Antiproliferative, antimigratory, and prooxidative potential of novel platinum(IV) complexes and resveratrol on breast cancer (MDA-MB-231) and choriocarcinoma (JEG-3) cell lines.

Platinum(IV) complexes offer the potential to overcome cisplatin resistance of cancer cells, with possible improved selectivity. Resveratrol, a natural polyphenol with anticancer and antioxidant capacity, could limit the possible side effects of chemotherapeutics on healthy cells. This study investigates the effects of platinum(IV) complexes containing some esters of the ethylenediamine-N,N'-di-S,S-(2,2'-dibenzyl)acetate acid (H2 -S,S-eddba), and resveratrol on proliferation, migration, and redox balance of breast cancer (MDA-MB-231), choriocarcinoma (JEG-3), and human lung fibroblast (MRC-5) cell line. According to IC50 values, all complexes exhibited a significantly stronger antiproliferative effect on tested cell lines compared to cisplatin. Due to reduced adverse effects on MRC-5 cells, the complex containing ethyl-substituent (10 µM) was selected for further examination with resveratrol (25 µM) cotreatment. Resveratrol enhanced the survival of MRC-5 cells while diminished the viability of both used cancer cell lines when applied combined with selected complex. Furthermore, cotreatment of these two compounds decreased the migratory potential of tested cancer cell lines. The examined platinum(IV) complex was able to induce oxidative stress in all tested cell lines. Resveratrol proved to be efficient in protecting MRC-5 cells from complex-induced oxidative damage, while it significantly amplified antiproliferative, antimigratory, and prooxidative effects of platinum(IV) complex on both examined cancer cell lines. These findings may be valuable in elucidating the mechanism of action of platinum(IV) drugs, which should be further investigated.

Newly synthesized palladium(II) complexes with dialkyl esters of (S,S)-propylenediamine-N,N'-di-(2,2'-di-(4-hydroxy-benzil))acetic acid: in vitro investigation of biological activities and HSA/DNA binding.

The four new ligands, dialkyl esters of (S,S)-propylenediamine-N,N'-di-(2,2'-di-(4-hydroxy-benzil))acetic acid (R2-S,S-pddtyr·2HCl) (R = ethyl (L1), propyl (L2), butyl (L3), and pentyl (L4)) and corresponding palladium(II) complexes have been synthesized and characterized by microanalysis, infrared, 1H NMR and 13C NMR spectroscopy. In vitro cytotoxicity was evaluated using the MTT assay on four tumor cell lines, including mouse mammary (4T1) and colon (CT26), and human mammary (MDA-MD-468) and colon (HCT116), as well as non-tumor mouse mesenchymal stem cells. Using fluorescence spectroscopy were investigated the interactions of new palladium(II) complexes [PdCl2(R2-S,S-pddtyr)]; (R = ethyl (C1), propyl (C2), butyl (C3), and pentyl (C4)) with calf thymus human serum albumin (HSA) and DNA (CT-DNA). The high values of the binding constants, Kb, and the Stern-Volmer quenching constant, KSV, show the good binding of all complexes for HSA and CT-DNA. The mentioned ligands and complexes were also tested on in vitro antimicrobial activity against 11 microorganisms. Testing was performed by the microdilution method, where the minimum inhibitory concentration (MMC) and the minimum microbicidal concentration (MMC) were determined.

Synthesis, characterization, HSA binding, molecular docking, cytotoxicity study, and antimicrobial activity of new palladium(II) complexes with propylenediamine derivatives of phenylalanine.

The four new ligands, propylenediamine derivatives of phenylalanine (R2-S,S-pddbaˑ2HCl; L1-L4) and their palladium(II) complexes (C1-C4) were synthesized and characterized by elemental analysis, infrared, 1H and 13C NMR spectroscopy. The interactions of new palladium(II) complexes with human serum albumin (HSA) were studied by fluorescence spectroscopy. All investigated compounds can be transported to target cells by binding to HSA, but complex C4 interacts most strongly. Molecular docking simulations were applied to comprehend the binding of the complex to the molecular target of HSA. Obtained results are in good correlations with experimental data regarding binding affinity by HSA. In vitro cytotoxicity activities were investigated on four tumor cell lines (mouse mammary (4 T1) and colon (CT26), human mammary (MDA-MD-468) and colon (HCT116)) and mouse mesenchymal stem cells as non-tumor control cells. Cytotoxic capacity was determined by MTT test and according to obtained results ligand L4 stands out as the most active and selective compound and as a good candidate for future in vivo testing. Further examination of the ligand L4 and corresponding complex C4 led to the conclusion that both induced cell death mainly by apoptosis. Ligand L4 facilitated cycle arrest in G0/G1 phase and decreased proliferative capacity of tumor cells. In vitro antimicrobial activity for ligands and corresponding Pd(II) complexes was investigated against eleven microorganisms (eight strains of pathogenic bacteria and three yeast species) using microdilution method. The minimum inhibitory concentration and minimum microbicidal concentration were determined.

Newly synthesized palladium(II) complexes with aminothiazole derivatives: in vitro study of antimicrobial activity and antitumor activity on the human prostate cancer cell line.

Five new complexes of the palladium(II) ion (C1-C5) having the general formula [(PdL2)]Cl2 with some 2-aminothiazoles (L1-L5), where L1 = 2-amino-4-(3,4-difluorophenyl)thiazole, L2 = 2-amino-5-methyl-4-phenylthiazole, L3 = 2-amino-4-phenylthiazole, L4 = 2-amino-4-(4-chlorophenyl)thiazole, and L5 = 2-amino-4-(2,4-difluorophenyl)thiazole, have been synthesized and characterized by elemental microanalysis and infrared, 1H NMR and 13C NMR spectroscopy. The in vitro antimicrobial activity of the five ligands and the corresponding Pd(II) complexes is investigated. Testing is performed by the microdilution method and the minimum inhibitory concentration (MIC) and minimum microbicidal concentration (MMC) have been determined. Testing is conducted against 11 microorganisms (nine strains of pathogenic bacteria and two yeast species). The tested ligands and palladium(II) complexes show selective, high and moderate activity. There is a difference in antimicrobial activity between the ligands and the corresponding palladium(II) complexes. The complexes have significant anti-staphylococcal activity and activity on Pseudomonas aeruginosa which is better than the positive control. The interactions of newly synthesized palladium(II) complexes with calf thymus DNA (CT-DNA) were investigated using UV-Vis absorption and fluorescence spectroscopy. Analysis of UV-absorption and fluorescence spectra indicates the formation of a complex between the palladium(II) complexes and DNA. The high values of intrinsic binding constants, Kb, of the order 104 M-1 and Stern-Volmer quenching constants, KSV, of the order 105 M-1 indicated very good binding of all complexes to CT-DNA. Also, the new Pd(II) complexes show high cytotoxic activity towards the human prostate cancer cell line and insignificant activity towards non-cancerous human fibroblasts. Future research could additionally explore the biological activity of Pd(II) complexes presented in this paper and investigate the possibility of their implementation in clinical practice.

Synthesis, characterization, DNA interactions and biological activity of new palladium(II) complexes with some derivatives of 2-aminothiazoles.

Newly palladium(II) complexes (C1, C2) with derivatives of 2-aminothiazoles (L1 = 2-amino-6-methylbenzothiazole, L2 = 2-amino-6-chlorobenzothiazole), general formula [PdL2Cl2] were synthesized and characterized by elemental microanalyses, IR, NMR spectroscopy and X-ray spectroscopy in case of [Pd(L2)2Cl2]. The kinetic of the substitution reactions of complexes and the nucleophiles, such as guanosine-5'-monophosphate (5'-GMP), tripeptide glutathione (GSH) and amino acid L-methionine (L-Met), were studied by stopped-flow technique. The complex C2 was always more reactive, while the order of the reactivity of the nucleophiles, due to the associative mode of the reaction, was L-Met > GSH > 5'-GMP. In order to determine the type of interactions between palladium(II) complexes and calf thymus DNA (CT-DNA), we used electronic absorption spectroscopy, viscosity measurements, and fluorescence spectroscopic studies, while interactions with bovine serum albumin (BSA) were determined only with fluorescence spectroscopic studies. The observed results confirmed that both complexes bound to DNA by groove binding. The significantly strong interaction with BSA, especially for complex C2, was also observed. In vitro cytotoxic activity was evaluated against four tumor cell lines, 4 T1, CT26, MDA-MB-468, HCT116 and mesenchymal stem cells (mMSC). C1 complex showed higher cytotoxic activity against CT26 cell line. Flow cytometry analysis showed that C1 stimulated apoptosis of tumor cells via inhibition of expression of antiapoptotic Bcl-2 molecule and decelerated proliferation by decreasing Cyclin-D and increasing expression of P21. In vitro antimicrobial activity for ligands and corresponding palladium(II) complexes was investigated by microdilution method and minimum inhibitory concentration (MIC) and minimum microbicidal concentration (MMC) were determined. Tested compounds exhibited selective and moderate activity.

The Effects of Newly Synthesized Platinum(IV) Complexes on Cytotoxicity and Radiosensitization of Human Tumour Cells In Vitro.

AIM: Newly synthesized platinum(IV) complexes with ethylenediamine-N,N'-diacetate ligands (EDDA-type) (butyl-Pt and pentyl-Pt) were investigated against two cancer (A549 lung, and HTB 140 melanoma) and one non-cancerous (MRC-5 embryonic lung fibroblast) human cell lines. MATERIALS AND METHODS: The effects of these agents were compared with those of cisplatin after 6-, 24- and 48-h treatment. Sulforhodamine-B (SRB) assay was performed to estimate the cytotoxic effect, while the inhibitory effect on cell proliferation was measured using 5-bromo-2,-deoxyuridine (BrdU) incorporation assay. Cell cycle analysis was performed by flow cytometry. Type of cell death induced by these agents was determined by electrophoretic analysis of DNA, flow cytometry and by western blot analysis of proteins involved in induction of apoptosis. The effects of gamma irradiation, alone and in combination with platinum-based compounds, were examined by clonogenic and SRB assays. RESULTS: All examined platinum-based compounds had inhibitory and antiproliferative effects on A549 cells, but not on HTB140 and MRC-5 cells. Butyl-Pt, pentyl-Pt and cisplatin arrested the cell cycle in the S-phase and induced apoptotic cell death via regulation of expression of B-cell lymphoma 2 (BCL2) and BCL2-associated X (BAX) proteins. Platinum-based compounds increased the sensitivity of A549 cells to gamma irradiation. Butyl-Pt and pentyl-Pt showed better antitumour effects against A549 cells than did cisplatin, by interfering in cell proliferation and the cell cycle, and by triggering apoptosis. CONCLUSION: The effects of gamma irradiation on tumour cells may be amplified by pre-treatment of cells with platinum-based compounds.

Stereospecific ligands and their complexes. XXII. Synthesis and antitumor activity of palladium(II) complexes with some esters of (S,S)-ethylenediamine-N,N'-di-(2,2'-di(4-hydroxy-benzyl))-acetic acid.

Four new ligands and their palladium(II) complexes of general formula R2-S,S-eddtyr (L1-L4) and [PdCl2(R2-S,S-eddtyr)] (C1-C4) (R=ethyl, n-propyl, n-butyl and n-pentyl; S,S-eddtyr·2HCl=ethylenediamine-N,N'-di-(2,2'-di(4-hydroxy-benzyl))-acetic acid dihydrochloride have been synthesized and characterized by microanalysis, infrared, (1)H and (13)C NMR spectroscopy. Cytotoxicity for ligands and complexes on two different cell lines (human breast cancer, MDA-MB-231 and human lung cancer, A549 cell lines) and human chronic lymphocytic leukemia cells (CLL) was investigated using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay.