated high intracellular concentration in the drug-resistant leukemia K562/Dox. P-gp inhibition by CsA confirmed that these new analogues are no longer P-gp substrates. ADNR exhibited potent anticancer activity in both drug-sensitive (K562) and drug-resistant leukemia cells (K562/Dox), with a 25-fold lower drug resistance index than DNR. An in vivo xenograft model demonstrated that ADNR showed more than 2.5-fold higher maximum growth inhibition rate against drug-resistant cancers and significant improvement for animal survival rate versus DNR. No significant body weight reduction in mice was observed for ADNR at the maximum tolerable dose, as compared to more than 70% body weight reduction for DNR. These data suggest that sugar modifications of anthracyclines avert P-gp binding, abolish P-gp-mediated drug efflux, increase intracellular drug concentration, and thus overcome P-gp-mediated drug resistance in cancer therapy.