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.

• Keywords
• ROS, cell cycle, copper(II) complexes, in vitro cytotoxicity, inflammation, nuclease activity, pomiferin,
• MeSH
• Anti-Inflammatory Agents pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Benzopyrans chemistry   pharmacology   MeSH
• Flavonoids metabolism   pharmacology   MeSH
• Isoflavones chemistry   pharmacology   MeSH
• Coordination Complexes chemistry   pharmacology   MeSH
• Humans MeSH
• Copper chemistry   metabolism   pharmacology   MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Inflammatory Agents MeSH
• Benzopyrans MeSH
• Flavonoids MeSH
• Isoflavones MeSH
• Coordination Complexes MeSH
• Copper MeSH
• pomiferin MeSH Browser
• Antineoplastic Agents MeSH
• Reactive Oxygen Species MeSH

A series of sixteen ring-substituted N-arylcinnamanilides, previously described as highly antimicrobially effective against a wide spectrum of bacteria and fungi, together with two new derivatives from this group were prepared and characterized. Moreover, the molecular structure of (2E)-N-(2-bromo-5-fluorophenyl)-3-phenylprop-2-enamide as a model compound was determined using single-crystal X-ray analysis. All the compounds were tested for their anti-inflammatory potential, and most tested compounds significantly attenuated the lipopolysaccharide-induced NF-κB activation and were more potent than the parental cinnamic acid. (2E)-N-[2-Chloro-5-(trifluoromethyl)phenyl]-3-phenylprop-2-enamide, (2E)-N-(2,6-dibromophenyl)- 3-phenylprop-2-enamide, and (2E)-N-(2,5-dichlorophenyl)-3-phenylprop-2-enamide demonstrated the highest inhibition effect on transcription factor NF-κB at the concentration of 2 µM and showed a similar effectiveness as the reference drug prednisone. Several compounds also decreased the level of TNF-α. Nevertheless, subsequent tests showed that the investigated compounds affect neither IκBα level nor MAPKs activity, which suggests that the N-arylcinnamanilides may have a different mode of action to prednisone. The modification of the C(2,5)' or C(2,6)' positions of the anilide core by rather lipophilic and bulky moieties seems to be preferable for the anti-inflammatory potential of these compounds.

• Keywords
• X-ray structure, anti-inflammatory potential, cinnamamides, polypharmacology,
• MeSH
• Anti-Inflammatory Agents chemical synthesis   chemistry   pharmacology   MeSH
• Cinnamates chemical synthesis   chemistry   pharmacology   MeSH
• Crystallography, X-Ray MeSH
• Humans MeSH
• Lipopolysaccharides adverse effects   MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• NF-kappa B metabolism   MeSH
• Gene Expression Regulation drug effects   MeSH
• Signal Transduction drug effects   MeSH
• THP-1 Cells MeSH
• Tumor Necrosis Factor-alpha metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Inflammatory Agents MeSH
• Cinnamates MeSH
• Lipopolysaccharides MeSH
• NF-kappa B MeSH
• TNF protein, human MeSH Browser
• Tumor Necrosis Factor-alpha MeSH