Synthesis and Anti-Non-Small Cell Lung Cancer Activity of Novel Coumarin Derivatives

doi:10.6023/cjoc202603042

Chinese Journal of Organic Chemistry ›› 2026, Vol. 46 ›› Issue (8): 3079-3088.DOI: 10.6023/cjoc202603042 Previous Articles Next Articles

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新型香豆素衍生物的合成及其抗非小细胞肺癌活性研究

朱凯^a, 邢琳^a, 李璐璐^a, 范君婷^b, 盛瑞隆^c, 郭锐华^a^,^*()

^a 上海海洋大学食品学院海洋药物教研室中国上海 201306
^b 南京医科大学药学院药物分析学系中国南京 211166
^c 马德拉大学木材化学研究中心(CQM) 葡萄牙丰沙尔市佩恩特阿达校区 9000-390

收稿日期:2026-03-30 修回日期:2026-04-25 发布日期:2026-06-03
通讯作者: 郭锐华
基金资助:
国家自然科学基金(82173731); 国家自然科学基金(81502955)

Synthesis and Anti-Non-Small Cell Lung Cancer Activity of Novel Coumarin Derivatives

Kai Zhu^a, Lin Xing^a, Lulu Li^a, Junting Fan^b, Ruilong Sheng^c, Ruihua Guo^a^,^*()

^a Department of Marine Drugs, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
^b Department of Pharmaceutical Analysis, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
^c Centro de Química da Madeira (CQM), Universidade da Madeira, Campus da Penteada, Funchal 9000-390, Portugal

Received:2026-03-30 Revised:2026-04-25 Published:2026-06-03
Contact: Ruihua Guo
Supported by:
National Natural Science Foundation of China(82173731); National Natural Science Foundation of China(81502955)

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Abstract

A series of novel coumarin derivatives 1~15 were synthesized and evaluated for their anticancer activity against A549 cell. Most derivatives showed moderate inhibitory activities. Among them, 4-(chloromethyl)-2-oxo-2H-chromene-7,8- diyl diacetate (2), 3-benzyl-7-((2-chloropyrimidin-4-yl)oxy)-4-methyl-2H-chromen-2-one (13), 3-benzyl-4-methyl-2-oxo-2H- chromene-7,8-diyl diacetate (14) and 3-benzyl-4-methyl-2-oxo-2H-chromene-7,8-diyl dipropionate (15) presented remarkable bioactivities with IC₅₀ values range from (4.7±0.7) to (17.9±2.1) μmol/L. Derivative 13 exhibited remarkable inhibitory activity against A549 (IC₅₀=4.7±0.7 μmol/L) in vitro. Network pharmacology analysis of derivative 13 yielded a total of 166 intersecting targets. The protein-protein interaction (PPI) network identified epidermal growth factor receptor (EGFR) as a key target, and enrichment analysis suggested that derivative 13 may exert its anti-lung cancer effects through multi target regulation of key signaling pathways associated with cell survival and proliferation. Docking analysis showed that derivative 13 exhibited a docking score of －33.18 kJ/mol for EGFR. It was found to exert potential regulatory effects on the EGFR by interacting with Ser-784, Arg-748, and Lys-754 residues. Additionally, derivative 13 significantly affected the cell cycle of A549 cells, inducing G0/G1-phase arrest. Thus, these results suggest that derivative 13 is a promising lead compound for the treatment of non-small cell lung cancer.

Key words: coumarin, derivative, structure activity relationships, lung cancer

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Kai Zhu, Lin Xing, Lulu Li, Junting Fan, Ruilong Sheng, Ruihua Guo. Synthesis and Anti-Non-Small Cell Lung Cancer Activity of Novel Coumarin Derivatives[J]. Chinese Journal of Organic Chemistry, 2026, 46(8): 3079-3088.

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Fig. & Tab. 9

Figure 1. Chemical structure of coumarin derivatives

Scheme 1. Synthesis method of a series coumarin derivatives Reagents and conditions: (a) Sc(OTf)3, β-ketoesters, 85 ℃, 2 h; (b) anhydrides, pyridine/DMAP, r.t., 2~3 h; (c) 2,4-dichloropyrimidine derivatives, NaOH, acetone, reflux, 2~3 h

Compound	IC₅₀/(μmol•L^－1)
Daphnetin	>100
1	>100
2	11.7±0.2
3	38.7±1.1
4	>100
5	29.6±0.9
6	31.7±0.6
7	22.0±0.3
8	61.4±1.5
9	>100
10	59.2±0.6
11	>100
12	>100
13	4.7±0.7
14	11.8±1.3
15	17.9±2.1
DOX	1.3±0.5

Table 1. IC50 values of tested compounds against A549 cells

Figure 2. SARs of coumarin derivatives for inhibitory activity on A549 cells

Figure 3. Venn diagram of overlapping protein targets associated with derivative 13 and lung cancer

Figure 4. PPI network of the connected targets involved in derivative 13 and lung cancer

Figure 5. Analysis of GO and KEGG enrichment (A) BP, CC, and MF categories; (B) KEGG pathways.

Figure 6. Binding models of derivative 13 to EGFR (PDB ID:5HG8)

Figure 7. Effects of derivative 13 on A549 cell cycle progression (A) Control; (B) 2 μmol/L; (C) 5 μmol/L; (D) 10 μmol/L derivative 13 treatments; (E) different cell cycle distribution.

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新型香豆素衍生物的合成及其抗非小细胞肺癌活性研究

Synthesis and Anti-Non-Small Cell Lung Cancer Activity of Novel Coumarin Derivatives

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