新型含反式双键哈尔碱衍生物的设计、合成及抗癌活性研究

doi:10.6023/cjoc202512020

研究论文

新型含反式双键哈尔碱衍生物的设计、合成及抗癌活性研究

胡冬燕^a,b, 卢雨彤^a, 韩广田^a, 余莎^c, 李喜安^a, 任华忠^a, 肖吉^d,*, 易东^c,*

^a乐山职业技术学院生物医药学院乐山市药物开发工程技术研究中心四川乐山 614000;
^b甘肃农业大学植物保护学院甘肃兰州 730070;
^c西南医科大学药学院泸州市绿色制药技术重点实验室四川泸州 646000;
^d四川卫生康复职业学院基础医学院四川自贡 643000

收稿日期:2025-12-16 修回日期:2026-03-16
基金资助:
天然产物化学与小分子催化四川省高校重点实验室开放课题(No.TRCWYXFZCH2025B03 )、乐山市科技计划项目（Nos. 23SZD002、23SZD028）资助项目.

Design, Synthesis, and Anticancer Activity Evaluation of trans-Double Bond-Containing Harmine Derivatives

Dongyan Hu^a,b, Yutong Lu^a, Guangtian Han^a, Sha Yu^c, Xi'an Li^a, Huazhong Ren^a, Ji Xiao^d,*, Dong Yi^c,*

^aDrug Development Engineering Technology Research Center of Leshan, College of Biomedicine, Leshan Vocational and Technical College, Leshan , Sichuan 614000;
^bCollege of Plant Protection, Gansu Agricultural University, Lanzhou, Gansu 730070;
^cGreen Pharmaceutical Technology Key Laboratory of Luzhou City, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000;
^dDepartment of Basic Medical Sciences, Sichuan Vocaticnal College of Health and Rehabilitation, Zigong, Sichuan 643000

Received:2025-12-16 Revised:2026-03-16
Contact: *E-mail:jixiao_1992@163.com; yidong@swmu.edu.cn
Supported by:
Opening Project of Sichuan Province Key Laboratory of Natural Products and Small molecule Synthesis (No. TRCWYXFZCH2025B03), the Science and Technology Plan of Leshan (Nos. 23SZD002、23SZD028).

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摘要/Abstract

为探究反式双键引入对哈尔碱抗癌活性的影响,本研究合成了19种新型6位被反式双键取代的哈尔碱衍生物,并测试了其对A549、HepG2、MDA-MB-231细胞系的抑制活性。结果显示,大部分衍生物的抗癌活性强于母体哈尔碱。其中,化合物4i展现出最强的抗增殖活性,对MDA-MB-231细胞的IC₅₀值为1.67 μM。进一步的机制研究显示,该化合物能以浓度依赖性方式诱导细胞凋亡,同时将MDA-MB-231细胞的细胞周期阻滞于G2/M期。此外,分子对接研究显示,化合物4i通过氢键、疏水作用和π-π相互作用与EGFR活性位点表现出强结合力。针对EGFR激酶下游信号通路关键基因的RT-qPCR分析表明,化合物4i可能确是一个EGFR抑制剂。值得注意的是,化合物4i在正常人肺上皮细胞BEAS-2B与癌细胞MDA-MB-231之间呈现出良好的选择性（SI=3.06）,具备进一步研究的潜力。

关键词: β-咔啉, 哈尔碱, 抗癌活性, 反式双键

To investigate the impact of introducing a trans-double bond on the anticancer activity of harmine, nineteen novel harmine derivatives substituted with a trans-double bond at the 6-position were designed and synthesized. Their inhibitory activities against A549, HepG2, and MDA-MB-231 cell lines were then evaluated. The results indicated that the majority of the derivatives exhibited higher activities than the parent compound harmine. Among these derivatives, compound 4i demonstrated the most potent anti-proliferative activity, with an IC₅₀ value of 1.67 μM against MDA-MB-231 cells. Further mechanistic studies revealed that this compound could induce apoptosis in a concentration-dependent manner and arrest the cell cycle of MDA-MB-231 at the G2/M phase. Furthermore, molecular docking studies indicated that compound 4i exhibited a strong binding affinity to the EGFR active site through hydrogen bonding, hydrophobic interactions, and π-π stacking. RT-qPCR analysis of the key genes in the downstream signaling pathway of EGFR kinase suggested that 4i might indeed serve as an EGFR inhibitor. Notably, compound 4i exhibited favorable selectivity (SI=3.06) between normal lung epithelial cells BEAS-2B and cancer cells MDA-MB-231, highlighting its potential for further investigation.

Key words: β-Carboline, Harmine, antitumor activity, trans-double bond

引用此文

胡冬燕, 卢雨彤, 韩广田, 余莎, 李喜安, 任华忠, 肖吉, 易东. 新型含反式双键哈尔碱衍生物的设计、合成及抗癌活性研究[J]. 有机化学, doi: 10.6023/cjoc202512020.

Dongyan Hu, Yutong Lu, Guangtian Han, Sha Yu, Xi'an Li, Huazhong Ren, Ji Xiao, Dong Yi. Design, Synthesis, and Anticancer Activity Evaluation of trans-Double Bond-Containing Harmine Derivatives[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202512020.

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