Copper(II) Complexes Containing Natural Flavonoid Pomiferin Show Considerable In Vitro Cytotoxicity and Anti-inflammatory Effects

• Published in: International journal of molecular sciences Vol. 22; no. 14; p. 7626
• Main Authors: Vančo, Ján, Trávníček, Zdeněk, Hošek, Jan, Malina, Tomáš, Dvořák, Zdeněk
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 16.07.2021; MDPI
• Subjects: Adenocarcinoma; Annexin V; Antiproliferatives; Apoptosis; Biomedical materials; Breast cancer; Cell cycle; Cervix; Cisplatin; Colorectal carcinoma; Copper compounds; copper(II) complexes; Cytotoxicity; Flavonoids; Hepatocytes; in vitro cytotoxicity; Inflammation; Infrared analysis; Leukemia; Ligands; Lung cancer; Mass spectrometry; Mass spectroscopy; Melanoma; Membrane potential; Mimicry; Mitochondria; Monocytes; Monocytic leukemia; NF-κB protein; Nitrates; Nuclease; Osteosarcoma; Ovarian carcinoma; Ovaries; pomiferin; Prostate; ROS; Thermal analysis; Transcription factors; Tumor cell lines
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22147626

A series of new heteroleptic copper(II) complexes of the composition [Cu(L)(bpy)]NO3·2MeOH (1), [Cu(L)(dimebpy)]NO3·2H2O (2), [Cu(L)(phen)]NO3·2MeOH (3), [Cu(L)(bphen)]NO3·MeOH (4), [Cu(L)(dppz)]NO3·MeOH (5) was prepared, where HL = 3-(3,4-dihydroxyphenyl)-5-hydroxy-8,8-dimethyl-6-(3-methylbut-2-ene-1-yl)-4H,8H-benzo[1,2-b:3,4-b′]dipyran-4-one, (pomiferin) and bpy = 2,2′-bipyridine, dimebpy = 4,4′-dimethyl-2,2′-bipyridine, phen = 1,10-phenanthroline, bphen = 4,7-diphenyl-1,10-phenanthroline, and dppz = dipyrido[3,2-a:2′,3′-c]phenazine. The complexes were characterized using elemental analysis, infrared and UV/Vis spectroscopies, mass spectrometry, thermal analysis and conductivity measurements. The in vitro cytotoxicity, screened against eight human cancer cell lines (breast adenocarcinoma (MCF-7), osteosarcoma (HOS), lung adenocarcinoma (A549), prostate adenocarcinoma (PC-3), ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R), colorectal adenocarcinoma (Caco-2) and monocytic leukemia (THP-1), revealed the complexes as effective antiproliferative agents, with the IC50 values of 2.2–13.0 μM for the best performing complexes 3 and 5. All the complexes 1–5 showed the best activity against the A2780R cells (IC50 = 2.2–6.6 μM), and moreover, the complexes demonstrated relatively low toxicity on healthy human hepatocytes, with IC50 > 100 μM. The complexes were evaluated by the Annexin V/propidium iodide apoptosis assay, induction of cell cycle modifications in A2780 cells, production of reactive oxygen species (ROS), perturbation of mitochondrial membrane potential, inhibition of apoptosis and inflammation-related signaling pathways (NF-κB/AP-1 activity, NF-κB translocation, TNF-α secretion), and tested for nuclease mimicking activity. The obtained results revealed the corresponding complexes to be effective antiproliferative and anti-inflammatory agents.