((2S,3S)-3-(4-Hydroxy-3-methoxyphenyl)-6-((2R,3R)-3,5,7-trihydroxy-4-oxochroman-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-methyl 4-oxo-4-(6-(1,2,3,4-tetrahydroacridin-9-ylamino)-hexylamino)butanoate Hydrochloride | 1379505-86-8

• 分子结构分类: 有机化合物 - 木脂素、新木脂素和相关化合物 - 黄酮木脂素
• 英文名称: ((2S,3S)-3-(4-Hydroxy-3-methoxyphenyl)-6-((2R,3R)-3,5,7-trihydroxy-4-oxochroman-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-methyl 4-oxo-4-(6-(1,2,3,4-tetrahydroacridin-9-ylamino)-hexylamino)butanoate Hydrochloride
• 英文别名: [(2S,3S)-3-(4-hydroxy-3-methoxyphenyl)-6-[(2R,3R)-3,5,7-trihydroxy-4-oxo-2,3-dihydrochromen-2-yl]-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-oxo-4-[6-(1,2,3,4-tetrahydroacridin-9-ylamino)hexylamino]butanoate
• CAS: 1379505-86-8
• 化学式: C₄₈H₅₁N₃O₁₂
• 分子量: 861.946
• InChiKey: GIZUBEWPWIDDGU-NQPBXATLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  63
• 可旋转键数：
  17
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  215
• 氢给体数：
  6
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  silybin B 在 偶氮二甲酸二异丙酯 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三苯基膦 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 36.5h， 生成 ((2S,3S)-3-(4-Hydroxy-3-methoxyphenyl)-6-((2R,3R)-3,5,7-trihydroxy-4-oxochroman-2-yl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-methyl 4-oxo-4-(6-(1,2,3,4-tetrahydroacridin-9-ylamino)-hexylamino)butanoate Hydrochloride
  参考文献：
  名称：

  Tacrine-Silibinin Codrug Shows Neuro- and Hepatoprotective Effects in Vitro and Pro-Cognitive and Hepatoprotective Effects in Vivo

  摘要：

  A codrug of the anti-Alzheimer drug tacrine and the natural product silibinin was synthesized. The codrug's biological and pharmacological properties were compared to an equimolar mixture of the components. The compound showed potent acetyl- and butyrylcholinesterase inhibition. In a cellular hepatotoxicity model, analyzing the influence on viability and mitochondria of hepatic stellate cells (HSC), the toxicity of the codrug was markedly reduced in comparison to that of tacrine. Using a neuronal cell line (HT-22), a neuroprotective effect against glutamate-induced toxicity could be observed that was absent for the 1:1 mixture of components. In subsequent in vivo experiments in rats, in contrast to the effects seen after tacrine treatment, after administration of the codrug no hepatotoxicity and no induction of the cytochrome P450 system were noticed. In a scopolamine-induced cognitive impairment model using Wistar rats, the codrug was as potent as tacrine in reversing memory dysfunction. The tacrine silibinin codrug shows high AChE and BChE inhibition, neuroprotective effects, lacks tacrine's hepatotoxicity in vitro and in vivo, and shows the same pro-cognitive effects in vivo as tacrine, being superior to the physical mixture of tacrine and silibinin in all these regards.

  DOI：

  10.1021/jm300246n

文献信息

• Tacrine-Silibinin Codrug Shows Neuro- and Hepatoprotective Effects <i>in Vitro</i> and Pro-Cognitive and Hepatoprotective Effects <i>in Vivo</i>
  作者：Xinyu Chen、Katharina Zenger、Amelie Lupp、Beata Kling、Jörg Heilmann、Christian Fleck、Birgit Kraus、Michael Decker

  DOI：10.1021/jm300246n

  日期：2012.6.14

  A codrug of the anti-Alzheimer drug tacrine and the natural product silibinin was synthesized. The codrug's biological and pharmacological properties were compared to an equimolar mixture of the components. The compound showed potent acetyl- and butyrylcholinesterase inhibition. In a cellular hepatotoxicity model, analyzing the influence on viability and mitochondria of hepatic stellate cells (HSC), the toxicity of the codrug was markedly reduced in comparison to that of tacrine. Using a neuronal cell line (HT-22), a neuroprotective effect against glutamate-induced toxicity could be observed that was absent for the 1:1 mixture of components. In subsequent in vivo experiments in rats, in contrast to the effects seen after tacrine treatment, after administration of the codrug no hepatotoxicity and no induction of the cytochrome P450 system were noticed. In a scopolamine-induced cognitive impairment model using Wistar rats, the codrug was as potent as tacrine in reversing memory dysfunction. The tacrine silibinin codrug shows high AChE and BChE inhibition, neuroprotective effects, lacks tacrine's hepatotoxicity in vitro and in vivo, and shows the same pro-cognitive effects in vivo as tacrine, being superior to the physical mixture of tacrine and silibinin in all these regards.