Tamara R. Todorović

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.

Synthesis, structure and characterization of novel Cd(II) and Zn(II) complexes with the condensation product of 2-formylpyridine and selenosemicarbazide Antiproliferative activity of the synthesized complexes and related selenosemicarbazone complexes.

Two novel Cd(II) and Zn(II) complexes with the condensation product of 2-formylpyridine and selenosemicarbazide were synthesized. The structure of Cd(II) complex was determined by X-ray crystallography. The ligand is coordinated in a neutral form via pyridine and azomethine nitrogen atoms and the selenium donor. The cadmium ion completes its five-coordination by two chloride ligands, forming a square-pyramidal geometry. The structure of Zn(II) complex was established by analysis of spectroscopic data, which indicated coordination of the ligand as a bidentate via the selenium and the azomethine nitrogen atoms. The cytotoxic activity of the newly synthesized complexes, as well as if five structurally related complexes and the ligand evaluated against eight tumor cell lines. The new Cd(II) complex showed the highest activity similar to cisplatin with IC50 less than 10muM for all cell lines. Cell cycle distribution and apoptosis study showed that Cd(II) complex and cisplatin might have some similarity in anticancer activity, which was not the case for cisplatin and other studied complexes. Effects of the complexes on matrix metalloproteinases (MMPs) MMP-9 and MMP-2 was also studied. Cd(II) and Zn(II) complexes and cisplatin increased MMP-2 activity in supernatants of tested cells, while Ni(II) complex with the same ligand decreased the activity, implying a possible activity in preventing tumor invasion and metastasis processes.

Non-substituted N-heteroaromatic selenosemicarbazone metal complexes induce apoptosis in cancer cells via activation of mitochondrial pathway

We previously published the synthesis, characterization and cytotoxic effect of the novel Zn(II), Ni(II), and Cd(II) complexes with 2-formylpyridine selenosemicarbazone. Here we further investigate the mechanism of their antiproliferative activity against several cancer and vascular endothelial cell lines and compared it to the activity of the ligand itself, corresponding salts and, as a referent compound, cisplatin. Investigated complexes induced apoptosis in a time- and dose-dependent manner as well as changes in a cell cycle distribution. Caspase-3 activation in HeLa cells, MDA-MB-361 and vascular endothelial cells EA.hy 926 cells by ligand alone, as well as Zn(II), Ni(II), and Cd(II) complexes was preceded by the activation of the p53 tumor-suppressor gene family protein p73. In addition to activation of p73, these compounds also trigger cytochrome C release by upregulation of Bax expression. The release of cytochrome C has been linked to loss of mitochondrial membrane potential. However, our data indicated that the increased phosphorylation of ERK could be also one of the mechanism involved in the Zn(II), and Cd(II) complexes- induction of apoptosis. Selenosemicarbazone complexes with Cd(II) and Ni(II), possess dual ability to induce apoptosis as well as necrosis, and might present an added advantage for inducing cell death in a diverse array of malignant cells. Taken together, our findings could indicate potential role of these complexes as activator of cross-talk between different signaling pathways that leads to cell death, and thus making the complex intriguing field for further scientific, and maybe clinical investigations.

Zn(II) complex with 2-quinolinecarboxaldehyde selenosemicarbazone: synthesis, structure, interaction studies with DNA/HSA, molecular docking and caspase-8 and -9 independent apoptose induction

A new Zn(II)-based potential chemotherapeutic agent was synthesized from the ligand 2-quinolinecarboxaldehyde selenosemicarbazone (Hqasesc). Single crystal X-ray diffraction analysis showed that the Zn(II) complex consists of a cation [Zn(Hqasesc)2]2+, two perchlorate anions and one ethanol solvent molecule. The interaction of calf thymus (CT) DNA and human serum albumin (HSA) with the Zn(II) complex was explored using absorption and emission spectral methods, and also has been supported by molecular docking studies. The complex has more affinity to minor DNA groove than major, with no significant intercalation. The HSA interaction studies of the complex revealed the quenching of the intrinsic fluorescence of the HSA through a static quenching mechanism. The antitumor activity of the ligand and the complex against pancreatic adenocarcinoma cell line (AsPC-1) and acute monocytic leukemia (THP-1) cells was evaluated. Both compounds are strong concentration-dependent apoptosis inducers in THP-1 cells. While Hqasesc in AsPC-1 cells induces apoptosis only at the highest concentration, treatment with the Zn complex shows a concentration-dependent apoptotic response, where the treated cells are arrested in the G1-to-S phase accompanied with extensive activation of caspase-8 and -9. These results indicate that the ligand and Zn(II) complex display cell phenotype specific activity.

Biological activity of two isomeric N-heteroaromatic selenosemicarbazones and their metal complexes

AbstractNew square-planar Pd(II) and Pt(II) complexes with 8-quinolinecarboxaldehyde selenosemicarbazone have been synthesized and characterized by use of elemental analysis, molar conductivity measurements, and IR and NMR spectroscopy. The cytotoxic activity of the ligand, new Pt(II) and Pd(II) compounds, and previously synthesized Pd(II), Pt(II), Cd(II), and Ni(II) complexes with the analogous ligand, 2-quinolinecarboxaldehyde selenosemicarbazone, was tested against two human cancer cell lines: lung carcinoma (H460) and glioma (U251). The potential of these compounds to induce perturbations of the H460 cell cycle was also evaluated. These substances had an excellent radical-scavenging effect against ABTS radical cations. The best antimicrobial activity, among two yeasts and eight bacterial strains tested, was against Bacillus cereus.Graphical Abstract

Palladium(II) complexes with N-heteroaromatic bidentate hydrazone ligands: the effect of the chelate ring size and lipophilicity on in vitro cytotoxic activity.

Novel Pd(II) complex with N‐heteroaromatic Schiff base ligand, derived from 8‐quinolinecarboxaldehyde (q8a) and ethyl hydrazinoacetate (haOEt), was synthesized and characterized by analytical and spectroscopy methods. The structure of novel complex, as well as structures of its quinoline and pyridine analogues, was optimized by density functional theory calculations, and theoretical data show good agreement with experimental results. A cytotoxic action of the complexes was evaluated on cultures of human promyelocytic leukemia (HL‐60), human glioma (U251), rat glioma (C6), and mouse fibrosarcoma (L929) cell lines. Among investigated compounds, only complexes with quinoline‐based ligands reduce the cell numbers in a dose‐dependent manner in investigated cell lines. The observed cytotoxic effect of two isomeric quinoline‐based complexes is predominantly mediated through the induction of apoptotic cell death in HL‐60 cell line. The cytotoxicity of most efficient novel Pd(II) complex is comparable to the activity of cisplatin, in all cell lines investigated.

A comparative study of in vitro cytotoxic, antioxidant, and antimicrobial activity of Pt(II), Zn(II), Cu(II), and Co(III) complexes with N-heteroaromatic Schiff base (E)-2-[N'-(1-pyridin-2-yl-ethylidene)hydrazino]acetate.

In search for novel biologically active metal based compounds, an evaluation of in vitro cytotoxic, antioxidant, and antimicrobial activity of new Pt(II) complex and its Zn(II), Cu(II), and Co(III) analogues, with NNO tridentately coordinated N‐heteroaromatic Schiff base ligand (E)‐2‐[N′‐(1‐pyridin‐2‐yl‐ethylidene)hydrazino]acetate, was performed. Investigation of antioxidative properties showed that all of the compounds have strong radical scavenging potencies. The Zn(II) complex showed potent inhibition of DNA cleavage by hydroxyl radical. A cytotoxic action of investigated compounds was evaluated on cultures of human promyelocitic leukaemia (HL‐60), human glioma (U251), rat glioma (C6), and mouse melanoma (B16) cell lines. It was shown that binuclear pentacoordinated Zn(II) complex possesses a strong dose‐dependent cytotoxic activity, of the same order of magnitude as cisplatin on B16, C6, and U251 cells. Furthermore, Zn(II) complex causes oxidative stress‐induced apoptotic death of HL‐60 leukemic cells, associated with caspase activation, phosphatidylserine externalization, and DNA fragmentation.

Ru(III) complexes derived from N -methyl derivatives of glycine and 1,3-propylenediamine- N , N ′-diacetato ligands and their activities against HeLa, K562 cell lines and human PBMC

Ruthenium(III) complexes formulated as K2[Ru(sar)Cl4]·H2O and K[Ru(dmgly)2Cl2]·3H2O containing bidentate chelates N-methylglycine (sarcosine, sar) or N,N-dimethylglycine (dmgly) as well as K[Ru(pdda)Cl2]·2.5H2O complex with tetradentate 1,3-propylenediamine-N,N′-diacetato were synthesized. The complexes were obtained by direct reaction of ruthenium(III) chloride with the corresponding bidentate or tetradentate ligand followed by addition of a base (KOH). These new complexes were characterized by elemental analysis, IR and electronic absorption spectroscopy. To assess selectivity in the antitumor action of these complexes, their antiproliferative activities against human adenocarcinoma HeLa cells, human myelogenous leukemia K562 cells, human breast carcinoma MDA-MB-361 and MDA-MB-453 cells and normal immunocompetent PBM cells were determined.

Synthesis, Characterization and Biological Activity Evaluation of Novel Pd(II) and Pt(II) Complexes with Heterocyclic Hydrazone Ligands

New complexes of Pt(II) with condensation derivatives of ethyl hydrazinoacetate and either 2-acetylpyridine or 2-quinolinecarboxaldehyde, and of Pd(II) with the condensation derivative of ethyl hydrazinoacetate and 2-quinolinecarboxaldehyde were synthesized and characterized by elemental analysis, IR, 1H- and 13C-NMR spectroscopy, and molar conductivity measurements. The complexes have a square planar geometry, ligands binding as bidentates in the neutral form, and the remaining two coordination sites being occupied by chloride ions. Biological activity of new complexes, and of previously synthesized Pd(II), Cd(II), Co(III) and Zn(II) complexes with this ligand type was evaluated by the brine shrimp test. All the complexes showed a moderate activity.

Synthesis, characterization, DFT calculations, and antimicrobial activity of Pd(II) and Co(III) complexes with the condensation derivative of 2-(diphenylphosphino)benzaldehyde and Girard’s T reagent

Complexes of Pd(II) and Co(III) with the condensation derivative of 2-(diphenylphosphino)benzaldehyde and Girard T reagent were synthesized, characterized, and their antimicrobial activities were evaluated. The ligand and the complexes were characterized by elemental analysis, IR and NMR spectroscopies, and X-ray crystallography. In both complexes, the deprotonated ligand was coordinated to the metal through the phosphorus, the imine nitrogen, and the carbonyl oxygen atoms. In the octahedral Co(III) complex, two molecules of ligands were coordinated to metal ion, while square-planar environment of Pd(II) complex was constituted of one tridentate ligand and chloride in the fourth coordination place. The ligand and complexes showed moderate antibacterial activity. The molecular structures of the obtained metal complexes and the relative stabilities of two stereoisomers of the ligand were calculated using density functional theory at the S12g/TZ2P level. Graphical Abstract