(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 5-((4R)-2-(2,6-dichlorophenyl)-1,3-dithian-4-yl)pentanoate

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: (R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 5-((4R)-2-(2,6-dichlorophenyl)-1,3-dithian-4-yl)pentanoate
• 英文别名: [(1R)-1-(5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl] 5-[(4R)-2-(2,6-dichlorophenyl)-1,3-dithian-4-yl]pentanoate
• 化学式: C₃₁H₃₂Cl₂O₆S₂
• 分子量: 635.629
• InChiKey: RSYDSPDDZLBGCC-BCMHXXDVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.9
• 重原子数：
  41
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  152
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  R-(+)-硫辛酸 在 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 碳酸氢钠 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 14.25h， 生成 (R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 5-((4R)-2-(2,6-dichlorophenyl)-1,3-dithian-4-yl)pentanoate
  参考文献：
  名称：

  Design and characterization of α -lipoic acyl shikonin ester twin drugs as tubulin and PDK1 dual inhibitors

  摘要：

  Shikonin exhibits powerful anticancer activities for various cancer cells, but its poor solubility and strong toxicity hinder its development as clinical anticancer agent. We previously confirmed that shikonin and its derivatives can disturb mitosis through targeting tubulin. In this study, alpha-lipoic acid, the naturally occurring co-factor of pyruvate dehydrogenase (PDH), was introduced into shikonin to design the twin drugs against both mitosis (tubulin) and glycolysis (PDK). 18 kinds of alpha-lipoic acid shikonin ester derivatives were achieved through three rounds of screening process performed by computer assistant drug design method, being designated as the outstanding compounds. Among them, is displayed the most potent cytotoxicity towards cervical cancer cells (HeLa) with an IC50 value of 3.14 +/- 0.58 mu M and inhibited xenotransplanted tumor growth in a dose-dependent manner. Further pharmacologic study demonstrated that 1c can cause cell cycle arrest in G2/M phase as tubulin polymerization inhibitor. Moreover, it also showed good PDK1 inhibitory activity, promoting PDH activity and forced HeLa cells to process more aerobic metabolism to undergo cell apoptosis. We reported here the first dual inhibitors of tubulin and PDK1 based on shikonin. It may form a basis for shikonin optimization through twin drug design framework for the discovery of new and potent shikonin derivatives in the study of targeted cancer therapy. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.12.019

文献信息

• Design and characterization of α -lipoic acyl shikonin ester twin drugs as tubulin and PDK1 dual inhibitors
  作者：Hong-Yan Lin、Hong-Wei Han、Wen-Xue Sun、Yu-Shun Yang、Cheng-Yi Tang、Gui-Hua Lu、Jin-Liang Qi、Xiao-Ming Wang、Yong-Hua Yang

  DOI：10.1016/j.ejmech.2017.12.019

  日期：2018.1

  Shikonin exhibits powerful anticancer activities for various cancer cells, but its poor solubility and strong toxicity hinder its development as clinical anticancer agent. We previously confirmed that shikonin and its derivatives can disturb mitosis through targeting tubulin. In this study, alpha-lipoic acid, the naturally occurring co-factor of pyruvate dehydrogenase (PDH), was introduced into shikonin to design the twin drugs against both mitosis (tubulin) and glycolysis (PDK). 18 kinds of alpha-lipoic acid shikonin ester derivatives were achieved through three rounds of screening process performed by computer assistant drug design method, being designated as the outstanding compounds. Among them, is displayed the most potent cytotoxicity towards cervical cancer cells (HeLa) with an IC50 value of 3.14 +/- 0.58 mu M and inhibited xenotransplanted tumor growth in a dose-dependent manner. Further pharmacologic study demonstrated that 1c can cause cell cycle arrest in G2/M phase as tubulin polymerization inhibitor. Moreover, it also showed good PDK1 inhibitory activity, promoting PDH activity and forced HeLa cells to process more aerobic metabolism to undergo cell apoptosis. We reported here the first dual inhibitors of tubulin and PDK1 based on shikonin. It may form a basis for shikonin optimization through twin drug design framework for the discovery of new and potent shikonin derivatives in the study of targeted cancer therapy. (C) 2017 Elsevier Masson SAS. All rights reserved.