一类新型小檗碱衍生物的合成与生理活性

蒋小飞; 刘九辉; 李虎; 张伟; 骆衡

doi:10.13422/j.cnki.syfjx.20192115

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一类新型小檗碱衍生物的合成与生理活性

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- 一类新型小檗碱衍生物的合成与生理活性
- Synthesis and Physiological Activity of Novel Berberine Derivatives
- 中国实验方剂学杂志 2019年25卷第23期页码：156-164
- 作者机构：
  
  1.贵州师范学院　化学与材料学院，贵阳　 551088；
  2.贵州师范学院　地理与旅游环境学院，贵阳　 551088；
  3.贵州省中国科学院天然产物化学重点实验室，贵阳　 550014
- 作者简介：
  
  蒋小飞，博士，副教授，从事天然产物提取分离结构修饰与生理活性研究，Tel：0851-85816647，E-mail：jxf1104@163.com
  骆衡，博士，副研究员，从事抗肿瘤重要小分子药理研究，Tel：0851-39671868，E-mail：359223910@qq.com
- 基金信息：
  
  贵州省自然科学基金项目([2015]2123;[2015]2127);贵州省教育厅科技拔尖人才支持项目(黔教合KY字[2016084])
- DOI：10.13422/j.cnki.syfjx.20192115
  中图分类号： R914.5; R284.2; R289; R22
- 收稿日期：2019-06-19，
  
  网络出版日期：2019-07-18，
  
  纸质出版日期：2019-12-05
- 稿件说明：
移动端阅览
蒋小飞, 刘九辉, 李虎, 等. 一类新型小檗碱衍生物的合成与生理活性[J]. 中国实验方剂学杂志, 2019,25(23):156-164.

Xiao-fei JIANG, Jiu-hui LIU, Hu LI, et al. Synthesis and Physiological Activity of Novel Berberine Derivatives[J]. Chinese journal of experimental traditional medical formulae, 2019, 25(23): 156-164.
蒋小飞, 刘九辉, 李虎, 等. 一类新型小檗碱衍生物的合成与生理活性[J]. 中国实验方剂学杂志, 2019,25(23):156-164. DOI： 10.13422/j.cnki.syfjx.20192115.

Xiao-fei JIANG, Jiu-hui LIU, Hu LI, et al. Synthesis and Physiological Activity of Novel Berberine Derivatives[J]. Chinese journal of experimental traditional medical formulae, 2019, 25(23): 156-164. DOI： 10.13422/j.cnki.syfjx.20192115.

摘要

目的：

以具有多种生理活性的小檗碱为原料合成新型衍生物，并研究其细胞增殖抑制作用，抑制乙酰胆碱酯酶和丁酰胆碱酯酶的活性。

方法：

运用药效团整合策略将具有多种生理活性的小檗碱与抑制组蛋白去乙酰化酶的药效团异羟肟酸、邻苯二胺、巯基进行拼合，通过有机合成手段得到了7个文献未见报道的小檗碱新型衍生物，通过核磁共振氢谱(

H-NMR)，碳谱(

C-NMR)和质谱(MS)进行结构表征，并采用噻唑蓝(MTT)比色法检测了7种小檗碱衍生物对人结肠癌细胞(HCT116)，人肝癌细胞(HepG2)，人宫颈癌细胞(HeLa)，人急性淋巴白血病细胞(CCRF-CEM)的增殖活性，采用

Ellman

法对乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BuChE)抑制活性进行了测试。

结果：

含甲基酮的小檗碱衍生物同时具有较好细胞增殖抑制作用，抑制乙酰胆碱酯酶的活性，化合物5b对CCRF-CEM细胞株的版抑制浓度(IC

)达到了1.48 μmol·L

－1

，对乙酰胆碱酯酶的抑制活性IC

为(0.38±0.004)μmol·L

－1

，明显高于先导化合物小檗碱。

结论：

目标化合物的合成路线为此类生物碱衍生物的合成与活性研究提供了参考，其中化合物5b细胞增殖抑制作用和乙酰胆碱酯酶抑制活性较强，后续值得进一步研究。

Abstract

Objective:

TO synthesize novel berberine derivatives with a variety of physiological activities

and study their antitumor activity and acetylcholinesterase inhibitory activity.

Method:

Berberines with a variety of physiological activities were pieced together isohydroxamic acid

-phenylenediamine

and sulfhydryl pharmacophore with effects in inhibiting histones and removing acetylases. Totally 7 novel berberine derivatives were obtained by means of organic synthesis. The structures of these derivatives were characterized and confirmed by

H-NMR

C-NMR and MS spectral data.Thiazolyl blue tetrazolium bromide(MTT) method was used in the determination of the cytotoxic activity of HCT116

HepG2

HeLa and CCRF-CEM human cancer cell lines

in vitro

Ellman

method was used to reveal the inhibitory activities of acetylcholinesterase and butyrylcholinesterase.

Result:

The results showed that the berberine derivatives containing methyl ketone had good antitumor and acetylcholinesterase inhibitory activities. The results demonstrated that compound 5bhad the highest anti-proliferative activity against CCRF-CEM cell line and the acetylcholinesterase inhibitory activities

with IC

=1.48 μmol·L

-1

and IC

=0.38 μmol·L

-1

respectivly.

Conclusion:

This paper provides a reference for the synthesis and biological evaluation of this kind of alkaloid derivatives. Compound 5bis a promising candidate drug and worth further study.

关键词

Keywords

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