药学学报, 2018, 53(10): 1689-1695
引用本文:
李启麟, 邓安珺, 闫征, 李志宏, 王楠, 秦海林. 烷基-去-血根碱-N5-甲基衍生物的合成及肿瘤细胞株生长抑制活性评价[J]. 药学学报, 2018, 53(10): 1689-1695.
LI Qi-lin, DENG An-jun, YAN Zheng, LI Zhi-hong, WANG Nan, QIN Hai-lin. Syntheses of alkyl-de-sanguinarine-N5-methyl derivatives and evaluation of in vitro growth inhibitory activities against cancer cell lines[J]. Acta Pharmaceutica Sinica, 2018, 53(10): 1689-1695.

烷基-去-血根碱-N5-甲基衍生物的合成及肿瘤细胞株生长抑制活性评价
李启麟, 邓安珺, 闫征, 李志宏, 王楠, 秦海林
中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050
摘要:
采用汇聚合成方式,分别以6-溴-2,3-二羟基苯甲醛、5-硝基-2,3-萘二酚和二溴甲烷为起始原料,经二氧-去-二溴亲核取代反应、还原反应、席夫碱生成反应以及三丁基锡烷和AIBN诱导的自由基关环反应等反应合成2:3,7:8-双亚甲二氧基苯并[c]菲啶;以2:3,7:8-双亚甲二氧基苯并[c]菲啶为中间体,以NaBH4和不同的脂肪酸为烷基化试剂,合成5,6-二氢-2:3,7:8-双亚甲二氧基-N5-烷基苯并[c]菲啶;以DDQ为氧化剂,在碱性条件下将2:3,7:8-双亚甲二氧基-5,6-二氢-N5-烷基苯并[c]菲啶氧化芳构化,并经盐酸盐化反应,得到具有系列性特征的目标化合物2,3:7,8-双亚甲二氧基-N5-烷基苯并[c]菲啶-5-阳离子季铵盐。与阳性对照药物以及天然血根碱对比,本文合成的系列烷基-去-血根碱-N5-甲基型血根碱类似物在体外显示出明显获得改善的肿瘤细胞株生长抑制活性;在对5种肿瘤细胞株进行的药理实验中,与血根碱比较,目标化合物的活性提高5倍;表明了对血根碱-N5-甲基进行长链烷基的替换修饰,可以通过增加脂溶性和空间位阻、提高5,6-位亚胺结构的稳定性而改善其肿瘤细胞株生长抑制活性。
关键词:    血根碱      烷基-去-血根碱-N5-甲基衍生物      汇聚合成      N-烷基化反应      肿瘤细胞株生长抑制活性     
Syntheses of alkyl-de-sanguinarine-N5-methyl derivatives and evaluation of in vitro growth inhibitory activities against cancer cell lines
LI Qi-lin, DENG An-jun, YAN Zheng, LI Zhi-hong, WANG Nan, QIN Hai-lin
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
2,3:7,8-Bis(methylenedioxy)benzo[c]phenanthridine was synthesized in a strategy of converging synthesis with 6-bromo-2,3-dihydroxybenzaldehyde, 5-nitronaphthalene-2,3-diol, and dibromomethane, respectively, as starting materials. The reaction process included dioxy-de-dibromo nucleophilic substitution under alkaline condition, reduction reaction, Schiff base-forming reaction, and an arene radical cyclization step under the presence of Bu3SnH and AIBN as radical initiator, among others. The 2,3:7,8-bis(methylenedioxy)benzo[c] phenanthridine as intermediate was reacted with NaBH4 and different aliphatic acids as alkylation agent to afford 2,3:7,8-bis(methylenedioxy)-5,6-dihydro-N5-alkylbenzo[c]phenanthridines. These dihydro-type products were aromatized using DDQ as oxidant under alkaline condition, and then, salinized using HCl as source of equilibrium anion to yield the series of target alkyl-de-sanguinarine-N5-methyl derivatives. All the synthesized alkyl-de-sanguinarine-N5-methyl derivatives exhibited significantly improved in vitro growth inhibitory activities against cancer cell lines as compared with sanguinarine and the positive control. In pharmacological experiments targeting five cancer cell lines, the target compounds showed activities five-fold active than that of sanguinarine. The findings of this study indicated that the structure modification strategy of substituting n-alkyls for the N5-methyl of natural sanguinarine can be used to improve the growth inhibitory activities against cancer cell lines through increasing liposolubility and steric hindrance to protect the active 5,6-imine structure.
Key words:    sanguinarine    alkyl-de-sanguinarine-N5-methyl derivative    converging synthesis    N-alkylation reaction    growth inhibitory activities against tumor cell lines   
收稿日期: 2018-07-16
DOI: 10.16438/j.0513-4870.2018-0645
基金项目: 中国医学科学院医学与健康科技创新工程资助项目(2016-I2M-1-010).
通讯作者: 秦海林,Tel:86-10-83172503,E-mail:qinhailin@imm.ac.cn
Email: qinhailin@imm.ac.cn
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