Investigation of the interaction between S-isoalkyl derivatives of the thiosalicylic acid and human serum albumin.

S-isoalkyl derivatives of thiosalicylic acid (isopropyl-(L1), isobutyl-(L2) and isoamyl-(L3)) were selected in order to investigate the binding interaction with the human serum albumin (HSA) using different spectroscopic methods and molecular docking simulation. Association constants and number of binding sites were used to analyze the quenching mechanism. The experimental results showed that the fluorescence quenching of HSA by L1, L2 and L3 occurs because of static quenching and that binding processes were spontaneous, with the leading forces in bonding by hydrogen bonding, hydrophobic interactions, and electrostatic interactions. Fluorescence spectroscopy, UV-Vis spectroscopy and synchronous fluorescence spectroscopy showed that ligands (L1, L2 and L3) can bind to HSA and that the binding of ligands induced some microenvironmental and conformational changes in HSA. The calculated distance between the donor and the acceptor according to fiFörster's theory confirms the energy transfer efficiency between the acceptor and HSA. Results of site marker competitive experiments showed that the tested compounds bind to HSA in domain IIA (Site I). Molecular dynamics and docking calculations demonstrated that L3 binds to the Sudlow site I of HSA with lower values of binding energies compared to L1 and L2, indicating the formation of the most stable ligand-HSA complex. Understanding the binding mechanisms of S-isoalkyl derivatives of the thiosalicylic acid to HSA may provide valuable data for the future studies of their biological activity and application as potential antitumor drugs.Communicated by Ramaswamy H. Sarma.

Exploring heterometallic bridged Pt(II)-Zn(II) complexes as potential antitumor agents.

The four novel complexes [{cis-PtCl(NH3)2(µ-4,4'-bipyridyl)ZnCl(terpy)}](ClO4)2 (C1), [{trans-PtCl(NH3)2(µ-4,4'-bipyridyl)ZnCl(terpy)}](ClO4)2 (C2), [{cis-PtCl(NH3)2(µ-pyrazine)ZnCl(terpy)}](ClO4)2 (C3) and [{trans-PtCl(NH3)2(µ-pyrazine)ZnCl(terpy)}](ClO4)2 (C4) (where terpy = 2,2':6',2''-terpyridine) were synthesized and characterized. Acid-base titrations and concentration dependent kinetic measurements for the reactions with biologically relevant ligands such as guanosine-5'-monophosphate (5'-GMP), inosine-5'-monophosphate (5'-IMP) and glutathione (GSH), were studied at pH 7.4 and 37 °C. The binding of the heterometallic bridged cis- or trans-Pt(II)-Zn(II) complexes to calf thymus DNA (CT-DNA) was studied by UV absorption and fluorescence emission spectroscopy and molecular docking. The results indicated that the complexes bind strongly to DNA, through groove binding, hydrogen bonds, and hydrophobic or electrostatic interaction. The possible in vitro DNA protective effect of cis- and trans-Pt-L-Zn complexes has shown that C3 had significant dose-dependent DNA-protective effect and the same ability to inhibit peroxyl as well as hydroxyl radicals. Antiproliferative effect of the complexes, mRNA expression of apoptosis and repair-related genes after treatment in cancer cells indicated that newly synthesized C2 exhibited highly selective cytotoxicity toward colon carcinoma HCT116 cells. Only treatment with trans analog C2 induced effect similar to the typical DNA damaging agent such as cisplatin, characterized by p53 mediated cell response, cell cycle arrest and certain induction of apoptotic related genes. Both cis- and trans-isomers C1 and C2 showed potency to elicit expression of PARP1 mRNA and in vitro DNA binding.

Effect of Caffeine and Flavonoids on the Binding of Tigecycline to Human Serum Albumin: A Spectroscopic Study and Molecular Docking.

Human serum albumin (HSA) has a very significant role in the transport of drugs, in their pharmacokinetic and pharmacodynamic properties, as well as the unbound concentration of drugs in circulating plasma. The aim of this study was to look into the competition between tigecycline (TGC) and alkaloid (ALK) (caffeine (CAF)), and flavonoids (FLAVs) (catechin (CAT), quercetin (QUE), and diosmin (DIO)) in binding to HSA in simulated physiological conditions using multiple spectroscopic measurements and docking simulations. Fluorescence analysis was used to find the binding and quenching properties of double HSA-TGC and triple HSA-TGC-CAF/FLAV systems. The conformational change of the HSA was analyzed using synchronous fluorescence spectroscopy, Fourier transform infrared spectroscopy, and circular dichroism. Obtained results of spectroscopic analyses indicate that triple complexes of HSA-TGC-CAF/FLAVs are formed without problems and have higher binding affinities than double HSA-TGC. In addition, TGC does not change the microenvironments around the tryptophan (Trp) and tyrosine (Tyr) residues in the presence of ALK and FLAVs. Ultimately, the binding affinity, competition, and interaction nature were explored by docking modeling. Computational outcomes are in good accordance with experimentally obtained results. Accordingly, concluding remarks may be very useful for potential interactions between common food components and drugs.

Interaction between olanzapine and human serum albumin and effect of metal ions, caffeine and flavonoids on the binding: A spectroscopic study.

In this study, the binding of olanzapine (OLZ) to human serum albumin (HSA) and the influence of metal ions (Ca2+, Mg2+, Cu2+, Zn2+, Fe3+), caffeine (CAF) and flavonoids (diosmin (DIO), catechin (CAT), quercetin (QUE)), on their affinity, was investigated by fluorescence spectroscopy and UV-vis absorption spectroscopy. Fluorescence experiments suggest that OLZ quench the fluorescence of HSA through the mixed quenching mechanism and non-radiation energy transferring as a result of the HSA-OLZ complex formation. OLZ spontaneously bind in the site I on HSA, and according to thermodynamic parameters, the reaction was spontaneous and mainly driven by hydrogen bonds and van der Waals interactions. The presence of Mn+ ions, CAF, DIO and CAT decreased binding affinity between OLZ and HSA which indicates that they could compete against OLZ in the site I. Contrary, in the presence of QUE the binding affinity of the HSA-OLZ system enhanced, which may be explained by conformational changes in HSA (non-competitive interference).

Synthesis of novel palladium(II) complexes with oxalic acid diamide derivatives and their interaction with nucleosides and proteins. Structural, solution, and computational study.

Novel palladium complexes, KH[Pd(obap)]2·3H2O (3) with oxamido-N-aminopropyl-N'-benzoic acid and [Pd(apox)] (4) with N,N'-bis(3-aminopropyl)ethanediamide, were synthesized. Exhaustive synthetic, solution and structural studies of the two Pd(ii) complexes are reported. The binary and ternary systems of the Pd(ii) ion with H2apox or H3obap as primary ligands and nucleosides (Ado or Cyt) as secondary ligands, are investigated in order to better understand their equilibrium chemistry. The relative stabilities of the ternary complexes are determined and compared with those of the corresponding binary complexes in terms of their Δlog K values. The species distribution of all complexes in solution is evaluated. Fluorescence spectroscopy data shows that the fluorescence quenching of HSA is a result of the formation of the [PdL]-HSA complex. The structure of complex 3 is confirmed using X-ray crystallography. The results are compared to those obtained for palladium complexes of similar structures. Density functional theory (DFT) has been applied for modelling and energetic analysis purposes. The nature of the Pd-N(O) bond interaction is analyzed using NBO. We report here docking simulation experiments in order to predict the most probable mechanism of pro-drug-action. The next free binding energy order of the best scores from the [PdL]-DNA docking simulations, cis-[Pt(NH3)2(H2O)2](2+) > [Pd(obap)] > [Pd(mda)], has been observed in the case of DNA alteration. For the ER and cytosolic stress mechanisms the results of the docking simulations to the chaperons Grp78 and Hsc70 are promising for possible applications as potent protein inhibitors (Ki of [Pd(mda)]/GRP78 being ∼66 µM and Ki for [Pd(obap)]/HSC70 being 14.39 µM).

Synthesis, characterization, thermal and DNA-binding properties of new zinc complexes with 2-hydroxyphenones.

The neutral mononuclear zinc complexes with 2-hydroxyphenones (ketoH) having the formula [Zn(keto)2(H2O)2] and [Zn(keto)2(enR)], where enR stands for a N,N'-donor heterocyclic ligand such as 2,2'-bipyridine (bipy), 1,10-phenanthroline (phen) or 2,2'-dipyridylamine (dpamH), have been synthesized and characterized by IR, UV and (1)H NMR spectroscopies. The 2-hydroxyphenones are chelated to the metal ion through the phenolate and carbonyl oxygen atoms. The crystal structures of [bis(2-hydroxy-4-methoxy-benzophenone)(2,2'-bipyridine)zinc(II)] dimethanol solvate and [bis(2-hydroxy-benzophenone)(2,2'-bipyridine)zinc(II)] dimethanol solvate have been determined by X-ray crystallography. The thermal stability of the zinc complexes has been investigated by simultaneous TG/DTG-DTA technique. The ability of the complexes to bind to calf-thymus DNA (CT DNA) has been studied by UV-absorption and fluorescence emission spectroscopy as well as viscosity measurements. UV studies of the interaction of the complexes with DNA have shown that they can bind to CT DNA and the corresponding binding constants to DNA have been calculated and evaluated. The complexes most probably bind to CT DNA via intercalation as concluded by studying the viscosity of a DNA solution in the presence of the complexes. Competitive studies with ethidium bromide (EB) have shown that the reported complexes can displace the DNA-bound EB, suggesting strong competition with EB for the intercalation site.

Antitumor effects of a tetradentate amido-carboxylate ligands and corresponding square-planar palladium(II) complexes toward some cancer cells. Crystal structure, DFT modeling and ligand to DNA probe docking simulation.

Novel square-planar palladium(II) complexes with O-N-N-O-type ligands H4mda (H4mda=malamido-N,N'-diacetic acid) and H4obp (H4obp=oxamido-N,N'-di-3-propionic acid) were prepared and characterized. The ligands coordinate to the palladium(II) ion via two pairs of deprotonated ligating atoms with square chelation. A four coordinate, square-planar geometry was verified crystallographicaly for the K2[Pd(mda)]·H2O complex. The binary and ternary systems of Pd(II) ion with H4mda or H4obp (L) as primary ligands and guanosine (A) as secondary ligand were studied in aqueous solutions in 0.1 M NaCl ionic medium at 25 °C by potentiometric titrations. In addition, calculations based on density functional methods (DFT) were carried out. A natural bonding orbital analysis indicated that the Pd-N bonds are three-centric in nature and mainly governed by charge transfer via a strong delocalization of the oxygen lone pair with "p" character into the bonding Pd-N orbital. Mononuclear palladium(II) complexes together with amido acid N,O-containing ligands were tested against several tumor cells and reveal significant antitumor activity and lower resistance of tumor cells in vitro than cisplatin. In this paper, interactions of palladium complexes with DNA are discussed in order to provide guidance and determine structure and antitumor activity relationships for continuing studies of these systems. Docking simulation on DNA dodecamer or 29-mer (Lippard solved crystal structures), suggests several favorable interactions with the hydrogen pocket/binding site for the incoming ligands. These results support amidoacids/Pd complexes as novel antitumor drugs and suggest that their potent cell life inhibition may contribute to its anti-cancer efficacy.

Antiproliferative and proapoptotic activities of methanolic extracts from Ligustrum vulgare L. as an individual treatment and in combination with palladium complex.

The aim of this study is to examine the growth inhibitory effects of methanolic leaf and fruit extracts of L. vulgare on HCT-116 cells over different time periods and their synergistic effect with a Pd(apox) complex. The antiproliferative activity of plant extracts alone or in combination with the Pd(apox) complex was determined using MTT cell viability assay, where the IC(50) value was used as a parameter of cytotoxicity. Results show that antiproliferative effects of L. vulgare extracts increase with extension of exposure time, with decreasing IC(50) values, except for 72 h where the IC(50) values for methanolic leaf extract were lower than for the fruit extract. The Pd(apox) complex alone had a weak antiproliferative effect, but combination with L. vulgare extracts caused stronger effects with lower IC(50) values than with L. vulgare extracts alone. The type of cell death was explored by fluorescence microscopy using the acridin orange/ethidium bromide method. Treatments with plant extracts caused typical apoptotic morphological changes in HCT-116 cells and co-treatments with Pd(apox) complex caused higher levels of apoptotic cells than treatment with plant extracts alone. The results indicate that L. vulgare is a considerable source of natural bioactive substances with antiproliferative activity on HCT-116 cells and which have a substantial synergistic effect with the Pd(apox) complex.