新型含反式双键哈尔碱衍生物的设计、合成及抗癌活性评价

doi:10.6023/cjoc202512020

有机化学 ›› 2026, Vol. 46 ›› Issue (8): 3189-3201.DOI: 10.6023/cjoc202512020 上一篇下一篇

研究论文

新型含反式双键哈尔碱衍生物的设计、合成及抗癌活性评价

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 发布日期:2026-05-13
通讯作者: 肖吉, 易东
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(TRCWYXFZCH2025B03); 乐山市科技计划(23SZD002); 乐山市科技计划(23SZD028)

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^,^*()

^a Drug Development Engineering Technology Research Center of Leshan, College of Biomedicine, Leshan Vocational and Technical College, Leshan, Sichuan 614000
^b College of Plant Protection, Gansu Agricultural University, Lanzhou, Gansu 730070
^c Green Pharmaceutical Technology Key Laboratory of Luzhou City, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000
^d Department of Basic Medical Sciences, Sichuan Vocational College of Health and Rehabilitation, Zigong, Sichuan 643000

Received:2025-12-16 Revised:2026-03-16 Published:2026-05-13
Contact: Ji Xiao, Dong Yi
Supported by:
Opening Project of Sichuan Province Key Laboratory of Natural Products and Small Molecule Synthesis(TRCWYXFZCH2025B03); Science and Technology Plan of Leshan(23SZD002); Science and Technology Plan of Leshan(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, 反-6-(4-氟苯乙烯基)-7-甲氧基-1,9-二甲基-9H-吡啶并[3,4-b]吲哚(4i)展现出最强的抗增殖活性, 对MDA-MB-231细胞的IC₅₀值为1.67 μnol/L. 进一步机制研究显示, 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, 与表皮生长因子受体酪氨酸激酶(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 (E)-6-(4-fluorostyryl)-7-methoxy-1,9-dimethyl-9H-pyrido[3,4-b]indole (4i) demonstrated the most potent anti-proliferative activity, with an IC₅₀ value of 1.67 μmol/L 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 epidermal growth factor receptor (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、合成及抗癌活性评价[J]. 有机化学, 2026, 46(8): 3189-3201.

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, 2026, 46(8): 3189-3201.

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图/表 9

Figure 1. Representative drugs containing trans-double bonds and the design rationale of this study

Scheme 1. Synthetic route of compounds 3, 4a~4r Reagents and conditions: (i) NaH, CH3I, dry DMF, 0 ℃ to r.t., 2 h; (ii) NIS, AcOH, r.t., overnight; (iii) Pd(OAc)2, tri(o-tolyl)phosphine, NEt3, CH3CN, N2, 70 ℃, 10 h; (iv) Pd(OAc)2, X-phos (564483-18-7), K3PO4, 1,4-dioxane, H2O, N2, 100 ℃, 8 h

Compound	Alkenyl	IC₅₀^b/(μmol•L^－1)
Compound	Alkenyl	A549	HepG2	MDA-MB-231
Harmine	—	26.03±0.34	15.27±0.63	9.93±0.63
3		20.59±0.29	5.91±0.25	5.99±0.03
4a		4.68±0.04	4.15±0.08	2.58±0.11
4b		20.94±0.04	8.96±0.11	3.22±0.17
4c		3.81±0.03	12.44±0.39	7.42±1.19
4d		6.09±0.13	12.87±0.40	2.93±0.20
4e		>50	40.57±1.70	>50
4f		3.79±0.01	4.60±0.01	5.47±0.19
4g		5.68±0.15	6.34±0.04	20.99±0.86
4h		5.29±0.22	22.16±0.14	9.76±0.82
4i		3.98±0.05	4.19±0.04	1.67±0.15
4j		4.82±0.05	4.38±0.09	4.67±0.24
4k		21.73±0.58	16.98±0.66	5.59±0.04
4l		3.89±0.04	17.12±0.23	2.42±0.12
4m		4.75±0.02	15.27±0.69	4.66±0.11
4n		13.82±0.37	22.78±0.65	5.43±0.15
4o		20.29±0.23	20.28±0.16	4.56±0.13
4p		3.95±0.06	4.42±0.05	2.95±0.44
4q		4.41±0.04	19.30±0.34	2.90±0.09
4r		21.81±0.22	22.28±0.28	11.75±0.32
Cisplatin^c	—	18.99±0.77	15.72±0.24	28.82±0.87

Table 1. Antiproliferative activities of target compounds 3 and 4a~4r against three cancer cell linesa

Figure 2. Compound 4i induced G2/M arrest in MDA-MB-231 cancer cells MDA-MB-231 cells were incubated with different concentrations of 4i (0, 2, 5 and 10 μmol/L) for 24 h.

Figure 3. Effect of 4i on induction of apoptosis in MDA-MB-231 cells Each data point represents the average of three independent experiments. (A) MDA-MB-231 cells were incubated with different concentrations of 4i (0, 5, 10 and 20 μmol/L) for 24 h, then stained with Annexin V-FITC/PI, and the apoptosis was detected by flow cytometry. Q1: Necrotic cells, Q2: Late apoptosis, Q3: Early apoptosis, Q4: Live cells. (B) The percentage of cell distribution was shown in the histograms.

Figure 4. Effect of 4i on cell viability in MDA-MB-231 cells MDA-MB-231 cells were incubated with different concentrations of 4i (0, 10 and 20 μmol/L) for 24 h. Each data point represents the average of five independent experiments.

Figure 5. Predicted binding model of compound 4i (A) and Lapatinib (B) with EGFR (PDB code: 3W2S)

Figure 6. Effects of 4i and Lapatinib on key genes related to EGFR downstream signaling pathways Statistical differences were analyzed via Student’s t-test, *: p≤0.05, **: p≤0.01, ns (not significant): P>0.05

Compound	IC₅₀^b/(μmol/L)		Selective index (SI)^c
Compound	MDA-MB-231	BEAS-2B	Selective index (SI)^c
4i	1.67±0.15	5.11±0.27	3.06
Cisplatin^d	28.82±0.87	41.83±0.96	1.45

Table 2. In vitro assessment of the anti-proliferative effects of compound 4i on MDA-MB-231 cells and normal BEAS-2B cells along with its selectivity index a

参考文献 29

[1]	Jemal, A.; Center, M. M.; DeSantis, C.; Ward, E. M. Cancer Epidemiol., Biomarkers Prev. 2010, 19, 1893.
[2]	Thun, M. J.; DeLancey, J. O.; Center, M. M.; Jemal, A.; Ward, E. M. Carcinogenesis 2010, 31, 100.
[3]	Newman, D. J.; Cragg, G. M. J. Nat. Prod. 2020, 83, 770.
[4]	Atanasov, A. G.; Waltenberger, B.; Pferschy-Wenzig, E.-M.; Linder, T.; Wawrosch, C.; Uhrin, P. Biotechnol. Adv. 2015, 33, 1582.
[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.
[8]	Gao, J.; Zhu, H.; Wan, H.; Zou, X.; Ma, X.; Gao, G. Oncol. Rep. 2017, 38, 2927.
[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.
[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.
[15]	Koolaji, N.; Abu-Mellal, A.; Tran, V. H.; Duke, R. K.; Duke, C. C. Eur. J. Med. Chem. 2013, 63, 415.
[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.
[17]	Wang, Y.-F.; Peiffer, B. J.; Su, Q.; Liu, J.-O. ACS Med. Chem. Lett. 2019, 10, 1279.
[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.
[19]	Huang, J.-W.; Wang, Y.-M.; Xu, F.; Wang, Z.-Y.; Wu, G.-Y.; Kong, W.; Cheoklong, N. G.; Tricard, T.; Wu, X.-R.; Zhai, W.; Zhang, W.; Zhang, J.-Y.; Zhang, D.; Chen, S.-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.
[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 (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.)
[24]	Liu, Z.-W.; Hu, D.-Y.; Han, G.-T.; Yang, S.-Y. J. Agric. Food Chem. 2026, 74, 1688.
[25]	Wakelin, L. P. G.; Bu, X. Y.; Eleftheriou, A.; Parmar, A.; Hayek, C.; Stewart, B. W. J. Med. Chem. 2003, 46, 5790.
[26]	Evan, G. I.; Vousden, K. H. Nature 2001, 411, 342.
[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.
[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.

新型含反式双键哈尔碱衍生物的设计、合成及抗癌活性评价

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

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