The effects of two anticancer active copper(II) mixed-ligand complexes of the type [Cu(qui)(mphen)]Y·H2O, where Hqui = 2-phenyl-3-hydroxy- 1H-quinolin-4-one, mphen = bathophenanthroline, and Y = NO3 (complex 1) or BF4 (complex 2) on the activities of different isoenzymes of cytochrome P450 (CYP) have been evaluated. The screening revealed significant inhibitory effects of the complexes on CYP3A4/5 (IC50 values were 2.46 and 4.88 μM), CYP2C9 (IC50 values were 16.34 and 37.25 μM), and CYP2C19 (IC50 values were 61.21 and 77.07 μM). Further, the analysis of mechanisms of action uncovered a non-competitive type of inhibition for both the studied compounds. Consequent studies of pharmacokinetic properties proved good stability of both the complexes in phosphate buffer saline (>96% stability) and human plasma (>91% stability) after 2 h of incubation. Both compounds are moderately metabolised by human liver microsomes (<30% after 1 h of incubation), and over 90% of the complexes bind to plasma proteins. The obtained results showed the potential of complexes 1 and 2 to interact with major metabolic pathways of drugs and, as a consequence of this finding, their apparent incompatibility in combination therapy with most chemotherapeutic agents.

• Keywords
• copper(II) complexes, cytochrome P450, isothermal titration calorimetry, quinolinonato derivatives,
• Publication type
• Journal Article MeSH

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 gold(I) complexes involving triphenylphosphine (PPh3) and one N-donor ligand derived from deprotonated mono- or disubstituted hypoxanthine (HLn) of the general composition [Au(Ln)(PPh3)] (1-9) is reported. The complexes were thoroughly characterized, including multinuclear high resolution NMR spectroscopy as well as single crystal X-ray analysis (for complexes 1 and 3). The complexes were screened for their in vitro cytotoxicity against human cancer cell lines MCF7 (breast carcinoma), HOS (osteosarcoma) and THP-1 (monocytic leukaemia), which identified the complexes 4-6 as the most promising representatives, who antiproliferative activity was further tested against A549 (lung adenocarcinoma), G-361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) cell lines. Complexes 4-6 showed a significantly higher in vitro anticancer effect against the employed cancer cells, except for G-361, as compared with the commercially used anticancer drug cisplatin, with IC50 ≈ 1-30 µM. Anti-inflammatory activity was evaluated in vitro by the assessment of the ability of the complexes to modulate secretion of the pro-inflammatory cytokines, i.e. tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), in the lipopolysaccharide-activated macrophage-like THP-1 cell model. The results of this study identified the complexes as auspicious anti-inflammatory agents with similar or better activity as compared with the clinically applied gold-based antiarthritic drug Auranofin. In an effort to explore the possible mechanisms responsible for the biological effect, the products of interactions of selected complexes with sulfur-containing biomolecules (L-cysteine and reduced glutathione) were studied by means of the mass-spectrometry study.

• MeSH
• Anti-Inflammatory Agents chemistry   pharmacology   toxicity   MeSH
• Cell Line MeSH
• Hypoxanthine chemistry   pharmacology   toxicity   MeSH
• Humans MeSH
• Macrophages drug effects   metabolism   MeSH
• Molecular Conformation MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Nuclear Magnetic Resonance, Biomolecular MeSH
• Organophosphorus Compounds chemistry   pharmacology   toxicity   MeSH
• Antineoplastic Agents chemistry   pharmacology   toxicity   MeSH
• Gold chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Inflammatory Agents MeSH
• Hypoxanthine MeSH
• Organophosphorus Compounds MeSH
• Antineoplastic Agents MeSH
• triphenylphosphine MeSH Browser
• Gold MeSH

A series of a new type of Schiff bases 1-7, derived from 2-phenyl-3-amino-4(1H)-quinolinone and R-salicyladehyde derivatives wherein R = 3-hydroxy (1), 3,4-dihydroxy (2), 3-methoxy (3), 3-carboxy (4), 3-allyl (5), 5-chloro (6), and 5-nitro (7), was synthesized and structurally characterized. Each of the molecules 1, 3 and 7 consists of three planar moieties (i.e., a quinolinone and two phenyl rings), which are mutually oriented differently depending on the appropriate substituent R and the extent of non-covalent contacts stabilizing the crystal structures. The compounds were studied for their fluorescence properties, where compound 6 yielded the strongest intensity both in the solid phase and in 100 μM ethanol solution with a quantum yield of φ = 3.6% as compared to quinine sulfate used as a standard. The in vitro cytotoxicity of these compounds was tested against the human osteosarcoma (HOS) and breast adenocarcinoma (MCF7) cell lines, revealing no activity up to the concentration of 50 µM.

• MeSH
• Quinolones chemistry   MeSH
• Spectrometry, Fluorescence MeSH
• Spectrometry, Mass, Electrospray Ionization MeSH
• Magnetic Resonance Spectroscopy MeSH
• Molecular Structure MeSH
• Schiff Bases chemistry   MeSH
• Spectroscopy, Fourier Transform Infrared MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Quinolones MeSH
• Schiff Bases MeSH

Kinetin (N6-furfuryladenine) belongs to a group of plant growth hormones involved in cell division, differentiation and other physiological processes. One of the possible ways to obtain biologically active compounds is to complex biologically relevant natural compounds to suitable metal atoms. In this work, two structural groups of Zn(II) complexes [Zn(L(n))2Cl2]·Solv (1-5) and [Zn(HL(n))Cl3] · xL(n) (6-7); n=1-5, Solv=CH3OH for 1 and 2H2O for 2; x =1 for 6 and 2 for 7; involving a phytohormone kinetin and its derivatives (L(n)) were evaluated for their ability to modulate secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and matrix metalloproteinase (MMP)-2 in a lipopolysaccharide (LPS)-activated macrophage-like THP-1 cell model. The penetration of the complexes to cells was also detected. The mechanism of interactions of the zinc(II) complexes with a fluorescent sensor N-(6-methoxy-8-quinolyl)-p-toluene sulphonamide (TSQ) and sulfur-containing biomolecules (l-cysteine and reduced glutathione) was studied by electrospray-ionization mass spectrometry and flow-injection analysis with fluorescence detection. The present study showed that the tested complexes exhibited a low cytotoxic effect on the THP-1 cell line (IC50>40 µM), apart from complex 4, with an IC50=10.9 ± 1.1 µM. Regarding the inflammation-related processes, the Zn(II) complexes significantly decreased IL-1β production by a factor of 1.47-2.22 compared with the control (DMSO), but did not affect TNF-α and MMP-2 secretions. However, application of the Zn(II) complexes noticeably changed the pro-MMP-2/MMP-2 ratio towards a higher amount of maturated MMP-2, when they induced a 4-times higher production of maturated MMP-2 in comparison with the vehicle-treated cells under LPS stimulation. These results indicated that the complexes are able to modulate an inflammatory response by influencing secretion and activity of several inflammation-related cytokines and enzymes.

• MeSH
• Macrophage Activation drug effects   MeSH
• Aminoquinolines MeSH
• Anti-Inflammatory Agents chemical synthesis   pharmacology   MeSH
• Biological Transport MeSH
• Chlorides chemistry   MeSH
• Cysteine chemistry   MeSH
• Gene Expression drug effects   MeSH
• Fluorescent Dyes MeSH
• Glutathione chemistry   MeSH
• Interleukin-1beta antagonists & inhibitors   genetics   metabolism   MeSH
• Cations, Divalent MeSH
• Kinetin chemistry   MeSH
• Coordination Complexes chemical synthesis   pharmacology   MeSH
• Humans MeSH
• Lipopolysaccharides pharmacology   MeSH
• Macrophages cytology   drug effects   metabolism   MeSH
• Matrix Metalloproteinase 2 genetics   metabolism   MeSH
• Cell Line, Tumor MeSH
• Tumor Necrosis Factor-alpha genetics   metabolism   MeSH
• Tosyl Compounds MeSH
• Cell Survival drug effects   MeSH
• Zinc chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Aminoquinolines MeSH
• Anti-Inflammatory Agents MeSH
• Chlorides MeSH
• Cysteine MeSH
• Fluorescent Dyes MeSH
• Glutathione MeSH
• Interleukin-1beta MeSH
• Cations, Divalent MeSH
• Kinetin MeSH
• Coordination Complexes MeSH
• Lipopolysaccharides MeSH
• Matrix Metalloproteinase 2 MeSH
• N-(6-methoxy-8-quinolyl)-4-toluenesulfonamide MeSH Browser
• Tumor Necrosis Factor-alpha MeSH
• Tosyl Compounds MeSH
• Zinc MeSH

BACKGROUND: Inspired by the unprecedented historical success of cisplatin, one of the most important research directions in bioinorganic and medicinal chemistry is dedicated to the development of new anticancer compounds with the potential to surpass it in antitumor activity, while having lower unwanted side-effects. Therefore, a series of copper(II) mixed-ligand complexes of the type [Cu(qui)(L)]Y · xH2O (1-6), where Hqui = 2-phenyl-3-hydroxy-4(1H)-quinolinone, Y = NO3 (1, 3, 5) or BF4 (2, 4, 6), and L = 1,10-phenanthroline (phen) (1, 2), 5-methyl-1,10-phenanthroline (mphen) (3, 4) and bathophenanthroline (bphen) (5, 6), was studied for their in vitro cytotoxicity against several human cancer cell lines (A549 lung carcinoma, HeLa cervix epitheloid carcinoma, G361 melanoma cells, A2780 ovarian carcinoma, A2780cis cisplatin-resistant ovarian carcinoma, LNCaP androgen-sensitive prostate adenocarcinoma and THP-1 monocytic leukemia). RESULTS: The tested complexes displayed a stronger cytotoxic effect against all the cancer cells as compared to cisplatin. The highest cytotoxicity was found for the complexes 4 (IC50 = 0.36 ± 0.05 μM and 0.56 ± 0.15 μM), 5 (IC50 = 0.66 ± 0.07 μM and 0.73 ± 0.08 μM) and 6 (IC50 = 0.57 ± 0.11 μM and 0.70 ± 0.20 μM) against A2780, and A2780cis respectively, as compared with the values of 12.0 ± 0.8 μM and 27.0 ± 4.6 μM determined for cisplatin. Moreover, the tested complexes were much less cytotoxic to primary human hepatocytes than to the cancer cells. The complexes 5 and 6 exhibited significantly high ability to modulate secretion of the pro-inflammatory cytokines TNF-α (2873 ± 238 pg/mL and 3284 ± 139 pg/mL for 5, and 6 respectively) and IL-1β (1177 ± 128 pg/mL and 1087 ± 101 pg/mL for 5, and 6 respectively) tested on the lipopolysaccharide (LPS)-stimulated THP-1 cells as compared with the values of 1173 ± 85 pg/mL and 118.5 ± 4.8 pg/mL found for the commercially used anti-inflammatory drug prednisone. The ability of the tested complexes to interact with sulfur-containing biomolecules (cysteine and reduced glutathione) at physiological levels was proved by electrospray-ionization mass spectrometry. CONCLUSIONS: Overall positive results of the biological activity studies revealed that the presented complexes may represent good candidates for non-platinum anticancer drugs, however, we are aware of the fact that further and deeper studies mainly in relation to the elucidation of their mechanisms of antiproliferative action will be necessary.

• Publication type
• Journal Article MeSH