SIOC English
化学学报
高级检索

化学学报 >

0 0

DOI: https://doi.org/10.6023/A26080293

研究论文

新型5,8-喹啉二酮-邻菲罗啉钴(II)配合物的设计及抗癌机制研究

  • 周虹宇 ,
  • 罗富柳 ,
  • 刘敏栅 ,
  • 谭明雄 ,
  • 周振 ,
  • 梁宏 ,
  • 覃其品
展开
  • a玉林师范学院化学与食品科学学院 广西农产资源化学与生物技术重点实验室 玉林 537000;
    b广西师范大学化学与药学学院 桂林 541004

收稿日期: 2026-08-19

  网络出版日期: 2026-09-17

基金资助

广西自然科学基金(nos. 2026GXNSFHA00640357, 2026GXNSFHA00640014 and 2025GXNSFAA069961)、国家自然科学基金(no. 22267020)、八桂青年拔尖人才(no. 2024ZKBGQB01)和大学生创新创业训练计划项目(nos. 202510606147, X2026106060034 and X2026106060148)资助项目.

收起

Design and anticancer mechanism study of a novel 5,8-quinolinedione-o-phenanthroline cobalt(II) complex

  • Zhou Hongyu ,
  • Luo Fuliu ,
  • Liu Minshan ,
  • Tan Mingxiong ,
  • Zhou Zhen ,
  • Liang Hong ,
  • Qin Qipin
Expand
  • aGuangxi Key Laboratory of Agricultural Resources, Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, Yulin 537000;
    bSchool of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004
†These authors contributed equally to this work.

Received date: 2026-08-19

  Online published: 2026-09-17

Supported by

Natural Science Foundation of Guangxi (nos. 2026GXNSFHA00640357, 2026GXNSFHA00640014 and 2025GXNSFAA069961), the National Natural Science Foundation (no. 22267020), the Bagui Youth top-notch personnel program of Guangxi (no. 2024ZKBGQB01) and the China University Students Innovative Project(nos. 202510606147, X2026106060034 and X2026106060148).

Fold

摘要

基于提高金属基药物的抗癌活性, 本研究以6,7-二氯-5,8-喹啉二酮(QL)和邻菲罗啉(phen)为配体, 与CoCl2·6H₂O反应, 合成QL钴配合物[Co(QL’)(phen)(CH3OH)Cl]·(CH3OH) (QLCo1)和[Co(QL’)2(CH3OH)2] (QLCo2), 并通过核磁(NMR)、元素分析(ELA)、紫外-可见吸收光谱(UV)、红外光谱(IRS)和质谱法(ESI-MS)等技术确定QL, QLCo1和QLCo2的结构. 在配合物QLCo1和QLCo2中, 中心钴(II)原子呈六配位的八面体‌结构. 此外, 以顺铂 (Cis-Pt)和QLCo2对照, 研究经phen改性后钴配合物QLCo1的抗癌活性及潜在机制. 相对于正常肝细胞(HL-7702、AML12)、人宫颈癌细胞(HeLa)和人肺癌细胞(A549), 配合物QLCo1对人肺癌顺铂耐药细胞(A549/CDDP)具有更好的抑制作用,其IC50值为0.30±0.02 μmol/L, 优于Cis-Pt (67.2 ± 1.3 μmol/L)、QL (>100.0 μmol/L)、CoCl2·6H₂O(>100.0 μmol/L)、phen (>100.0 μmol/L)和QLCo2 (IC50= 4.0±0.8 μmol/L). 系列生物实验显示, QLCo1和QLCo2诱导A549/CDDP细胞产生凋亡, 凋亡率分别为46.45%和44.17%, 它们通过线粒体自噬途径介导A549/CDDP癌细胞内源性凋亡, 说明了phen增强了钴配合物诱导A549/CDDP癌细胞凋亡的能力. 此外, QLCo1能明显抑制A549/CDDP实体瘤的生长, 抑制率为50.6%, 明显高于Cis-Pt (ca. 26.6%). 总之, 本研究获得一种能有效通过线粒体自噬通路诱导A549/CDDP癌细胞凋亡的6,7-二氯-5,8-喹啉二酮钴配合物QLCo1.

关键词： 钴(II)配合物; 6,7-二氯-5,8-喹啉二酮; 线粒体自噬

本文引用格式

周虹宇 , 罗富柳 , 刘敏栅 , 谭明雄 , 周振 , 梁宏 , 覃其品 . 新型5,8-喹啉二酮-邻菲罗啉钴(II)配合物的设计及抗癌机制研究[J]. 化学学报, 0 : 0 . DOI: 10.6023/A26080293

Abstract

To enhance the anti-cancer efficacy of metal-based drugs, two cobalt(II) complex, [Co(QL’)(phen)(CH3OH)Cl]·(CH3OH) (QLCo1) and [Co(QL’)2(CH3OH)2] (QLCo2), were synthesized via coordination of 6,7-dichloro-5,8-quinolinone (QL) and 1,10-phenanthroline (phen) with CoCl2·6H₂O under controlled conditions. The structures of QL, QLCo1 and QLCo2 were determined by nuclear magnetic resonance (NMR), elemental analysis (ELA), ultraviolet-visible absorption spectroscopy (UV-Vis), infrared spectroscopy (IRS) and mass spectrometry (ESI-MS). In the complexes QLCo1 and QLCo2, the central cobalt(II) atom exhibits a six-coordinated octahedral structure. Additionally, compared with cisplatin (Cis-Pt) and QLCo2, the anti-cancer activity and potential mechanism of the phen-modified cobalt(II) complex QLCo1 were investigated. Compared with normal liver cells (HL-7702, AML12), human cervical cancer cells (HeLa), and human lung cancer cells (A549), QLCo1 exhibited better inhibitory effects on human lung cancer cisplatin-resistant cells (A549/CDDP), with an IC50 value of 0.30±0.02 μmol/L; this potency was markedly superior to Cis-Pt (67.2 ± 1.3 μmol/L), QL (>100.0 μmol/L), CoCl2·6H₂O(>100.0 μmol/L), phen (>100.0 μmol/L) and QLCo2 (IC50= 4.0±0.8 μmol/L), respectively. Flow cytometry, Western blotting experiments, cell uptake and immunofluorescence experiments revealed showed that QLCo1 and QLCo2 induced apoptosis in A549/CDDP cells, with apoptosis rates of 46.45% and 44.17%, respectively. Complexes QLCo1 and QLCo2 mediated endogenous apoptosis in A549/CDDP cancer cells through the mitophagy pathway, indicating that phen enhanced the ability of the cobalt(II) complex QLCo2 to induce apoptosis in A549/CDDP cancer cells. From the cobalt uptake assay, complex QLCo1 exhibited obvious priority on the cell uptake effect than QLCo2, which should should be undoubtedly correlated with the key roles of the phen ligand of QLCo1. Moreover, QLCo1 could significantly inhibit the growth of A549/CDDP solid tumors, with an inhibition rate of 50.6%, which was markedly higher than that of Cis-Pt (ca. 26.6%). In conclusion, this study has identified a 6,7-dichloro-5,8-quinolinone dithiocarbamate complex, named QLCo1, which can effectively induce apoptosis in A549/CDDP cancer cells through mitochondrial autophagy.

Key words： Cobalt(II) complex; 6,7-dichloro-5,8-quinolinedione; mitophagy

参考文献

[1] (a) Feng, T.; Tang, Z.; Shu, J.; Wu, X.; Jiang, H.; Chen, Z.; Chen, Y.; Ji, L.; Chao, H. Angew. Chem. Int. Ed. 2024, 63, e202405679. (b) Liang, B.-B.; Liu, Q.; Liu, B.; Yao, H.-G.; He, J.; Tang, C.-F.; Peng, K.; Su, X.-X.; Zheng, Y.; Ding, J.-Y.; Shen, J.; Cao, Q.; Mao, Z.-W. Angew. Chem. Int. Ed. 2023, 62, e202312170. (d) Feng, T.; Tang, Z.; Shu, J.; Wu, X.; Jiang, H.; Chen, Z.; Chen, Y.; Ji, L.; Chao, H. Angew. Chem. Int. Ed. 2024, 63, e202405679.
[2] Pan Z.-Y.; Ling Y.-Y.; Zhang H.; Hao L.; Tan C.-P.; Mao, Z.-W. J. Med. Chem.2022, 65, 14692.
[3] Liu X.-M.; Zhu Z.-Z.; Li Q.-T.; Li Z.; Rong R.; Xie C.-Z.; Qiao X.; Feng Y.-K.; Xu J.-Y. J. Med. Chem. 2025, 68, 14995.
[4] Zhu M.; Xu S.; Li G.; Xu G.; Zhang, Z., Liang H.;Yang F.J. Med. Chem. 2025, 68, 13113.
[5] (a) Liu, R.-X.; Li, D.-M.; Luo, R.-Y.; Bi, X.-B.; Huang, Y.; Luo, S.-S.; Wu, Y.-S.; Ding, T.-Y.; Xie, J.-X.; Wen, C.-C.; Liu, Y.-C.; Storr, T.; Liang, H. J. Med. Chem. 2026, 69, 6835. (b) Xu, J.-Y.; Bi, X.-B.; Luo, S.-S.; Huang, Y.; Wang, C.-Y.; Wen, C.-C.; Liu, R.-X.; Liu, Y.-C.; Liang, H. J. Inorg. Biochem. 2026, 276, 113158.
[6] Icsel C.; Yilmaz V. T.; Aydinlik Ş.; Aygun M. Eur. J. Med. Chem. 2020, 202, 112535.
[7] Tabrizi L.; McArdle P.; Erxleben A.; Chiniforoshan, H. Eur. J. Med. Chem.2015, 103, 516.
[8] Protogeraki C.; Andreadou E. G.; Perdih F.; Turel I.; Pantazaki A. A.; Psomas, G. Eur. J. Med. Chem.2014, 86, 189.
[9] Qin Q.-P.; Qin J.-L.; Meng T.; Lin W.-H.; Zhang C.-H.; Wei Z.-Z.; Chen J.-N.; Liu Y.-C.; Liang H.; Chen, Z.-F. Eur. J. Med. Chem.2016, 124, 380.
[10] (a) Karumban, K. S.; Raut, R.; Gupta, P.; Muley, A.; Giri, B.; Kumbhakar, S.; Misra, A.; Maji, S. J. Inorg. Biochem. 2022, 233, 111866. (b) Rijwan, Arjmand, F.; Tabassum, S. Dalton Trans. 2024, 53, 10126. (c) Dutta, J.; Varshini, A.; Padaga, S. G.; Bera, A.; Sarkar, T.; Biswas, S.; Hussain, A. Dalton Trans. 2025, 54, 3027.
[11] Khakina E.; Nikovskiy I.; Spiridonov K.; Novikov V.; Antoshkina E.; Dzhalilova D.; Diatroptova M.; Martyanova A.; Rodionov A.; Nelyubina Y. V.Dalton Trans. 2025, 54, 3667.
[12] Deka B.; Sahoo S.; Kushwaha R.; Dutta J.; Bhattacharyya A.; Banerjee S.; Hussain A.Inorg. Chem. Commun. 2025, 180, 114915.
[13] Gautam,N.; Shukla A.; Chandra S.; Kumar S.; Acharya A.; Sing M.; Butcher, R. J. Bharty, M. K.Inorg. Chem. Commun. 2025, 171, 113521.
[14] (a) Hargreaves, R. H. J.; David, C. L.; Whitesell, L. J.; LaBarbera, D. V.; Jamil, A.; Chapuis, J. C.; Skibo, E. B. J. Med. Chem. 2008, 51, 2492. (b) Behforouz, M.; Cai, W.; Mohammadi, F.; Stocksdale, M. G.; Gu, Z.; Ahmadian, M.; Baty, D. E.; Etling, M. R.; Al-Anzi, C. H.; Swiftney, T. M.; Tanzer, L. R.; Merriman, R. L.; Behforouz, N. C. Bioorg. Med. Chem. 2007, 15, 495. (c) Ryu, C. K.; Kim, H. J. Arch. Pharm. Res. 1994, 17, 139.
[15] (a) Kadela-Tomanek, M.; Jastrzębska, M.; Pawełczak, B.; Bębenek, E.; Chrobak, E.; Latocha, M.; Książek, M.; Kusz, J.; Boryczka, S. Eur. J. Med. Chem. 2017, 126, 969. (b) Hassani, M.; Cai, W.; Holley, D. C.; Lineswala, J. P.; Maharjan, B. R.; Ebrahimian, G. R.; Seradj, H.; Stocksdale, M. G.; Mohammadi, F.; Marvin, C. C.; Gerdes, J. M.; Beall, H. D.; Behforouz, M. J. Med. Chem. 2005, 48, 7733. (c) Ling, Y.; Yang, Q.-X.; Teng, Y.-N.; Chen, S.; Gao, W.-J.; Guo, J.; Hsu, P.-L.; Liu, Y.; Morris-Natschke, S. L.; Hung, C.-C.; Lee, K.-H. Eur. J. Med. Chem. 2018, 154, 199.
[16] (a) Narwanti, I.; Yu, Z.-Y.; Sethy, B.; Lai, M.-J.; Lee, H.-Y.; Olena, P.; Lee, S.-B.; Liou, J.-P. Eur. J. Med. Chem. 2023, 258, 115505. (b) Lazo, J. S.; Aslan, D. C.; Southwick, E. C.; Cooley, K. A.; Ducruet, A. P.; Joo, B.; Vogt, A.; Wipf, P. J. Med. Chem. 2001, 44, 4042.
[17] Anderberg P. I.; Harding M. M.; Lay P. A.J. Inorg. Biochem. 2004, 98, 720.
[18] Prieto Y.; Muñoz M.; Arancibia V.; Valderrama M.; Lahoz F. J.; Martín M. L. Polyhedron2007, 26, 5527.
[19] Meng T.; Qin Q.-P.; Chen Z.-L.; Zou H.-H.; Wang K.; Liang F.-P.Dalton Trans. 2019, 48, 5352.
[20] Li Z.; Zhou J.; Gan Y.; Yin Y.; Zhang W.; Yang J.; Tang Y.; Dai, Y. J. Inorg. Biochem.2019, 197, 110701.
[21] Zou B.-Q.; Huang X.-L.; Qin Q.-P.; Wang Z.-F.; Wu X.-Y.; Tan M.-X.; Liang H. Polyhedron2020, 181, 114482.
[22] (a) Qin, Q.-P.; Li, Q.; Zhang, J.; Tan, M.; Liang, H. Acta Chim. Sinica 2026, 84, 109. (覃其品, 李秋明, 张菊梅, 谭明雄, 梁宏, 化学学报, 2026, 84, 109.). (b) Hu, J.; Zhang, C.; Zhu, W.; He, Y.; Peng, S.; Chen, Z.; Li, M.; Liu, Z.; Chen, H. Chin. J. Org. Chem. 2024, 44, 1870 (in Chinese). (胡健灵, 张超, 朱文达, 何业谱, 彭姝羚, 陈振强, 李明月, 刘志军, 陈河如, 有机化学, 2024, 44, 1870.).
[23] (a) Zhang, L.; Li, W.; Liu, L.; Zheng, C.; Wang, Y.; Xu, Y.; Shi, D.; Nie, X.; Guo, J.; Zhu, C.; Wang, J. Chin. J. Org. Chem. 2017, 37, 1721 (in Chinese). 张磊, 李文赟, 刘来, 郑诚月, 王杨, 徐应淑, 史大斌, 聂绪强, 国佳莹, 朱春媛, 王京, 有机化学, 2017, 37, 1721. (b) Zhang, L.; Li, W.; Liu, L.; Zheng, C.; Wang, Y.; Xu, Y.; Shi, D.; Nie, X.; Guo, J.; Zhu, C.; Wang, J. Chin. J. Org. Chem. 2017, 37, 1721 (in Chinese). (张 磊, 李文赟, 刘来, 郑诚月, 王杨, 徐应淑, 史大斌, 聂绪强, 国佳莹, 朱春媛, 王京, 有机化学, 2017, 37, 1721.) (c) Wang, C.; Wang, L.; Fan, J.; Sun, K.; Zhu, W. Chin. J. Org. Chem. 2017, 37, 658 (in Chinese). 王聪, 王立平, 范杰, 孙坤来, 朱伟明, 有机化学, 2017, 37, 658.
[24] (a) Huang, X.-M.; Xu, Y.; Qin, S.-M.; Tan, M.-X.; Qin, Q.-P.; Shao, T.-M.; Liang, H. J. Inorg. Biochem. 2026, 274, 113055. (b) Liao, L.-S.; Chen, Y.; Hou, C.; Liu, Y.-H.; Su, G.-F.; Liang, H.; Chen, Z.-F. J. Med. Chem. 2023, 66, 10497. (c) Qin, P.; Ma, H.; Zhang, F.-G.; Ma, J.-A. Acta Chim. Sinica 2023, 81, 697 (in Chinese). (秦沛, 马海, 张发光, 马军安, 化学学报, 2023, 81, 697).
[25] Du L.-Q.; Zeng C.-J.; Mo D.-Y.; Qin Q.-P.; Tan M.-X.; Liang, H. J. Inorg. Biochem.2024, 251, 112443.
[26] (a) Su, X.; Xu, H.; Zhou, H.; Wang, X.; Li, P.; Xia, X.; Chen, W.; Huo, L. Chin. J. Org. Chem. 2026, 46, 250 (in Chinese). (粟晓微, 徐浩, 周华锋, 王夏洁, 李培源, 夏星, 陈文雅, 霍丽妮, 王晓星, 顾彦, 陈登霞, 方艳芬, 黄应平, 有机化学, 2026, 46, 250.). (b) Zhao, T.; Zhang, Q.; Mei, D.; Zhou, Y.; Zhao, J.; Lv, B.; Ma, J.; Huhn, T.; Qin, Q.-P.; Liang, H.; Correia, I. J. Med. Chem. 2026, 69, 8316. (c) Jiang, H.; Lie, Q.; Wang, F.; Zeng, J.; Yang, L.-M.; Shi, Y.-Q.; Shu, J.; Liang, J.; Huang, K.-B.; Gasser, G.; Chao, H. J. Med. Chem. 2026, 69, 1710. (d) Wang, Y.; Xu, W.; Zhang, B.; Wang, X.; Gou, S. J. Med. Chem. 2025, 68, 7353.
[27] Li Y.; Liang Z.; Zhong Z.; Wei Y.; Liu Q.; Zhan J.; Gan C.Chin. J. Org. Chem. 2025, 45, 3017 (in Chinese). (李滢, 梁正会, 钟智薇, 韦幼迎, 刘清然, 展军颜, 甘春芳, 有机化学, 2025, 45, 3017.).
[28] (a) Zhang, H.-Q.; Lin, H.-C.; Wang, F.-X.; Liu, Y.-H.; Cen, L.-F.; Choudhary, M. I.; Liang, H.; Chen, Z.-F. J. Med. Chem. 2026, 69, 10964. (b) Qian, C.; Zhang, Y.; Dang, X.; Shao, Y.; Chu, C.; Guo, Z.; Xu, C.; Wang, X. J. Med. Chem. 2026, 69, 17171. (c) Ren, H.; Liu, J.; Wang, D.; Zhang, J.; Zhao, J.; Lai, X.; Lu, J.; Zhou, W.; Liang, X.; Fang, X.; Liu, H. J. Med. Chem. 2026, 69, 17118.
[29] (a) Chen Z.; Xie L.; Wang T.; Liang J.; Chen Y.; Chao, H. J. Med. Chem.2026, 69, 17025.(b) Huang, X.-Q.; Wu, R.-C.; Liang, J.-M.; Zhou, Z.; Qin, Q.-P.; Liang, H. Eur. J. Med. Chem. 2024, 272, 116478.
[30] Yang Y.; Chen C.-F.; Guo F.-F.; Gu Y.-Q.; Liang H.; Chen, Z.-F. J. Inorg. Biochem.2023, 246, 112284.
[31] (a) Wang, M.; Li, G.; Xu, N.; Wang, L.; Cai, J.; Huang, R.; Yang,Y.; Chen, G.; Liu, Z.; Zhang, Y.; Wang, H.; Huang, X. J. Med. Chem. 2025, 68, 5597. (b) Zhao, T.; Zhao, J.; Ma, J.; Mei, D.; Ding, Y.; Qin, Q.-P.; Correia, I.; Liang, H. J. Med. Chem. 2026, 69, 15974.
Options
文章导航

/

〈 〉