Nevenka Gligorijević

Synthesis and characterization of new Pt(II) and Pd(II) complexes with 2-quinolinecarboxaldehyde selenosemicarbazone: Cytotoxic activity evaluation of Cd(II), Zn(II), Ni(II), Pt(II) and Pd(II) complexes with heteroaromatic selenosemicarbazones

New complexes of Pt(II) and Pd(II) with 2-quinolinecarboxaldehyde selenosemicarbazone were synthesized and characterized by elemental analysis, NMR and IR spectroscopy and molar conductivity measurements. The assumed geometry of Pt(II) and Pd(II) complexes was square planar where the ligand was tridentately coordinated via the quinoline and imine nitrogen atoms and the selenium atom. The cytotoxic activity of the new Pt(II) and Pd(II) compounds, as well as of some previously synthesized Cd(II), Zn(II) and Ni(II) complexes with the same or analogous ligand, was tested against a panel of three human cancer cell lines: human cervix carcinoma cells (HeLa), human melanoma cells (FemX) and breast cancer cells (MDA-361). All investigated compounds, except Pt(II) complex, possess a strong dose-dependent cytotoxic activity of the same order of magnitude as cisplatin (CDDP). The investigation of potential of these compounds to induce HeLa cell cycle perturbations was also evaluated.

Picolinate ruthenium(II)–arene complex with in vitro antiproliferative and antimetastatic properties: Comparison to a series of ruthenium(II)–arene complexes with similar structure

In our previous study, ruthenium(II)-p-cymene complexes of general formula [(η(6)-p-cymene)Ru(L)Cl2], L: 3-acetylpyridine (1), 2-amino-5-chloropyridine (2); and [(η(6)-p-cymene)Ru(HL)Cl], HL: 2,3-pyridinedicarboxylic acid (3), 2,4-pyridinedicarboxylic acid (4), revealed low antiproliferative activity, except complex [(η(6)-p-cymene)RuCl(picolinic acid)]·H(2)O (5) which exhibited IC(50) around 80 μM. In this study we further investigated in vitro potential of antimetastatic action of ruthenium complexes on HeLa and two endothelial cell lines. Comparison of structure and activity of five complexes indicated heterogenic mode of activity, with regard to the potential of antimetastatic and antiproliferative effect. Replacement of substituted pyridine ligand with picolinic acid (complex 5) around Ru(II) center contributed to complex cytotoxicity and ruthenium DNA binding affinity. Analysis of ruthenium(II) accumulation in DNA and protein fractions of HeLa cells, using ICP-OES revealed significantly higher content of complex 5 in DNA fraction in comparison to the other tested compounds. It also altered cell cycle progression, affected expression of DNA repair enzymes ERCC1 and MSH2, and showed enhanced activity in combination with 3-aminobenzamide. Regardless of their effect on cell growth, Ru(II) complexes exerted antimetastatic effect on several tumor cell lines in vitro, achieved mostly by the effect on cell adhesion, migration and angiogenesis, while picolinate ruthenium(II)-arene additionally exerted inhibitory effect on extracellular matrix degradation.

Synthesis, characterization and biological activity of three square-planar complexes of Ni(II) with ethyl (2E)-2-[2-(diphenylphosphino)benzylidene]hydrazinecarboxylate and monodentate pseudohalides.

Three square-planar complexes of nickel(II) with the tridentate condensation derivative of 2-(diphenylphosphino)benzaldehyde and ethyl carbazate, and monodentate pseudohalides, have been synthesized. Their crystal structures have been determined. All the complexes showed a significant antifungal activity, while only the azido complex displayed antibacterial activity. All the complexes were cytotoxic to a panel of six tumor cell lines, the azido complex showing a similar activity as cisplatin to leukemia cell line K562 and lower toxicity to normal MRC-5 cells than that anticancer agent. The complexes interfered with cell cycle of tumor cells and induced plasmid DNA cleavage.

Antiproliferative activity and QSAR studies of a series of new 4-aminomethylidene derivatives of some pyrazol-5-ones.

Twenty five 4-aminomethylidene derivatives obtained from 3-phenyl-2-pyrazolin-5-one and 1,3-diphenyl-2-pyrazolin-5-one were synthesized and tested for their antiproliferative activity against human breast cancer MDA-MB-361 and MDA-MB-453 cell lines. The compounds derived from 1,3-diphenyl-2-pyrazolin-5-one exhibited the most remarkable activity in the treatment of both cell lines. In vitro antiproliferative activities were accompanied by an important apoptotic fraction of both cell lines; also, compounds inhibited key endothelial cell functions implicated in invasion and angiogenesis. QSAR methods were performed in order to analyze the influence of structural features of the compounds investigated on the antiproliferative potential on MDA-MB-361 and MDA-MB-453 cancer cells. One-parameter heuristic analysis was performed and different whole molecule and fragmental descriptors were considered for rationalization of mechanism of interaction of these compounds with active place of hypothetical target included in tumorigenesis.

Synthesis, characterization, DFT calculation and biological activity of square-planar Ni(II) complexes with tridentate PNO ligands and monodentate pseudohalides. Part II.

Three square-planar complexes of Ni(II) with condensation derivative of 2-(diphenylphosphino)benzaldehyde and 4-phenylsemicarbazide and monodentate pseudohalides have been synthesized and characterized on the basis of the results of X-ray, NMR and IR spectroscopy and elemental analysis. Investigated complexes exhibited moderate antibacterial and cytotoxic activity. The most pronounced cytotoxic activity (in the range of cisplatin) to HeLa cell line was observed for ligand and all the complexes. Azido complex and ligand induced concentration dependent cell cycle arrest in the S phase, as well as decrease of percentage of cells in G1 phase, without significant increase of apoptotic fraction of cells. The interaction of the azido complex and ligand with CT-DNA results in changes in UV-Vis spectra typical for non-covalent bonding. The observed intrinsic binding constant of azido complex-CT-DNA and ligand-CT-DNA were 3.22 × 10(5) M(-1) and 2.79 × 10(5) M(-1). The results of DNA cleavage experiments showed that azido complex nicked supercoiled plasmid DNA.

Investigation of antitumor potential of Ni(II) complexes with tridentate PNO acylhydrazones of 2-(diphenylphosphino)benzaldehyde and monodentate pseudohalides

Square-planar azido Ni(II) complex with condensation product of 2-(diphenylphosphino)benzaldehyde and Girard’s T reagent was synthesized and its crystal structure was determined. Cytotoxic activity of the azido complex and previously synthesized isothiocyanato, cyanato and chlorido Ni(II) complexes with this ligand was examined on six tumor cell lines (HeLa, A549, K562, MDA-MB-453, MDA-MB-361 and LS-174) and two normal cell line (MRC-5 and BEAS-2B). All the investigated nickel(II) complexes were cytotoxic against all tumor cell lines. The newly synthesized azido complex showed selectivity to HeLa and A549 tumor cell lines compared to the normal cells (for A549 IC50 was similar to that of cisplatin). Azido complex interferes with cell cycle phase distribution of A549 and HeLa cells and possesses nuclease activity towards supercoiled DNA. The observed selectivity of the azido complex for some tumor cell lines can be connected with its strong DNA damaging activity.

Cell cycle, apoptosis, cellular uptake and whole-transcriptome microarray gene expression analysis of HeLa cells treated with a ruthenium(II)-arene complex with an isoquinoline-3-carboxylic acid ligand.

Ruthenium(II)-arene complexes are promising drug candidates for the therapy of solid tumors. In previous work, seven new compounds of the general formula [Ru(η6-p-cymene)(L1-7)Cl] were synthesized and characterized, of which the complex with L=isoquinoline-3-carboxylic acid (RuT7) was two times as active on HeLa cells compared to normal cell line MRC-5, as indicated by IC50 values determined after 48h of incubation (45.4±3.0 vs. 84.2±5.7μM, respectively). In the present study, cell cycle analysis of HeLa cells treated with RuT7 showed S phase arrest and an increase in sub-G1 population. The apoptotic potential of the title compound was confirmed with the Annexin V-FITC/PI assay together with a morphological evaluation of cells using fluorescent microscopy. Analysis of the intracellular accumulation of ruthenium showed 8.9ng Ru/106 cells after 6h of incubation. To gain further insight in the molecular mechanism of action of RuT7 on HeLa cells, a whole-transcriptome microarray gene expression analysis was performed. Analysis of functional categories and signaling and biochemical pathways associated with the response of HeLa cells to treatment with RuT7 showed that it leads the cells through the intrinsic (mitochondrial) apoptotic pathway, via indirect DNA damage due to the action of reactive oxygen species, and through direct DNA binding of RuT7. Statistical analysis for enrichment of gene sets associated with known drug-induced toxicities identified fewer associated toxicity profiles in RuT7-treated cells compared to cisplatin treatment. Altogether these results provide the basis for further development of RuT7 in animal and pre-clinical studies as a potential drug candidate.

Antimicrobial synergism and cytotoxic properties of Citrus limon L., Piper nigrum L. and Melaleuca alternifolia (Maiden and Betche) Cheel essential oils

The chemical composition, antimicrobial and synergistic effect, and cytotoxic activity of Citrus limon (lemon), Piper nigrum (green pepper) and Melaleuca alternifoila (tea tree) essential oils (EOs) were investigated.

Ruthenium(II) bipyridine complexes: from synthesis and crystal structures to electrochemical and cytotoxicity investigation

Abstract Complexes 1–4, [Ru(L)(bpy)2]PF6, where bpy = 2,2′-bipyridine; HL = 3-methylpyridine-2-carboxylic acid (HL1), 6-methylpyridine-2-carboxylic acid (HL2), 5-bromopyridine-2-carboxylic acid (HL3) and 6-bromopyridine-2-carboxylic acid (HL4), were synthesized and characterized. The electrochemical character of the complexes was investigated by cyclic voltammetry revealing two reversible reduction waves in the negative range of potentials, most likely due to a reduction of the bipyridine moiety. Cytotoxicity studies by MTT assay for 72 h of drug action revealed that 2–4 exhibited moderate activity in cervical human tumor cells (HeLa). Complex 2 exhibited low activity in colon cancer LS-174 cells (180 ± 10), while all complexes were devoid of activity in lung cancer A549 and non-tumor MRC-5 cells, up to 200 μM. Combinational studies of the most active complex 2, with pharmacological modulators of cell redox status, L-buthionine-sulfoximine (L-BSO) or N-acetyl-L-cysteine (NAC), showed that when L-BSO potentiated, 2 induced a sub-G1 peak of the cell cycle in the HeLa cell line. UV–vis and cyclic voltammetry were performed in order to investigate the binding mode of 2 to DNA and suggested intercalation for the complex–DNA interaction.

Biological evaluation of transdichloridoplatinum( II) complexes with 3- and 4-acetylpyridine in comparison to cisplatin

Abstract Background. In our previous study we reported the synthesis and cytotoxicity of two trans-platinum(II) complexes: trans-[PtCl2(3-acetylpyridine)2] (1) and trans-[PtCl2(4-acetylpyridine)2] (2), revealing significant cytotoxic potential of 2. In order to evaluate the mechanism underlying biological activity of both trans-Pt(II) isomers, comparative studies versus cisplatin were performed in HeLa, MRC-5 and MS1 cells. Materials and methods. The cytotoxic activity of the investigated complexes was determined using SRB assay. The colagenolytic activity was determined using gelatin zymography, while the effect of platinum complexes on matrix metalloproteinases 2 and 9 mRNA expression was evaluated by quantitative real-time PCR. Apoptotic potential and cell cycle alterations were determined by FACS analyses. Western blot analysis was used to evaluate the effect on expression of DNA-repair enzyme ERCC1, and quantitative real-time PCR was used for the ERCC1 mRNA expression analysis. In vitro antiangiogenic potential was determined by tube formation assay. Platinum content in intracellular DNA and proteins was determined by inductively coupled plasma-optical emission spectrometry. Results. Compound 2 displayed an apparent cytoselective profile, and flow cytometry analysis in HeLa cells indicated that 2 exerted antiproliferative effect through apoptosis induction, while 1 induced both apoptosis and necrosis. Action of 1 and 2, as analyzed by quantitative real-time PCR and Western blot, was associated with down-regulation of ERCC1. Both trans-complexes inhibited MMP-9 mRNA expression in HeLa, while 2 significantly abrogated in vitro tubulogenesis in MS1 cells. Conclusions. The ability of 2 to induce multiple and selective in vitro cytotoxic effects encourages further investigations of trans-platinum(II) complexes with substituted pyridines.