新型氨基糖类席夫碱铜配合物的合成及抗肿瘤活性研究

doi:10.6023/A25090314

摘要/Abstract

将生物活性相关的有机部分引入过渡金属配合物的配位领域已成为提高金属药物选择性和生物相容性的有效策略. 本文设计并合成了2种具有叠氮乙酰化葡萄糖糖胺席夫碱结构的配体L¹和L²,进而与铜金属盐反应合成了3种新型铜配合物. 通过X射线单晶衍射技术解析了配体L¹和配合物3的单晶结构,通过噻唑蓝(MTT)法测定了化合物对人恶性肿瘤细胞系和正常细胞系的体外细胞毒性. 其中配合物2对肝癌细胞(HepG-2)和宫颈癌细胞(HeLa)细胞表现出高的细胞毒性,接近或优于阳性对照的值,但对正常细胞的毒性则远低于阳性对照. 对肿瘤细胞毒性较强的配合物 2 进行了后续抗肿瘤活性研究,包括细胞凋亡评估、细胞内活性氧生成、线粒体膜电位、细胞周期、细胞摄取、迁移和侵袭及血管生成实验,进一步证实了其对肿瘤细胞的抑制作用机制. 由于糖骨架在配体中具有优异的水溶性,使得配合物2表现出良好的溶解性和稳定性. 我们通过细胞内活性氧(ROS)产生、赫斯特(Hoechst 33342)染色实验、线粒体膜电位实验和膜联蛋白Ⅴ-红色荧光蛋白(Annexin V-mCherry)进一步证明,配合物2能提高癌症细胞内活性氧的水平,通过线粒体途径诱导细胞凋亡. 细胞周期实验证明配合物2可以延迟或抑制细胞周期通过S期和G2/M期的进展. 另外,配合物2能有效抑制癌症细胞的迁移和侵袭,且有效抑制正常细胞系脐静脉内皮细胞(HUVEC)的血管生成,分子对接结果显示配合物2与血管内皮细胞生长因子受体2(VEGFR-2)具有良好的结合能力.

关键词: 晶体结构, 氨基葡萄糖, 细胞凋亡, 细胞摄取, 迁移和侵袭

Introducing biologically active organic moieties into the coordination field of transition metal complexes has become an effective strategy for improving the selectivity and biocompatibility of metal drugs. In this paper, two ligands L¹and L² with azidoacetylated glucosamine Schiff base structure were designed and synthesized, and then reacts with copper metal salts to synthesize three novel copper complexes. The single crystal structures of ligand L¹and complex 3 were analyzed by X-ray single crystal diffraction technology, and the in vitro cytotoxicity of the compounds on human malignant tumor cell lines and normal cell lines was determined by MTT assay. Among them, complex 2 showed high cytotoxicity against HepG-2 and HeLa cells, approaching or exceeding the value of the positive control, but the toxicity to normal cells was much lower than that of the positive control. The subsequent anti-tumor activity studies of complex 2 with strong cytotoxicity to tumor cells, including apoptosis assessment, intracellular reactive oxygen species generation, mitochondrial membrane potential, cell cycle, cell uptake, migration and invasion, and angiogenesis experiments, further confirmed its inhibitory mechanism on tumor cells. Due to the excellent water solubility of the sugar skeleton in the ligand, complex 2 exhibited good solubility and stability. We further demonstrated through intracellular reactive oxygen species (ROS) production, Hoechst 33342 staining experiment, mitochondrial membrane potential experiment, and Annexin V-mCherry that complex 2 can increase the level of ROS in cancer cells and induce apoptosis through the mitochondrial pathway Cell cycle experiments have shown that complex 2 can delay or inhibit the progression of the cell cycle through the S and G2/M phases. The significant cell uptake results indicated that the high cytotoxicity of complex 2 might be due to its extensive accumulation in HepG-2 cells. In addition, complex 2 can effectively inhibit the migration and invasion of cancer cells, as well as the angiogenesis of normal cell line umbilical vein endothelial cells (HUVEC). Molecular docking results showed that complex 2 has good binding ability with vascular endothelial growth factor receptor 2 (VEGFR-2).

Key words: Crystal structures, Glucosamine, Apoptosis, Cellular Uptake, Migration and Invasion

引用此文

高春艳, 崔馨月, 王凯月, 石雪怡, 贺卿, 赵晋忠, 岳爱琴, 杜维俊, 张永坡. 新型氨基糖类席夫碱铜配合物的合成及抗肿瘤活性研究[J]. 化学学报, doi: 10.6023/A25090314.

Gao Chunyan, Cui Xinyue, Wang Kaiyue, Shi Xueyi, He Qing, Zhao Jinzhong, Yue Aiqin, Du Weijun, Zhang Yongpo. Synthesis and Antitumor Activity of Novel Amino Glucose Derivative Schiff Base Copper(II) Complexes[J]. Acta Chimica Sinica, doi: 10.6023/A25090314.

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参考文献

[1] Alfonso-Herrera L. A.; Hernández-Romero D.; Cruz-Navarro J. A.; Ramos-Ligonio Á.; López-Monteon A.; Rivera-Villanueva J. M.; Morales-Morales D.; Colorado-Peralta, R. Coord. Chem. Rev.2024, 505, 215698.
[2] Roufosse B.; Serbu C.; Marschner C.; Prince S.; Blom, B. Eur. J. Med. Chem.2024, 274, 116528.
[3] Lv L.; Zheng T.; Tang L.; Wang Z.; Liu, W. Coord. Chem. Rev.2025, 525, 216327.
[4] Prathima T. S.; Choudhury B.; Ahmad M. G.; Chanda K.; Balamurali, M. M. Coord. Chem. Rev.2023, 490, 215231.
[5] Bortolamiol E.; Visentin F.; Scattolin T. Appl. Sci.-Basel2023, 13, 5561.
[6] Vaidya S. P.; Patra, M. Curr. Opin. Chem. Biol.2023, 72, 102236.
[7] Zhang Y.; Wu W.; Xu W.; Fu Y.; Guo H.; Lu, Z. Acta Chim. Sinica2025, 83, 445(in Chinese).
(张一亮, 武卫龙, 许文磊, 傅玉琴, 郭辉, 卢志强.化学学报, 2025, 83, 445.)
[8] McCallum, N.; Najlah, M.Cancers 2024, 16, 2775.
[9] Zahedipour F.; Dalirfardouei R.; Karimi G.; Jamialahmadi K. Biomed. Pharmacother.2017, 95, 1051.
[10] Song S.; Zhou H.; Li X.; Wang L.; Li Y.; Wang, J. Chinese J. Org. Chem.2014, 34, 706(in Chinese).
(宋沙沙,周宏勇,李小娜,王丽华, 李云庆, 王家喜, 氨基葡萄糖衍生物配体在不对称合成中的应用进展.有机化学, 2014, 34, 706.)
[11] Benessere V.; Del Litto R.; De Roma A.; Ruffo, F. Coord. Chem. Rev.2010, 254, 390.
[12] Benessere V.; De Roma A.; Del Litto R.; Lega M.; Ruffo, F. Eur. J. Org. Chem.2011, 2011, 5779.
[13] Sivaguru P.; Ning Y.; Bi X. Chem. Rev.2021, 121, 4253.
[14] Wang H.; Liu Y.; Xu M.; Cheng J. Biomater. Sci.2019, 7, 4166.
[15] Cheng B.; Wan Y.; Tang Q.; Du Y.; Xu F.; Huang Z.; Qin W.; Chen X.Chinese J. Chem. 2022, 40, 806.
[16] Sinicropi M. S.; Ceramella J.; Iacopetta D.; Catalano A.; Mariconda A.; Rosano C.; Saturnino C.; El-Kashef, H.; Longo, P.Int. J. Mol. Sci. 2022, 23, 14840.
[17] Salassa, L. Eur. J. Inorg. Chem.2011, 2011, 4931.
[18] Santini C.; Pellei M.; Gandin V.; Porchia M.; Tisato F.; Marzano C. Chem. Rev.2014, 114, 815.
[19] Wang C.; Yang X.; Dong C.; Chai K.; Ruan J.; Shi, S. Coord. Chem. Rev.2023, 487, 215156.
[20] Garcia-Peiro J. I.; Bonet-Aleta J.; Hueso, J. L. Coord. Chem. Rev.2025, 534, 216542.
[21] Zhang Y.-P.; Ma Z.-Y.; Qiao P.-P.; Gao C.-Y.; Tian J.-L.; Zhao J.-Z.; Du W.-J.; Xu J.-Y.; Yan, S.-P. J. Mol. Struct.2021, 1236, 130278.
[22] Addison A. W.; Rao T. N.; Reedijk J.; van Rijn J.; Verschoor, G. C. J. Chem. Soc., Dalton Trans.1984, 7, 1349.
[23] Bhattacharya S.; Karki S. S.; Suresh R.; Manikandan L.; Senthilkumar G. P.; Gupta M.; Mazumder U. K.; Balaji R.; Murali, K. Med. Chem. Res.2012, 21, 1120.
[24] Laggner H.; Hermann M.; Gmeiner B. M. K.; Kapiotis, S. Anal. Bioanal. Chem.2006, 385, 959.
[25] Henrotin Y. E.; Bruckner P.; Pujol, J. P. L. Osteoarthr. Cartilage2003, 11, 747.
[26] Chen Z.-P.; Li M.; Zhang L.-J.; He J.-Y.; Wu L.; Xiao Y.-Y.; Duan J.-A.; Cai T.; Li, W.-D. J. Drug Target.2015, 24, 492.
[27] Guo X.; Yang N.; Ji W.; Zhang H.; Dong X.; Zhou Z.; Li L.; Shen H. M.; Yao S. Q.; Huang W. Adv. Mater.2021, 33, 2007778.
[28] Zhang Y.-P.; He Q.; Zhou X.-H.; Liu G.-H.; Yue A.-Q.; Gao C.-Y.; Zhao J.-Z.; Du W.-J.; Yan, S.-P. J. Mol. Struct.2023, 1292, 136090.
[29] Zhang Y. P.; He Q.; Zhao Y. Y.; Qiao P. P.; Tian Y. W.; Gao C. Y.; Tian J. L.; Du W. J.; Yan, S. P. Appl. Organomet. Chem.2023, 37, e7074.
[30] Zhang Y.-P.; Tian Y.-W.; Geng J.; Zhou X.-H.; Li M.-Z.; Liu G.-H.; Gao C.-Y.; Yue A.-Q.; Zhao J.-Z.; Du W.-J.Arab. J. Chem. 2024, 17, 105478.
[31] Elefantova K.; Lakatos B.; Kubickova J.; Sulova Z.; Breier A.Int. J. Mol. Sci. 2018, 19, 1985.
[32] Song G.; Shang C.; Zhu Y.; Xiu Z.; Li Y.; Yang X.; Ge C.; Han J.; Jin N.; Li Y.; Li X.; Fang, J. Curr. Cancer Drug Tar.2024, 24, 411.
[33] Chen G.; Liao X.; Sun P.; Cen H.; Shu S.; Li B.; Li, J. Nan fang yi ke da xue xue bao = Journal of Southern Medical University2024, 44, 1109(in Chinese).
(陈桂玲, 廖晓凤, 孙鹏涛, 岑欢, 舒盛春, 李碧晶, 黎金华.南方医科大学学报, 2024, 44, 1109.)
[34] Khan H.; Alam W.; Alsharif K. F.; Aschner M.; Pervez S.; Saso L. Molecules2022, 27, 920.
[35] Gao F.; Xu J.-C.; You X.-R.; Gao X.; Wei J.-L.; Li S.-X.; Zhu C.-L.; Yang, C. Transl. Cancer Res.2019, 8, 203.
[36] Xu X.; Li S.; Lin Y.; Chen H.; Hu Z.; Mao Y.; Xu X.; Wu J.; Zhu Y.; Zheng X.; Luo J.; Xie, L. J. Transl. Med.2013, 11, 276.
[37] Zhang J.; Liu H.; Hou L.; Wang G.; Zhang R.; Huang Y.; Chen X.; Zhu J. Mol. Cancer2017, 16, 151.
[38] Zhang P. L.; Hou X. X.; Liu M. R.; Huang F. P.; Qin, X. Y. Dalton Trans.2020, 49, 6043.
[39] Kastl A.; Wilbuer A.; Merkel A. L.; Feng L.; Di Fazio P.; Ocker M.; Meggers E. Chem. Commun.2012, 48, 1863.
[40] Fante C.; Eldar-Boock A.; Satchi-Fainaro R.; Osborn H. M. I.; Greco, F. J. Med. Chem.2011, 54, 5255.
[41] Trott O.; Olson, A. J. J. Comput. Chem.2010, 31, 455.
[42] Peach C. J.; Mignone V. W.; Arruda M. A.; Alcobia D. C.; Hill S. J.; Kilpatrick L. E.; Woolard, J. International journal of molecular sciences2018, 19, 1264.
[43] Asha M. S.; Zabiulla; Khamees H. A.; Al-Ostoot F. H.; Pinto O.; Gopichand T.; Shivappaa, M. J. Mol. Struct.2022, 1253, 132272.
[44] Lega M.; Figliolia R.; Moberg C.; Ruffo F. Tetrahedron2013, 69, 4061.
[45] Tropper F. D.; Andersson F. O.; Braun S.; Roy R. Synthesis1992, 1992, 612.
[46] Mistri T.; Alam R.; Dolai M.; Mandal S. K.; Guha P.; Khuda-Bukhsh A. R.; Ali, M. Eur. J. Inorg. Chem.2013, 34, 5854.