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

doi:10.6023/cjoc202512020

Chinese Journal of Organic Chemistry ›› 2026, Vol. 46 ›› Issue (8): 3189-3201.DOI: 10.6023/cjoc202512020 Previous Articles Next Articles

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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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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 (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

Cite this article

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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Fig. & Tab. 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

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新型含反式双键哈尔碱衍生物的设计、合成及抗癌活性评价

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

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