A novel water-soluble Cu(II) gluconate complex inhibits cancer cell growth by triggering apoptosis and ferroptosis related mechanisms.

Metal copper complexes have attracted extensive attention as potential alternatives to platinum-based anticancer drugs due to their possible different modes of action. Herein, a new copper(II) gluconate complex, namely [Cu(DPQ)(Gluc)]·2H2O (CuGluc, DPQ = pyrazino[2,3-f][1,10]phenanthroline), with good water-solubility and high anticancer activity was synthesized by using D-gluconic acid (Gluc-2H) as an auxiliary ligand. The complex was well characterized by single-crystal X-ray diffraction analysis, elemental analysis, molar conductivity, and Fourier transform infrared spectroscopy (FTIR). The DNA-binding experiments revealed that CuGluc was bound to DNA by intercalation with end-stacking binding. CuGluc could oxidatively cleave DNA, in which 1O2 and H2O2 were involved. In addition, CuGluc was bound to the IIA subdomain of human serum albumin (HSA) through hydrophobic interaction and hydrogen bonding, showing a good affinity for HSA. The complex showed superior anticancer activity toward several cancer cells than cisplatin in vitro. Further studies indicated that CuGluc caused apoptotic cell death in human liver cancer (HepG2) cells through elevated intracellular reactive oxygen species (ROS) levels, mitochondrial dysfunction, cell cycle arrest, and caspase activation. Interestingly, CuGluc also triggered the ferroptosis mechanism through lipid peroxide accumulation and inhibition of glutathione peroxidase 4 (GPX4) activity. More importantly, CuGluc significantly inhibited tumor growth in vivo, which may benefit from the combined effects of apoptosis and ferroptosis. This work provides a promising strategy to develop highly effective antitumor copper complexes by coordinating with the glucose metabolite D-gluconic acid and exploiting the synergistic effects of apoptosis and ferroptosis mechanisms.

Synthesis, characterization and biological activity of novel copper complexes containing a ß-carboline derivative and amino acids.

Copper complexes have long been considered as a promising class of anticancer or antibacterial therapeutics. In this paper, two novel copper(II) complexes containing a ß-carboline derivative and amino acids, namely [Cu(1-Im-ßc)(L-Val)]ClO4·0.5H2O (Cu1) and [Cu(1-Im-ßc)(L-Phe)]ClO4·0.5H2O (Cu2), where 1-Im-ßc = 1-(2-imidazolyl)-ß-carboline, L-Val = L-valine, and L-Phe = L-phenylalanine, were designed and synthesized. The complexes were characterized by elemental analysis, infrared spectroscopy, molar conductivity measurements, and mass spectrometry to determine their spatial structures and compositions. Both complexes bind to DNA by insertion. The complexes also show a good affinity for human serum albumin (HSA). In addition, the antitumor activity of the two complexes against lung cancer cells (A549), cervical cancer cells (HeLa), and breast cancer cells (MBA-MD-231) is significantly superior to that of the traditional antitumor drug, cisplatin. Finally, the anticancer mechanism results show that the complexes can induce apoptosis in HeLa cells, which is associated with mitochondrial damage, oxidative stress caused by reactive oxygen species (ROS) production, and activation of the caspase protein family. This study demonstrates that the introduction of aromatic heterocyclic alkaloid ligands with a broad spectrum of biological activities and water-soluble amino acid ligands into copper complexes can regulate their amphiphilic properties and biological activity, so as to obtain highly efficient copper-based therapeutics.

Synthesis, structural studies, interaction with DNA/HSA and antitumor evaluation of new Cu(II) complexes containing 2-(1H-imidazol-2-yl)pyridine and amino acids.

Copper complexes are considered as potential candidates for anticancer therapy and medical applications. In this paper, three new Cu(II) complexes, [Cu(IPY)2](ClO4)2·H2O (CuI1), [Cu(IPY)(L-Phe)H2O]ClO4·0.5H2O (CuI2) and [Cu(IPY)(L-Val)H2O]ClO4 (CuI3) (where IPY = 2-(1H-imidazol-2-yl)pyridine, L-Phe = L-phenylalanine, and L-Val = L-valine), with good amphipathic properties were synthesized and characterized. Their single crystal X-ray diffraction results revealed that CuI1 was four-coordinated, while CuI2 and CuI3 both adopted a five-coordinated tetragonal pyramidal configuration. Multi-spectral methods, viscosity experiment and molecular docking technique showed that the three complexes interacted with DNA through insertion. The results of the gel electrophoresis experiments indicated that DNA was oxidatively cleaved by all the complexes in a concentration-dependent manner. Moreover, singlet oxygen (1O2), hydrogen peroxide (H2O2) and superoxide anion radicals (˙O2-) were associated with the oxidative cleavage of DNA. All the complexes also had good binding affinity with human serum albumin (HSA). The MB degradation assay revealed that all complexes could react with H2O2 to form ˙OH through Fenton-like processes. The complexes displayed good antiproliferative activity against the tested human cancer cells in vitro, including cervical carcinoma cells (HeLa), liver cancer cells (HepG2 and BEL-7402) and gastric adenocarcinoma cells (SGC-7901), but showed lower toxicity to normal liver cells (LO2). The anticancer mechanism research revealed that CuI1, CuI2 and CuI3 arrested the cell cycle at the S phase, elevated intracellular reactive oxygen species (ROS) levels and induced loss of mitochondrial membrane potential (MMP). The results indicated that these Cu(II) complexes could induce DNA damage and ROS-mediated mitochondrial dysfunction, leading to cancer cell apoptosis. Our work provides a theoretical basis for the design of new low-toxicity and highly efficient anticancer Cu(II) complexes by incorporating biological metabolites and aromatic heterocyclic ligands.

Sparfloxacin - Cu(II) - aromatic heterocyclic complexes: synthesis, characterization and in vitro anticancer evaluation.

Two new copper(II) complexes of sparfloxacin (sf), [Cu(Hsf)(HPB)(H2O)](ClO4)2 (1) and [Cu(Hsf)(PBT)(H2O)](ClO4)2 (2) (where HPB = 2-(2'-pyridyl)benzimidazole and PBT = 2-(4'-pyridyl) benzothiazole), have been synthesized and characterized by physicochemical and spectroscopic techniques. The oil-water partition coefficient (log P) values of complexes 1 and 2 were 1.47 and 1.71, respectively. By studying the interaction between the complexes and DNA, it was found that the complexes could bind to DNA through an intercalation mode. Moreover, both complexes were evaluated for antitumor activity, revealing that the complexes displayed good inhibitory activity toward the tested cancer cell lines (human lung carcinoma A549 cells, human hepatocellular carcinoma Bel-7402 cells and human esophageal carcinoma Eca-109 cells), but showed relatively low toxicity against normal human hepatic LO2 cells. In particular, the antitumor mechanism of the complexes on Eca-109 cells was investigated by morphological analysis, apoptosis analysis and determination of cell cycle arrest, mitochondrial membrane potential, reactive oxygen species (ROS) levels, and release of cytochrome c and Ca2+. The results demonstrated that the complexes could induce loss of intracellular mitochondrial functions and increase of ROS levels, which led to an increase of Ca2+ levels and the release of cytochrome c into the cytoplasm. In addition, the cell cycle was arrested in the G2/M phase, and western blot analysis showed that the caspase family was activated. These results fully proved that the complexes could induce apoptosis through DNA damage and loss of mitochondrial functions, accompanied by the regulation of endogenous proteins.

Synthesis, DNA binding, antibacterial and anticancer properties of two novel water-soluble copper(II) complexes containing gluconate.

In this paper, two new Cu(II) complexes, [Cu(Gluc)(HPB)(H2O)]Gluc (CuG1) and [Cu(Gluc)(HPBC)(H2O)]Gluc (CuG2) (where HPB = 2-(2'-pyridyl)benzimidazole, HPBC = 5-chloro-2-(2'-pyridyl)benzimidazole, Gluc = d-Gluconic acid), with good water solubility were synthesized and characterized. These complexes exhibited a five-coordinated tetragonal pyramidal geometry. The DNA binding and cleavage properties of the complexes were investigated using multi-spectroscopy, viscosity measurement, molecular docking and gel electrophoresis analysis methods. The results showed that the complexes could interact with DNA by insertion and groove binding, and cleave CT-DNA through a singlet oxygen-dependent pathway in the presence of ascorbic acid. The studies on antibacterial and anticancer activities in vitro demonstrated that both complexes had good inhibitory activity against three Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, Listeria monocytogenes) and one Gram-negative bacterium (Escherichia coli) and good cytotoxic activity toward the tested cancer cells (A549, HeLa and SGC-7901). CuG2 showed higher antimicrobial and cytotoxic activities than CuG1, which was consistent with their binding strength and cleavage ability to DNA, indicating that their antimicrobial and cytotoxic activities may be related to the DNA interaction. Moreover, the cell-based mechanism studies have indicated that CuG1 and CuG2 could arrest the cell cycle at G2/M phase, elevate the levels of intracellular reactive oxygen species (ROS) and decrease the mitochondrial membrane potential (MMP). The results showed that the complexes could induce apoptosis through DNA-damaged and ROS-mediated mitochondrial dysfunction pathways. Finally, the in vivo antitumor study revealed that CuG2 inhibited tumor growth by 50.44%, which is better than that of cisplatin (40.94%).