新型香豆素衍生物的合成及其抗非小细胞肺癌活性研究

doi:10.6023/cjoc202603042

有机化学 ›› 2026, Vol. 46 ›› Issue (8): 3079-3088.DOI: 10.6023/cjoc202603042 上一篇下一篇

研究论文

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)

文章分享

1. cjoc202603042辅助材料.pdf(2337KB)

摘要/Abstract

合成了一系列新型香豆素衍生物1~15, 并评价了它们对A549细胞的抗癌活性. 多数衍生物表现出中等程度的抑制活性. 其中, 4-(氯甲基)-2-氧代-2H-色烯-7,8-二酰基二乙酸酯(2)、3-苄基-7-((2-氯吡啶-4-基)氧)-4-甲基-2H-色烯-2-酮(13)、3-苄基-4-甲基-2-氧代-2H-色烯-7,8-二基二乙酸酯(14)、3-苄基-4-甲基-2-氧代-2H-色烯-7,8-二基二丙酸酯(15)具有显著的生物活性, IC₅₀值范围为(4.7±0.7)~(17.9±2.1) μmol/L. 衍生物13在体外对A549细胞具有显著的抑制活性, IC₅₀值为(4.7±0.7) μmol/L. 对衍生物13进行网络药理学研究, 共得到166个交集靶点. 蛋白互作网络图(PPI)网络分析表明, 表皮生长因子(EGFR)是关键靶点; 富集性分析提示, 衍生物13可能通过多靶点调控与细胞存活及增殖相关的关键信号通路, 从而发挥抗肺癌的作用. 使用分子对接进行验证发现, 衍生物13对EGFR的对接得分为－33.18 kJ/mol. 分子对接结果显示, 衍生物13能够与EGFR蛋白的Ser-784、Arg-748和Lys-754残基形成相互作用, 这可能是其发挥调控作用的潜在机制. 同时, 衍生物13显著影响了A549细胞周期, 使之阻滞于G0/G1期. 研究结果表明, 衍生物13有望成为抗非小细胞肺癌的先导化合物.

关键词: 香豆素, 衍生物, 结构活性关系, 肺癌

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

引用此文

朱凯, 邢琳, 李璐璐, 范君婷, 盛瑞隆, 郭锐华. 新型香豆素衍生物的合成及其抗非小细胞肺癌活性研究[J]. 有机化学, 2026, 46(8): 3079-3088.

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.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 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.

参考文献 25

[1]	Siegel, R. L.; Miller, K. D.; Jemal, A. Ca-Cancer J. Clin. 2018, 68, 7.
[2]	Zhang, Y.; Cheng, K.; Xu, B.; Shi, J.; Qiang, J.; Shi, S.; Yi, Y.; Li, H.; Jin, T.; Guo, R.; Wu, Y.; Liu, Z.; Wei, X.; Huang, J. A.; Yang, X. H. Front. Cell Dev. Biol. 2020, 8, 652.
[3]	Testa, U.; Castelli, G.; Pelosi, E. Cancers (Basel) 2018, 10, 248.
[4]	An, B.; Pan, T.; Hu, J.; Pang, Y.; Huang, L.; Chan, A. S. C.; Li, X.; Yan, J. Eur. J. Med. Chem. 2019, 183, 111709.
[5]	Dandriyal, J.; Singla, R.; Kumar, M.; Jaitak, V. Eur. J. Med. Chem. 2016, 119, 141.
[6]	Ding, J.; Liu, J.; Zhang, Z.; Guo, J.; Cheng, M.; Wan, Y.; Wang, R.; Fang, Y.; Guan, Z.; Jin, Y.; Xie, S. S. Bioorg. Chem. 2020, 101, 104023.
[7]	Rosselli, S.; Maggio, A. M.; Faraone, N.; Spadaro, V.; Morris- Natschke, S. L.; Bastow, K. F.; Lee, K.-H.; Bruno, M. Nat. Prod. Commun. 2009, 4, 1701.
[8]	Bansal, Y.; Sethi, P.; Bansal, G. Med. Chem. Res. 2013, 22, 3049.
[9]	Amin, K. M.; Awadalla, F. M.; Eissa, A. A. M.; Abou-Seri, S. M.; Hassan, G. S. Bioorg. Med. Chem. 2011, 19, 6087.
[10]	Basanagouda, M.; Jambagi, V.B.; Barigidad, N. N.; Laxmeshwar, S. S.; Devaru, V.; Narayana, C. Eur. J. Med. Chem. 2014, 74, 225.
[11]	Wang, Y.; Wang, J.; Fu, Z.; Sheng, R.; Wu, W.; Fan, J.; Guo, R. Bioorg. Chem. 2020, 104, 104342.
[12]	Thakur, A.; Singla, R.; Jaitak, V. Eur. J. Med. Chem. 2015, 101, 476.
[13]	Bhattarai, N.; Kumbhar, A. A.; Pokharel, Y. R.; Yadav, P. N. Mini- Rev. Med. Chem. 2021, 21, 2996.
[14]	Ekowati, H., Astuti, I., Mustofa, M. Indones. J. Chem. 2010, 10, 247.
[15]	Katkevi, S.M.; Kontijevskis, A.; Mutule, I. Chem. Heterocycl. Compd. 2007, 43, 151.
[16]	Tiftikçi, E.; Erk, Ç. T. J. Heterocycl. Chem. 2010, 41, 867.
[17]	Madhav, J.V.; Kuarm, B.S.; Someshwar, P. J. Chem. Res. 2010, 2008, 867.
[18]	Lu, Z. L.; Neverov, A. A.; Brown, R. S. Org. Biomol. Chem. 2005, 3, 3379.
[19]	Shen, Q.; Peng, Q.; Shao, J.; Liu, X.; Huang, Z.; Pu, X.; Ma, L.; Li, Y.M.; Chan, A.S.; Gu, L. Eur. J. Med. Chem. 2005, 40, 1307.
[20]	Fall, Y.; Santana, L.; Uriarte, E. J. Heterocycl. Chem. 2001, 38, 1231.
[21]	Timonen, J. M.; Nieminen, R. M.; Sareila, O. Eur. J. Med. Chem. 2011, 46, 3845.
[22]	Pisani, L.; Muncipinto, G.; Miscioscia, T. F.; Nicolloti, O.; Leonetti, F.; Catto, M.; Caccia, C.; Salvati, P.; Soto-Otero, R.; Mendez Alvarez, E.; Passeleu, C.; Carotti, A. J. Med. Chem. 2009, 52, 6685.
[23]	Sun, X. J.; Xing, L.; Yuan, J. Y.; Wang, E. X.; Ding, Y. X.; Sheng, R. L.; Wang, F.; Wu, W. H.; Yang, X. W. H.; Guo, R. H. Fitoterapia 2023, 167, 105504.
[24]	Yang, J.; Mu, W. W.; Liu, G. Y. Eur. J. Pharmacol. 2020, 888, 173396.
[25]	Patil, J. V.; Soman, S. S.; Umar, S.; Girase, P.; Balakrishnan, S. ChemistrySelect 2024, 9, 1.

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

RichHTML

PDF

补充材料

可视化

摘要/Abstract

引用此文

分享此文

图/表 9

参考文献 25

相关文章 15

编辑推荐

相关统计

本文评价

[1]	敖选丽, 马超洁, 王淑冰, 何蕾, 赏宇, 朱锦阳, 李建秀, 张琴, 张荣平, 侯博. 2,4-二酮内酰胺衍生物的设计、合成及其抑制Mpro活性筛选[J]. 有机化学, 2026, 46(8): 3104-3113.
[2]	肖忠闪, 王涵, 徐露, 何瑞娟, 杨国静, 王亚坤, 刘兆敏, 张涛. 用于二氧化硫衍生物检测与成像的新型磷酸酯-吩噻嗪荧光探针[J]. 有机化学, 2026, 46(8): 3068-3078.
[3]	陈颂耀, 冯雪, 屠蔓苏, 郝文娟, 姜波. 镍(II)/双咪唑啉催化不对称高阶(5+3)环化反应构建兼具中心与轴手性的马鞍形八元桥联联芳基衍生物[J]. 有机化学, 2026, 46(7): 2796-2807.
[4]	孙晓娟, 张明, 田云飞, 王志强, 郑才俊. 一种π-桥三联蒽型深蓝光材料的合成与性能研究[J]. 有机化学, 2026, 46(6): 2415-2422.
[5]	刘妍伶, 张毅涵, 陈霞, 周晓玉, 崔颖娜, 刘海龙. 铜催化的Sonogashira偶联/亲电环化构建3-(苯硒基)苯并呋喃衍生物[J]. 有机化学, 2026, 46(6): 2379-2386.
[6]	佘慧娴, 汪晴, 查琴, 杨家强. 含膦酸酯结构的异噁唑酰胺衍生物的设计、合成及抗菌活性[J]. 有机化学, 2026, 46(5): 2059-2066.
[7]	许俊华, 张珂瑗, 贺重隆, 段新华, 刘乐. 磺酰基衍生物介导的自由基型芳基迁移反应进展[J]. 有机化学, 2026, 46(4): 1255-1283.
[8]	马超, 徐晓玲, 骆翔, 鲁瑞娟, 虞国棋, 蔡涛. 电化学促进邻炔基苯甲酸酯与硫酚的自由基串联环化反应合成4-硫代异香豆素[J]. 有机化学, 2026, 46(3): 1039-1049.
[9]	杨利婷, 潘慧茹, 许晓旭, 张益恺, 来姝妤, 曹信誉, 刘国群, 乔辉杰, 焦明立. 一种无过渡金属、绿色温和的一锅法合成3-碘代/溴代咪唑并[1,2-a]吡啶类化合物[J]. 有机化学, 2026, 46(3): 915-924.
[10]	刘琳, 周璐璐, 梁天宇, 钟克利, 燕小梅, 汤立军. 基于苯并吡喃衍生物的近红外荧光探针用于二氧化硫衍生物的高灵敏检测与生物成像[J]. 有机化学, 2026, 46(3): 866-871.
[11]	鹿馨元, 董学, 孙全春, 王滔, 雷川虎, 王新平. 含噻吩基团的二氧杂硼环蓝光自由基[J]. 有机化学, 2026, 46(2): 664-669.
[12]	王见见, 郑圣䶮, 张洁, 高文鹏, 孔凡栋, 李培海, 王聪, 曹树更. 海洋来源真菌Cladosporium sp. MDW-211次级代谢产物研究[J]. 有机化学, 2026, 46(2): 684-688.
[13]	顾运琼, 姚嘉伟, 钟智薇, 文舒婷, 杨坤, 刘亚璐, 甘春芳. 氨基酸修饰的孕甾衍生物设计合成及抗肿瘤活性研究[J]. 有机化学, 2026, 46(2): 545-553.
[14]	李科, 方鹏炜, 张新宇, 韦康, 袁冰, 杜平武. 多取代芘基碳纳米环的合成、表征和电荷传输性质[J]. 有机化学, 2026, 46(2): 539-544.
[15]	胡苏, 赵丽莲, 李昕宇, 叶雨蓓, 邓赟, 黄莉钧, 郭大乐. 羌活中两个新的线型呋喃香豆素类成分及其抗炎活性[J]. 有机化学, 2026, 46(1): 300-303.