Synthesis,Characterization And Antitumor Activity Of Zinc,nickel,and Cobalt Complexes With Quinoline Derivatives

Cisplatin and other approved second-generation drugs were a frequently used cytotoxic metal coordination compounds for cancer chemotherapeutic.However,their use is limited due to their remarkable side effects.To overcome these limitations of platinum coordination compounds,the quinoline derivative with biological activity is used as the lead compound,and some functional groups such as 2-ethylmorpholine,ethanol based,glucose based,amino,and halogens are introduced to improve their bioavailability,enhance their water solubility and anticancer activity.The modified compound is used to study the synthesis,structural characterization and anti-tumor activity of non-platinum metal coordination compounds.The main contents are as follows:1.With the aim of shedding some light on the mechanism of action of zinc（Ⅱ）complexes in antiproliferative processes and molecular signaling pathways,three novel zinc（Ⅱ）–cryptolepine complexes,i.e.,[Zn（QA1）Cl₂]（Zn-1）,[Zn（QA2）Cl₂]（Zn-2）,and[Zn（QA3）Cl₂]（Zn-3）,were prepared,followed by complexation of the resulting cryptolepine compounds N-（（1-（2-morpholinoethyl）-1H-1,2,3-triazol-4-yl）methyl）-benzofuro[3,2-b]quinolin-11-amine（QA1）,2-（4-（（benzofuro[3,2-b]quinolin-11-ylamino）methyl）-1H-1,2,3-triazol-1-yl）ethan-1-ol（QA2）,and（2S,3S,4R,5R,6S）-2-（4-（（benzofuro[3,2-b]quinolin-11-ylamino）-methyl）-1H-1,2,3-triazol-1-yl）-6-（hydroxymethyl）tetrahydro-2H-pyran-3,4,5-triol（QA3）with zinc（Ⅱ）,and their anticancer activity was evaluated.In CCK-8（Cell Counting Kit-8）assays,Zn-1–Zn-3 were more active againstcisplatin-resistant ovarian SK-OV-3/DDP cancer cells（SK-OV-3/DDP）than Zn Cl₂、cisplatin and the QA1–QA3 ligands,with IC₅₀ values of1.81±0.50,2.92±0.32,and 1.01±0.11μM,respectively.In addition,Zn-1–Zn-3showed high selectivities,as their IC₅₀ values for HL-7702 normal cells and SK-OV-3 tumor cells were obviously higher than those obtained for SK-OV-3/DDP cancer cells.Complexation of glycosylated cryptolepine QA3 with zinc（Ⅱ）increased the antiproliferative activity of the ligand,suggesting that Zn-3 could act as a chaperone to deliver the active ligand intracellularly,in contrast with other cryptolepine metal complexes previously reported.In vivo and in vitro investigations suggestedthat Zn-3 exhibited enhanced anticancer activity with treatment effects comparable to those of the clinical drug cisplatin.The SK-OV-3 tumor inhibition rate（TIR）of Zn-3 was 58.2%.Furthermore,Zn-1–Zn-3 triggered SK-OV-3/DDP cell apoptosis through mitophagy pathways in the order Zn-3>Zn-1>Zn-2.These results demonstrate the potential of glycosylated zinc（Ⅱ）–cryptolepine complexes for the development of chemotherapy drugs against cisplatin-resistant SK-OV-3/DDP cells.2.Herein,eight non-Pt-metal complexes,including[Ni（AQ）₂（L1）]（Ni-1）,[Ni（AQ）₂（L2）]（Ni-2）,[Ni（AQ）₂（L3）]·3CH₃OH（Ni-3）,[Ni（AQ）₂（L4）]·3CH₃OH（Ni-4）,[Ni（AQ）₂（L5）]·CH₃OH（Ni-5）,[Ni（AQ）₂（L6）]（Ni-6）,[Ni（AQ）₂（L7）]·2CH₃OH（Ni-7）and[Ni（AQ）₂（L8）]·3CH₃OH（Ni-8）with 2-amino-8-quinolinol（H-AQ）and 1,10-phenanthroline derivatives（4,7-dichloro-1,10-phenanthroline（L1）,5,5’-dimethyl-2,2’-bipyridine（L2）,5-chloro-1,10-phenanthroline（L3）,4,4’-dimethoxy-2,2’-bipyridine（L4）,5-amino-1,10-phenanthroline（L5）,1,10-phenanthroline（L6）,2,9-dimethylo-phenanthroline（L7）and 4,7-diphenyl-1,10-phenanthroline（L8））,have been synthesized and evaluated for their efficacy as anticancer drugs.The central atom Ni（Ⅱ）ion of complex Ni-1–Ni-8chelates with one N–N donor L1–L8 ligand and two deprotonation N–O donor AQ ligands to form a six coordinated octahedral configuration.All the Ni（Ⅱ）complexes Ni-1–Ni-8 were fully characterized by elemental analysis,infrared（IR）spectroscopy,electrospray ionization–mass spectrometry and X-ray crystallography.Among them,Ni-8 showed higher antineoplastic efficacy than H-AQ、L1–L8、Ni-1–Ni-7 and cisplatin against SK-OV-3/DDP cancer cells.In addition,the percentage of the SK-OV-3/DDP cells treated with Ni-6 and Ni-8 in the apoptosis was 17.62%and 18.25%.Furthermore,Ni-6and Ni-8 suppressed cancer cells by inducing mitochondrial dysfunction,and the inducibility followed the order:Ni-8>Ni-6.Overall,Ni-8 can also act as a new promising nickel（Ⅱ）-based antineoplastic drug candidate.3.Two Co-metal complexes,including[Co（Br Q）₃]（Co-1）,[Co（Q）₃]（Co-2）,with 5-Bromo-8-hydroxyquinoline（H-Br Q）and 8-Hydroxyquinoline（H-Q）,respectively,have been synthesized and evaluated for their efficacy as anticancer drugs.The chemical structures of complexes Co-1 and Co-2were characterized by IR,ESI-MS,single-crystal X-ray diffraction analyses.The Co（III）central atom in Co-1 and Co-2 presents a six-coordinated structure,and combines with three N-O donor deprotonated Br Q or Q ligands to form an octahedral geometry.CCK-8 assay showed that Co-1and Co-2 possess cytotoxicity against SK-OV-3/DDP cancer cells.They showed more effective activity and selectivity for SK-OV-3/DDP cancer cells,with IC₅₀ values of 0.27-9.57μM.The anti-tumor activity of Co-1 is higher than that of H-Br Q,H-Q,Co-2,and cisplatin.