Modes of Interactions with DNA/HSA Biomolecules and Comparative Cytotoxic Studies of Newly Synthesized Mononuclear Zinc(II) and Heteronuclear Platinum(II)/Zinc(II) Complexes toward Colorectal Cancer Cells.

A series of mono- and heteronuclear platinum(II) and zinc(II) complexes with 4,4',4″-tri-tert-butyl-2,2':6',2″-terpyridine ligand were synthesized and characterized. The DNA and protein binding properties of [ZnCl2(terpytBu)] (C1), [{cis-PtCl(NH3)2(µ-pyrazine)ZnCl(terpytBu)}](ClO4)2 (C2), [{trans-PtCl(NH3)2(µ-pyrazine)ZnCl(terpytBu)}](ClO4)2 (C3), [{cis-PtCl(NH3)2(µ-4,4'-bipyridyl)ZnCl(terpytBu)}](CIO4)2 (C4) and [{trans-PtCl(NH3)2(µ-4,4'-bipyridyl)ZnCl(terpytBu)}](CIO4)2 (C5) (where terpytBu = 4,4',4″-tri-tert-butyl-2,2':6',2″-terpyridine), were investigated by electronic absorption, fluorescence spectroscopic, and molecular docking methods. Complexes featuring transplatin exhibited lower Kb and Ksv constant values compared to cisplatin analogs. The lowest Ksv value belonged to complex C1, while C4 exhibited the highest. Molecular docking studies reveal that the binding of complex C1 to DNA is due to van der Waals forces, while that of C2-C5 is due to conventional hydrogen bonds and van der Waals forces. The tested complexes exhibited variable cytotoxicity toward mouse colorectal carcinoma (CT26), human colorectal carcinoma (HCT116 and SW480), and non-cancerous mouse mesenchymal stem cells (mMSC). Particularly, the mononuclear C1 complex showed pronounced selectivity toward cancer cells over non-cancerous mMSC. The C1 complex notably induced apoptosis in CT26 cells, effectively arrested the cell cycle in the G0/G1 phase, and selectively down-regulated Cyclin D.

Docking Studies, Cytotoxicity Evaluation and Interactions of Binuclear Copper(II) Complexes with S-Isoalkyl Derivatives of Thiosalicylic Acid with Some Relevant Biomolecules.

The numerous side effects of platinum based chemotherapy has led to the design of new therapeutics with platinum replaced by another transition metal. Here, we investigated the interactions of previously reported copper(II) complexes containing S-isoalkyl derivatives, the salicylic acid with guanosine-5'-monophosphate and calf thymus DNA (CT-DNA) and their antitumor effects, in a colon carcinoma model. All three copper(II) complexes exhibited an affinity for binding to CT-DNA, but there was no indication of intercalation or the displacement of ethidium bromide. Molecular docking studies revealed a significant affinity of the complexes for binding to the minor groove of B-form DNA, which coincided with DNA elongation, and a higher affinity for binding to Z-form DNA, supporting the hypothesis that the complex binding to CT-DNA induces a local transition from B-form to Z-form DNA. These complexes show a moderate, but selective cytotoxic effect toward colon cancer cells in vitro. Binuclear complex of copper(II) with S-isoamyl derivative of thiosalicylic acid showed the highest cytotoxic effect, arrested tumor cells in the G2/M phase of the cell cycle, and significantly reduced the expression of inflammatory molecules pro-IL-1ß, TNF-α, ICAM-1, and VCAM-1 in the tissue of primary heterotopic murine colon cancer, which was accompanied by a significantly reduced tumor growth and metastases in the lung and liver.

Complexes of copper(II) with tetradentate S,O-ligands: Synthesis, characterization, DNA/albumin interactions, molecular docking simulations and antitumor activity.

Four new complexes of copper(II) with S,O-tetradentate ligands, derivatives of thiosalicylic acid, encompassing an ethylene-, propylene-, butylene- and pentylene- bridge, were synthesized and characterized by microanalysis, molecular conductance and infrared (IR) spectra. The structures were assumed based on the previously mentioned analyses and confirmed with the results of electron paramagnetic resonance (EPR) spectra. The reactivity of complexes towards L-methionine (L-Met), L-cysteine (L-Cys) and guanosine-5'-monophosphate (5'-GMP) was also examined. Complex C1 ([Cu(S,O-ethylene-thiosalicylic acid)(H2O)2]) containing two inert methylene groups in the side chain of ligand shows the highest reactivity, while the least reactive is complex C4 ([Cu(S,O-pentylene-thiosalicylic acid)(H2O)2]) with five methylene groups. All complexes showed the highest reactivity towards L-Met and the lowest reactivity towards 5'-GMP. The interactions of complexes C1-C4 with calf thymus DNA (ct-DNA) were examined by ultraviolet-visible (UV-Vis) absorption and fluorescence spectral studies, revealing good DNA interaction abilities. All synthesized complexes C1-C4 show to interact with human serum albumin (HSA) with high values of binding constants. Complexes interaction with DNA/HSA was also confirmed using molecular docking simulations. All synthesized complexes reduce viability of human colon, breast and lung cancer cells, evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric technique. The complex [Cu(S,O-pentylene- thiosalicylic acid)(H2O)2] showed the highest binding affinity constants to DNA/HSA and highest cytotoxicity, thus presenting a good candidate for further pharmacological research in the field of colon, breast and lung cancer therapy.

Synthesis, Characterization and Biological Studies of Organoselenium trans-Palladium(II) Complexes.

BACKGROUND: Over the years, transition metal complexes have exhibited significant antimicrobial and antitumor activity. It all started with cisplatin discovery, but due to the large number of side effects it shows, there is a growing need to find a new metal-based compound with higher selectivity and activity on more tumors. OBJECTIVES: Two novel trans-palladium(II) complexes with organoselenium compounds as ligands, [Pd(L1)2Cl2] (L1 = 5-(phenylselanylmethyl)-dihydrofuran-2(3H)-one) and [Pd(L2)2Cl2] (L2 = 2- methyl-5-(phenylselanylmethyl)- tetrahydrofuran) were synthesized, in the text referred to as Pd-Se1 and Pd-Se2. Also, a structurally similar trans-palladium(II) complex, [Pd(L3)2Cl2] (L3= 2,2- dimethyl-3-(phenylselanylmethyl)-tetrahydro-2H-pyran) was synthesized according to an already published work and is referred to as Pd-Se3. The interaction of synthesized complexes with DNA and bovine serum albumin was observed. Also, antimicrobial activity and in vitro testing, cell viability, and cytotoxic effects of synthesized ligands and complexes on human epithelial colorectal cancer cell line HCT-116 were studied. Molecular docking simulations were performed to understand better the binding modes of the complexes reported in this paper with DNA and BSA, as well as to comprehend their antimicrobial activity. METHODS: The interactions of the synthesized complexes with DNA and bovine serum albumin were done using UV-Vis and emission spectral studies as well as docking studies. Antimicrobial activity was tested by determining the minimum inhibitory concentrations (MIC) and minimum microbicidal concentration (MMC) using the resazurin microdilution plate method. Cytotoxic activity on cancer cells was studied by MTT test. RESULTS: The Pd(II) complexes showed a significant binding affinity for calf thymus DNA and bovine serum albumin by UV-Vis and emission spectral studies. The intensity of antimicrobial activity varied with the complexes Pd-Se1 and Pd-Se3, showing significantly higher activity than the corresponding ligand. The most significant activity was shown on Pseudomonas aeruginosa. Under standardized laboratory conditions for in vitro testing, cell viability and cytotoxic effects of synthesized ligands and complexes were studied on human epithelial colorectal cancer cell line HCT-116, where Pd-Se2 showed some significant cytotoxic effects. CONCLUSION: The newly synthesized complexes have the potential to be further investigated as metallodrugs.

Experimental and quantum chemical study оn the DNA/protein binding and the biological activity of a rhodium(iii) complex with 1,2,4-triazole as an inert ligand.

The synthesis and structural characterization of a newly synthesized mononuclear rhodium(iii) complex, Rhtrz, with a ligand (2,2,6-bis((4S,7R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazol-3-yl)pyridine) and a ligand of 1,2,4-triazole, are presented in this paper. The kinetic interactions of the Rhtrz complex with essential biomolecules such as 5-GMP, L-Met, and GSH were examined. The study of the biological interactions was focused on the binding properties of the Rhtrz complex with CT-DNA and serum albumin. These interactions were investigated using UV-vis spectrophotometry, fluorescence spectroscopy, viscosity measurements, thermal denaturation studies, and electrophoresis. Fluorescence competition experiments with site-markers for BSA were used to locate the binding site of the Rhtrz-complex to the BSA. Molecular docking studies were carried out to obtain detailed binding information of the complex with CT-DNA, BSA, and HSA. Furthermore, the apparent distance between the donor (HSA) and acceptor (Rhtrz) was determined using fluorescence resonance energy transfer (FRET). The thermodynamic properties and relative stabilities of the Rhtrz complex were examined, constructing the two model equation by DFT calculations (B3LYP(CPCM)/LANL2DZp). In vitro cytotoxicity and redox status on the human epithelial colorectal cancer cell line (HCT-116) and healthy human fibroblast cell line (MRC-5) were also investigated.

Synthesis of Camphor-Derived Bis(pyrazolylpyridine) Rhodium(III) Complexes: Structure-Reactivity Relationships and Biological Activity.

Two novel rhodium(III) complexes, namely, [RhIII(X)Cl3] (X = 2 2,6-bis((4 S,7 R)-7,8,8-trimethyl-4,5,6,7-tetrahydro-1 H-4,7-methanoindazol-3-yl)pyridine or 2,6-bis((4 S,7 R)-1,7,8,8-tetramethyl-4,5,6,7-tetrahydro-1 H-4,7-methanoindazol-3-yl)pyridine), were synthesized from camphor derivatives of a bis(pyrazolylpyridine), tridentate nitrogen-donor chelate system, giving [RhIII(H2L*)Cl3] (1a) and [RhIII(Me2L*)Cl3] (1b). A rhodium(III) terpyridine (terpy) ligand complex, [RhIII(terpy)Cl3] (1c), was also synthesized. By single-crystal X-ray analysis, 1b crystallizes in an orthorhombic P212121 system, with two molecules in the asymmetric unit. Tridentate coordination by the N,N,N-donor localizes the central nitrogen atom close to the rhodium(III) center. Compounds 1a and 1b were reactive toward l-methionine (l-Met), guanosine-5'-monophosphate (5'-GMP), and glutathione (GSH), with an order of reactivity of 5'-GMP > GSH > l-Met. The order of reactivity of the RhIII complexes was: 1b> 1a > 1c. The RhIII complexes showed affinity for calf thymus DNA and bovine serum albumin by UV-vis and emission spectral studies. Furthermore, 1b showed significant in vitro cytotoxicity against human epithelial colorectal carcinoma cells. Since the RhIII complexes have similar coordination modes, stability differences were evaluated by density functional theory (DFT) calculations (B3LYP(CPCM)/LANL2DZp). With (H2L*) and (terpy) as model ligands, DFT calculations suggest that both tridentate ligand systems have similar stability. In addition, molecular docking suggests that all test compounds have affinity for the minor groove of DNA, while 1b and 1c have potential for DNA intercalation.

The perfusion of cisplatin and cisplatin structural analogues through the isolated rat heart: The effects on coronary flow and cardiodynamic parameters.

The therapeutic use of cisplatin for the treatment of solid tumours is associated with organ toxicity. Amongst those, the cardiotoxicity is an occasional but very serious and severe side effect. To prevent or reduce these negative effects, many cisplatin analogues have been synthesized and evaluated in terms of being a less toxic and more effective agent. In present study, we examined the effects of cisplatin and its three analogues in the isolated rat heart to determine whether changes in the structure of the platinum complexes (changing of carrier ligands - ethylenediamine; 1,2-diaminocyclohexane; 2,2':6',2''-terpyridine) can influence their cardiotoxic effects. The results of our research indicate that the introduction of aromatic rings in the structure of the platinum complexes has a negative influence on the heart function. Conversely, the other two examined complexes had less negative effects on heart function compared to cisplatin. Our findings may be of interest for a possible synthetic strategy of introducing a carrier ligand that will exert a less cardiotoxic effect.

Synthesis and structures of a pincer-type rhodium(iii) complex: reactivity toward biomolecules.

A novel rhodium(iii) complex [RhIII(H2LtBu)Cl3] (1) (H2LtBu = 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine) containing a pincer type, tridentate nitrogen-donor chelate system was synthesized. Single crystal X-ray structure analysis revealed that 1 crystallizes in the orthorhombic space group Pbcn with a = 20.7982(6), b = 10.8952(4), c = 10.9832(4) Å, V = 2488.80(15) Å3, and eight molecules in the unit cell. The rhodium center in the complex [RhIII(H2LtBu)Cl3] (1) is coordinated in a slightly distorted octahedral geometry by the tridentate N,N,N-donor and three chloro ligands, adopting a mer arrangement with an essentially planar ligand skeleton. Due to the tridentate coordination of the N,N,N-donor, the central nitrogen atom N1 is located closer to the RhIII center. The reactivity of the synthesized complex toward small biomolecules (l-methionine (l-Met), guanosine-5'-monophosphate (5'-GMP), l-histidine (l-His) and glutathione (GSH)) and to a series of duplex DNAs and RNA was investigated. The order of reactivity of the studied small biomolecules is: 5'-GMP > GSH > l-Met > l-His. Duplex RNA reacts faster with the [RhIII(H2LtBu)Cl3] complex than duplex DNA, while shorter duplex DNA (15mer GG) reacts faster compared with 22mer GG duplex DNA. In addition, a higher reactivity is achieved with a DNA duplex with a centrally located GG-sequence than with a 22GTG duplex DNA, in which the GG-sequence is separated by a T base. Furthermore, the interaction of this metal complex 1 with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) was examined by absorption (UV-Vis) and emission spectral studies (EthBr displacement studies). Overall, the studied complex exhibited good DNA and BSA interaction ability.

Antiproliferative properties and biomolecular interactions of three Pd(II) and Pt(II) complexes.

Three Pd(II) and Pt(II) complexes with chelating mono(imidazolin-2-imine) and bis(imidazolin-2-imine) ligands i.e. [Pd(DMEAImiPr)Cl2] (1) (DMEAImiPr, 2-(1,3-diisopropyl-4,5-dimethylimidazolin-2-imine)ethan-1-dimethylamine), [Pd(DACH(ImiPr)2)Cl2] (2) (DACH(ImiPr)2, N,N'-(cyclohexane-1,2-diyl)bis(1,3-diisopropyl-4,5-dimethylimidazolin-2-imine)) and [Pt(DMEAImiPr)Cl2] (3), are evaluated here as potential cytotoxic and anticancer agents. An acceptable solution behaviour was found for the three study compounds in terms of solubility and stability. Notably, the three metal complexes demonstrated moderate to high cytotoxic properties in selected cancer cell lines (liquid and solid tumor). To gain deeper mechanistic insight, the reactivity of the study complexes with model DNA oligos and protein molecules was investigated through spectrometric and spectroscopic methods; in both cases adduct formation was clearly documented by ESI-MS measurements. The binding of these metal complexes to calf thymus DNA (CT-DNA) was further examined by absorption (UV-Vis) and emission spectral studies (Ethidium bromide displacement studies, EtBr). Overall, the studied complexes 1-3 exhibited a remarkable DNA binding ability that might be linked to the observed cytotoxic effects. Interestingly our results revealed that DNA binding, as well as anticancer activity of 1-3 follows the order 2>3>1. The implications of these findings are discussed.

Palladium(II) complexes with highly basic imidazolin-2-imines and their reactivity toward small bio-molecules.

A series of novel Pd(ii) complexes with chelating mono(imidazolin-2-imine) and bis(imidazolin-2-imine) ligands were synthesized. The crystal structures of [Pd(DMEAIm(iPr))Cl2] and [Pd(DPENIm(iPr))Cl2] were determined by X-ray diffraction analysis. The reactivity of the six Pd(ii) complexes, namely, [Pd(en)Cl2], [Pd(EAIm(iPr))Cl2], [Pd(DMEAIm(iPr))Cl2], [Pd(DPENIm(iPr))Cl2], [Pd(BL(iPr))Cl2] and [Pd(DACH(Im(iPr))2)Cl2], were investigated. Spectrophotometric acid-base titrations were performed to determine the pKa values of the coordinated water molecules in [Pd(en)(H2O)2](2+), [Pd(EAIm(iPr))(H2O)2](2+), [Pd(DMEAIm(iPr))(H2O)2](2+), [Pd(DPENIm(iPr))(H2O)2](2+), [Pd(BL(iPr))(H2O)2](2+) and [Pd(DACH(Im(iPr))2)(H2O)2](2+). The substitution of the chloride ligands in these complexes by TU, l-Met, l-His and Gly was studied under pseudo-first-order conditions as a function of the nucleophile concentration and temperature using stopped-flow techniques; the sulfur-donor nucleophiles have shown better reactivity than nitrogen-donor nucleophiles. The obtained results indicate that there is a clear correlation between the nature of the imidazolin-2-imine ligands and the acid-base characteristics and reactivity of the resulting Pd(ii) complexes; the order of reactivity of the investigated Pd(ii) complexes is: [Pd(en)Cl2] > [Pd(EAIm(iPr))Cl2] > [Pd(DMEAIm(iPr))Cl2] > [Pd(DPENIm(iPr))Cl2] > [Pd(BL(iPr))Cl2] > [Pd(DACH(Im(iPr))2)Cl2]. The solubility measurements revealed good solubility of the studied imidazolin-2-imine complexes in water, despite the fact that these Pd(ii) complexes are neutral complexes. Based on the performed studies, three unusual features of the novel imidazolin-2-imine Pd(ii) complexes are observed, that is, good solubility in water, very low reactivity and high pKa values. The coordination geometries around the palladium atoms are distorted square-planar; the [Pd(DMEAIm(iPr))Cl2] complex displays Pd-N distances of 2.013(2) and 2.076(2) Å, while the [Pd(DPENIm(iPr))Cl2] complex displays similar Pd-N distances of 2.034(4) and 2.038(3) Å. The studied systems are of interest because little is known about the substitution behavior of imidazolin-2-imine Pd(ii) complexes with bio-molecules under physiological conditions.

Mechanistic studies on the reactions of platinum(II) complexes with nitrogen- and sulfur-donor biomolecules.

A brief overview of mechanistic studies on the reactions of different Pt(II) complexes with nitrogen- and sulfur-donor biomolecules is presented. The first part describes the results obtained for substitution reactions of mono-functional Pt(II) complexes with different biomolecules, under various experimental conditions (temperature, pH and ionic strength). In addition, an overview of the results obtained for the substitution reactions of bi-functional Pt(II) complexes, analogous to cisplatin, with biomolecules is given. The last part of this report deals with different polynuclear Pt(II) complexes and their substitution behaviour with different biomolecules. The purpose of this perspective is to improve the understanding of the mechanism of action of Pt(II) complexes as potential anti-tumour drugs in the human body.

Equilibrium studies of the reactions of palladium(II) bis(imidazolin-2-imine) complexes with biologically relevant nucleophiles. The crystal structures of [(TLtBu)PdCl]ClO4 and [(BLiPr)PdCl2].

The kinetics and the mechanism of the substitution reactions of the complex [(TL(tBu))PdCl](+), where TL(tBu) is 2,6-bis[(1,3-di-tert-butylimidazolin-2-imino)methyl]pyridine, with nucleophiles (guanosine-5'-monophosphate (5'-GMP), l-Methionine (l-Met) and l-Histidine (l-His)) were studied using variable-temperature stopped-flow techniques in aqueous 0.1 M NaClO(4) with 10 mM NaCl at 298 K. The order of reactivity is: l-Met > 5'-GMP > l-His. The formation equilibria of [(BL(iPr))Pd(H(2)O)(2)](2+), where BL(iPr) is 1,2-bis(1,3diisopropyl-4,5-dimethylimidazolin-2-imino)ethane, and [(TL(tBu))Pd(H(2)O)](2+) with some biologically relevant ligands (l-Met, 5'-GMP and l-His) were also studied. The stoichiometry and stability constants of the newly formed complexes are reported, and the concentration distribution of the various complex species has been evaluated as a function of pH. Comparing the values of logß(1,1,0) for 5'-GMP, l-His and l-Met complexes, the most stable complex is with 5'-GMP followed by l-His and l-Met for both complexes, [(BL(iPr))Pd(H(2)O)(2)](2+) and [(TL(tBu))Pd(H(2)O)](2+). The crystal structures of [(TL(tBu))PdCl]ClO(4) and [(BL(iPr))PdCl(2)] were determined by X-ray diffraction. The coordination geometries around the palladium atoms are distorted square-planar, with the Pd-N1 distance to the central nitrogen atom of the TL(tBu) ligand, 1.944(2) Å, being shorter than those to the other two nitrogen atoms of TL(tBu), viz. 2.034(3) and 2.038(2) Å. The BL(iPr) complex displays similar Pd-N distances of 2.031(2) and 2.047(2) Å.