Copper is kind of life element, which plays an important role in the development of tumor and is used to predict the prognosis and treatment of tumor. Copper ions play a vital role in living organisms after forming copper(Ⅱ)-based complexes with corresponding ligands. Copper(Ⅱ)-based complexes are considered as an alternative to cisplatin-based antitumor drugs due to with the characteristics of low toxicity and low drug resistance. In this paper, the synthesis of Copper(II)-based complexes and their antitumor activities by inducing apoptosis, inhibiting inflammation and tumor angiogenesis in vivo and in vitro studies are reviewed, which is important for the development of highly efficient and low-toxicity metal-complexed antitumor drugs.

Aiqiu Liao, Xiuying Qin. Progress in the synthesis and antitumor activity of copper(Ⅱ)-based complexes. International Journal of Frontiers in Medicine (2024), Vol. 6, Issue 5: 104-108. https://doi.org/10.25236/IJFM.2024.060514.

[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-49. doi:10.3322/caac.21660.

[2] Cao BB, Li D, Xing X, Zhao Y, Wu K, Jiang F et al. Effect of cisplatin on the clock genes expression in the liver, heart and kidney. Biochem Biophys Res Commun. 2018;501(2):593-7. doi:10.1016/j.bbrc.2018.05.056.

[3] Barry NP, Sadler PJ. Exploration of the medical periodic table: towards new targets. Chem Commun (Camb). 2013;49(45):5106-31. doi:10.1039/c3cc41143e.

[4] Jiang Y, Huo Z, Qi X, Zuo T, Wu Z. Copper-induced tumor cell death mechanisms and antitumor theragnostic applications of copper complexes. Nanomedicine (Lond). 2022;17(5):303-24. doi:10.2217/nnm-2021-0374.

[5] Gul NS, Khan TM, Chen M, Huang KB, Hou C, Choudhary MI et al. New copper complexes inducing bimodal death through apoptosis and autophagy in A549 cancer cells. J Inorg Biochem. 2020;213:111260. doi:10.1016/j.jinorgbio.2020.111260.

[6] Sun M, Xin H, Wang KZ, Zhang YA, Jin LP, Huang CH. Bright and monochromic red light-emitting electroluminescence devices based on a new multifunctional europium ternary complex. Chem Commun (Camb). 2003(6):702-3. doi:10.1039/b212467j.

[7] Pivetta T, Trudu F, Valletta E, Isaia F, Castellano C, Demartin F et al. Novel copper(II) complexes as new promising antitumour agents. A crystal structure of [Cu(1,10-phenanthroline-5,6-dione) 2(OH2)(OClO3)](ClO4). J Inorg Biochem. 2014;141:103-13. doi:10.1016/j.jinorgbio.2014.08.011.

[8] Angel NR, Khatib RM, Jenkins J, Smith M, Rubalcava JM, Le BK et al. Copper (II) complexes possessing alkyl-substituted polypyridyl ligands: Structural characterization and in vitro antitumor activity. J Inorg Biochem. 2017;166:12-25. doi:10.1016/j.jinorgbio.2016.09.012.

[9] Filho JC, Sarria AL, Becceneri AB, Fuzer AM, Batalhão JR, da Silva CM et al. Copper (II) and 2,2'-bipyridine complexation improves chemopreventive effects of naringenin against breast tumor cells. PLoS One. 2014;9(9):e107058. doi:10.1371/journal.pone.0107058.

[10] Liu X, Hamon J-R. Recent developments in penta-, hexa- and heptadentate Schiff base ligands and their metal complexes. Coordination Chemistry Reviews. 2019;389:94-118. doi:https://doi.org/10.1016/j.ccr.2019.03.010.

[11] More MS, Joshi PG, Mishra YK, Khanna PK. Metal complexes driven from Schiff bases and semicarbazones for biomedical and allied applications: a review. Mater Today Chem. 2019;14:100195. doi:10.1016/j.mtchem.2019.100195.

[12] Daravath S, Rambabu A, Ganji N, Ramesh G, Anantha Lakshmi PV, Shivaraj. Spectroscopic, quantum chemical calculations, antioxidant, anticancer, antimicrobial, DNA binding and photo physical properties of bioactive Cu(II) complexes obtained from trifluoromethoxy aniline Schiff bases. Journal of Molecular Structure. 2022;1249:131601. doi:https://doi.org/10.1016/j.molstruc.2021.131601.

[13] Qin XY, Yang LC, Le FL, Yu QQ, Sun DD, Liu YN et al. Structures and anti-cancer properties of two binuclear copper complexes. Dalton Trans. 2013;42(41):14681-4. doi:10.1039/c3dt51548f.

[14] Zhao C, Rakesh KP, Ravidar L, Fang WY, Qin HL. Pharmaceutical and medicinal significance of sulfur (S(VI))-Containing motifs for drug discovery: A critical review. Eur J Med Chem. 2019;162:679-734. doi:10.1016/j.ejmech.2018.11.017.

[15] Chohan ZH, Youssoufi MH, Jarrahpour A, Ben Hadda T. Identification of antibacterial and antifungal pharmacophore sites for potent bacteria and fungi inhibition: indolenyl sulfonamide derivatives. Eur J Med Chem. 2010;45(3):1189-99. doi:10.1016/j.ejmech.2009.11.029.

[16] Chen P, Yang J, Zhou Y, Li X, Zou Y, Zheng Z et al. Design, synthesis, and bioactivity evaluation of novel amide/sulfonamide derivatives as potential anti-inflammatory agents against acute lung injury and ulcerative colitis. Eur J Med Chem. 2023;259:115706. doi:10.1016/j.ejmech.2023.115706.

[17] Mandal MK, Ghosh S, Naesens L, Bhat HR, Singh UP. Facile synthesis, antimicrobial and antiviral evaluation of novel substituted phenyl 1,3-thiazolidin-4-one sulfonyl derivatives. Bioorg Chem. 2021;114:105153. doi:10.1016/j.bioorg.2021.105153.

[18] Refat MS, Sharshar T, Elsabawy KM, El-Sayed MY, Adam AMA. Synthesis, physicochemical characterization and anticancer screening of sulfa drug ruthenium complexes as anticancer agent. Journal of Molecular Liquids. 2016;222:334-49. doi:https://doi.org/10.1016/j.molliq.2016.07.006.

[19] Hangan A, Borodi G, Filip X, Tripon C, Morari C, Oprean L et al. Structure of N-(5-ethyl-[1,3,4]-thiadiazole-2-yl)toluenesulfonamide by combined X-ray powder diffraction, 13C solid-state NMR and molecular modelling. Acta Crystallogr B. 2010;66(Pt 6):615-21. doi:10.1107/s0108768110039327.

[20] Hangan A, Borras J, Liu-Gonzalez M, Oprean L. Synthesis, Crystal Structures and Properties of [Cu(L1)2(py)2(H2O)](H2O) [HL1 = N-(5-ethyl-[1,3,4]–thiadiazole-2-yl)-toluenesulfonamidate] and [Cu(L2)2(py)2(H2O)] [HL2 = N-(5-ethyl-[1,3,4]–thiadiazole-2-yl)-benzenesulfonamidate]. Zeitschrift für anorganische und allgemeine Chemie. 2007;633(11-12):1837-41. doi:https://doi.org/10.1002/zaac.200700214.

[21] Tommasino J-B, Renaud FNR, Luneau D, Pilet G. Multi-biofunctional complexes combining antiseptic copper(II) with antibiotic sulfonamide ligands: Structural, redox and antibacterial study. Polyhedron. 2011;30(10):1663-70. doi:https://doi.org/10.1016/j.poly.2011.03.033.

[22] Chebout O, Trifa C, Bouacida S, Boudraa M, Imane H, Merzougui M et al. Two new copper (II) complexes with sulfanilamide as ligand: Synthesis, structural, thermal analysis, electrochemical studies and antibacterial activity. Journal of Molecular Structure. 2022;1248:131446. doi:https://doi.org/10.1016/j.molstruc.2021.131446.

[23] Hangan AC, Turza A, Lucaciu RL, Sevastre B, Páll E, Oprean LS et al. New Cu(+2) Complexes with N-Sulfonamide Ligands: Potential Antitumor, Antibacterial, and Antioxidant Agents. Molecules. 2022;27(10). doi:10.3390/molecules27103338.

[24] Zhang PL, Hou XX, Liu MR, Huang FP, Qin XY. Two novel chiral tetranucleate copper-based complexes: crystal structures, nanoparticles, and inhibiting angiogenesis and the growth of human breast cancer by regulating the VEGF/VEGFR2 signal pathway in vitro. Dalton Trans. 2020;49(18):6043-55. doi:10.1039/d0dt00380h.

[25] Qin XY, Wang YN, Liu HF, Luo ZH, Zhang PL, Li-Fang H et al. Anti-cancer activities of metal-based complexes by regulating the VEGF/VEGFR2 signaling pathway and apoptosis-related factors Bcl-2, Bax, and caspase-9 to inhibit angiogenesis and induce apoptosis. Metallomics. 2020;12(1):92-103. doi:10.1039/c9mt00248k.

[26] Qin XY, Wang YN, Yang XP, Liang JJ, Liu JL, Luo ZH. Synthesis, characterization, and anticancer activity of two mixed ligand copper(ii) complexes by regulating the VEGF/VEGFR2 signaling pathway. Dalton Trans. 2017;46(47):16446-54. doi:10.1039/c7dt03242k.

[27] Qin XY, Liu YN, Yu QQ, Yang LC, Liu Y, Zhou YH et al. Mixed-ligand mononuclear copper(II) complex: crystal structure and anticancer activity. ChemMedChem. 2014;9(8):1665-71. doi:10.1002/cmdc.201402060.

[28] Fan R, Wei JC, Xu BB, Jin N, Gong XY, Qin XY. A novel chiral oxazoline copper(II)-based complex inhibits ovarian cancer growth in vitro and in vivo by regulating VEGF/VEGFR2 downstream signaling pathways and apoptosis factors. Dalton Trans. 2023;52(33):11427-40. doi:10.1039/d3dt01648j.

[29] Caruso Bavisotto C, Nikolic D, Marino Gammazza A, Barone R, Lo Cascio F, Mocciaro E et al. The dissociation of the Hsp60/pro-Caspase-3 complex by bis(pyridyl)oxadiazole copper complex (CubipyOXA) leads to cell death in NCI-H292 cancer cells. J Inorg Biochem. 2017;170:8-16. doi:10.1016/j.jinorgbio.2017.02.004.

[30] Hou XX, Ren YP, Luo ZH, Jiang BL, Lu TT, Huang FP et al. Two novel chiral tetranucleate copper-based complexes: syntheses, crystal structures, inhibition of angiogenesis and the growth of human breast cancer in vitro and in vivo. Dalton Trans. 2021;50(41):14684-94. doi:10.1039/d1dt02033a.

[31] Chakraborty A, Kumar P, Ghosh K, Roy P. Evaluation of a Schiff base copper complex compound as potent anticancer molecule with multiple targets of action. Eur J Pharmacol. 2010;647(1-3):1-12. doi:10.1016/j.ejphar.2010.08.003.

[32] Balsa LM, Baran EJ, León IE. Copper Complexes as Antitumor Agents: In vitro and In vivo Evidence. Curr Med Chem. 2023;30(5):510-57. doi:10.2174/0929867328666211117094550.