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

doi:10.6023/cjoc202512020

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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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Abstract

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

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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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[1] Jemal A.; Center M. M.; DeSantis C.; Ward E. M. Cancer Epidemiol., Biomarkers Prev. 2010, 19, 1893–907.
[2] Thun M. J.; DeLancey J. O.; Center M. M.; Jemal A.; Ward E. M. Carcinogenesis.2010, 31, 100-110.
[3] Newman D. J.; Cragg, G. M. J. Nat. Prod.2020, 83, 770-803.
[4] Atanasov A. G.; Waltenberger B.; Pferschy-Wenzig E.-M.; Linder T.; Wawrosch C.; Uhrin P. Biotechnol. Adv.2015, 33, 1582-614.
[5] Tshikhudo P. P.; Mabhaudhi T.; Koorbanally N. A.; Mudau F. N.; Avendaño Caceres E. O.; Popa D.; Calina D.; Sharifi-Rad J. Chem. Biodiversity.2024, 21, e202301263.
[6] Luo B.; Song, X. Q. Eur. J. Med. Chem.2021, 224, 113688.
[7] Sharma S.; Yadav M.; Gupta S. P.; Pandav K.; Kumar S. Chem.-Biol. Interact.2016, 260, 256-262.
[8] Gao J.; Zhu H.; Wan H.; Zou X.; Ma X.; Gao G. Oncol. Rep.2017, 38, 2927-2934.
[9] Nafie E.; Lolarga J.; Lam B. PLoS One.2021, 16, e0247652.
[10] Ding Y.; He J.; Huang J.; Yu T.; Shi X.; Zhang T.; Yan G.; Chen S.; Peng, C. Int. J. Oncol. 2019, 54, 1995-2004.
[11] Zhu Y.-G.; Lv Y.-X.; Guo C.-Y.; Xiao Z.-M.; Jiang Q.-G.; Kuang H. Life Sci.2021, 270, 119112.
[12] Baldini E.; Cardarelli S.; Campese A. F.; Lori E.; Fallahi P.; Virili C.; Forte F.; Pironi D.; Di Matteo F. M.; Palumbo P.; Costanzo M. L.; DAndrea V.; Centanni M.; Sorrenti S.; Antonelli A.; Ulisse, S. Int. J. Mol. Sci.2024, 25, 1121.
[13] Kwasniewski S. P.; Claes L.; François J.-P.; Deleuze, M. S. J. Chem. Phys.2003, 118, 7823.
[14] Rummela L.; Hankea K.; Beckerb J.; Schreiner P. R. Synlett.2023, 34, 1129-1134.
[15] Koolaji N.; Abu-Mellal A.; Tran V. H.; Duke R. K.; Duke, C. C. Eur. J. Med. Chem.2013, 63, 415-422.
[16] Gao Y.- Z.; van Haren M. J.; Buijs N.; Innocenti P.; Zhang Y.-R.; Sartini D.; Campagna R.; Emanuelli M.; Parsons R. B.; Jespers W.; Gutiérrez-de-Terán H.; van Westen, G. J. P.; Martin, N. I. J. Med. Chem.2021, 64, 12938-12963.
[17] Wang Y.-F.; Peiffer B. J.; Su, Q. ; Liu, J.-O. ACS Med. Chem. Lett.2019, 10, 1279-1283.
[18] Mao J.-l.; Yuan H.; Wang Y.-H.; Wan B.-J.; Pieroni M.; Huang Q.-Q.; van Breemen R. B.; Kozikowski A. P.; Franzblau S. G.J. Med. Chem. 2009, 52, 6966-6978.
[19] Huang J.-W Wang Y.-M.; Xu F, Wang Z.-Y.; Wu G.-Y.; Kong W.; Cheoklong, NG; Tricard, T,; Wu,X.-R.; Zhai,W.; Zhang,W,; Zhang J.-Y.; Zhang,D.; Chen Sh.-Y.; Lian,Y.-Q.; Chen,Y.-H.; Zhang,J,; Huang Y.-R.; Xue W. J. Immunother. Cancer.2024, 12, e008475.
[20] Lu R.-T.; Wu G.-X.; Chen M.-L.; Ji D.-M.; Liu Y.-H.; Zhou , G. G. Y.; Fu, W.-M. Mol. Ther.: Oncol.2021, 23, 477-487
[21] Hu, D.-Y.; Han, G.-T.; Yu, S.; Ren, H.-Z.; Li, X.-A.; Xu, J.; Feng, J.-F.; Yi. D. Chem. Biodiversity. 2025, 22, e00130.
[22] Hu D.-Y.; Han G.-T.; Ren H. Z.; Li X. W.; Li X. A.; Yue L.-R.; Xu J.; Feng J. F.; Guo L. Fitoterapia.2022, 163, 105329.
[23 ]Hu D.-Y.; Han G.-T.; Li X.-A.; Ren H.-Z.; Yue L.-R.; Guo L.; Feng, J.-F. Chin. J. Org. Chem.2022, 42, 1863-1871. (in Chinese)
(胡冬燕, 韩广田, 李喜安, 任华忠, 岳李荣, 郭力, 封家福. 有机化学, 2022, 42, 1863-1871.)
[24] Liu Z.-W.; Hu D.-Y.; Han. G.-T.; Yang. S.-Y. J. Agric. Food Chem.2026, 74, 1688-1697.
[25] Wakelin L. P. G.; Bu X. Y.; Eleftheriou A.; Parmar A.; Hayek C.; Stewart, B. W. J. Med. Chem.2003, 46, 5790-5802.
[26] Evan G.I.; Vousden K.H.Nature. 2001, 411, 342-348.
[27] Bello E. D.; Sian,V.; Bontempi G.; Zwergel C.; Fioravanti R.; Noce B.; Castiello C.; Tomassi S.; Corinti D.; Passeri,D.; Pellicciari,R.; Mercurio,C.; Varasi,M.; Altucci L.; Tripodi,M.; Strippoli,R.; Nebbioso,A.; Valente S.; Mai, A. Eur J. Med. Chem.2023, 247, 115022.
[28] Kamal A.; Faazil S.; Malik, M. S. Expert Opin. Ther. Pat.2014, 24 , 339-354.
[29] Dhawan S.; Kerru N.; Awolade P.; Singh-Pillay A.; Saha S. T.; Kaur M.; Jonnalagadda S. B.; Singh, P. Bioorg. Med. Chem.2018, 26, 5612-5623.

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

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

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