Journal of Inorganic Biochemistry最新文献

Cancer and infection diseases pose severe threats to public health worldwide stressing the need for more effective and efficient treatments. Thus, the search for broad-spectrum activity drugs seems justifiable and urgent. Herein, we investigate the anticancer and antitrypanosomatid (anti-Trypanosoma cruzi) activities of eight monoanionic metal bis(dithiolene) complexes, [Ph₄P][M(R-thiazdt)₂] with Mⁿ⁺ = Au³⁺, Pt²⁺, Pd²⁺, Ni²⁺, containing N-alkyl-1,3-thiazoline-2-thione dithiolene ligands (R-thiazdt) with different alkyl groups (R = Et, tBu). Compared to auranofin (AF) and cisplatin (CP), two reference drugs in clinical use, all complexes showed high anticancer activities against A2780 ovarian cancer cells (IC₅₀ values of 0.6-3.8 μM) some also being able to overcome CP resistance in A2780cisR cells. The selectivity index (SI), the IC₅₀ values on normal cells (HDF) vs. A2780 cells, indicated good anticancer specificity (SI > 3) for most of the complexes but with clinical relevance for [Ph₄P][Pd(tBu-thiazdt)₂] (SI = 10). All complexes showed relevant antitrypanosomatid activities (IC₅₀ values of 2.6-5.8 μM) some even exhibiting lower IC₅₀ values than the reference drug nifurtimox (NFX). The mechanism of cell death seemed to be mediated mainly by the formation of reactive oxygen species (ROS), although to lesser extent for the gold complexes but superior to AF. Although ROS play a role in the main apoptotic pathways, cell death by apoptosis was not evident as shown by the caspase-3/7 assay and the morphological cell features studies by electron microscopy (SEM). Results obtained evidenced that [Ph₄P][Pt(tBu-thiazdt)₂] and [Ph₄P][Pd(tBu-thiazdt)₂] complexes might have potential as novel anticancer and antitrypanosomatid agents as alternatives to current therapeutics.

Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic malignancy, has a dismal 5-year survival rate, making palliative chemotherapy the only treatment option. Targeted therapy has limited efficacy in PDAC, underscoring the need for novel therapeutic approaches. The inducible stress-response protein, haem oxygenase-1 (HMOX1), has been implicated in treatment failure in PDAC. Copper coordination complexes have shown promise as anticancer agents against various cancers, and are associated with apoptotic cell death. The different ligands to which copper is complexed, determine the specificity and efficacy of each complex. Three different classes of copper complexes were evaluated for anti-cancer activity against AsPC-1 and MIA PaCa-2 pancreatic cancer cell lines. A copper-phenanthroline-theophylline complex (CuPhTh₂), a copper-8-aminoquinoline-naphthyl complex (Cu8AqN), and two copper-aromatic-isoindoline complexes (CuAIsI) were effective inhibitors of cell proliferation with clinically relevant IC₅₀ values below 5 μM. The copper complexes caused reactive oxygen species (ROS) formation, promoted annexin-V binding, disrupted the mitochondrial membrane potential (MMP) and activated caspase-9 and caspase-3/7, confirming apoptotic cell death. Expression of nuclear HMOX1 was increased in both cell lines, with the CuPhTh₂ complex being the most active. Inhibition of HMOX1 activity significantly decreased the IC₅₀ values of these copper complexes suggesting that HMOX1 inhibition may alter treatment outcomes in PDAC.

This study investigates the effects of Pt and Ru complexes containing a Schiff base with a diimine structure on Alzheimer's disease. The Schiff base (N1E,N2E)-N1,N2-bis(isoquinolin-4-ylmethylene)benzene-1,2-diamine (I) and the novel Pt(II) and Ru(II) complexes (Ia and Ib) were synthesized and characterized using FTIR, NMR (¹H, ¹³C), mass spectrometry, and elemental analyses. Their ability to inhibit amyloid beta (Aβ_1-42) aggregation was determined in vitro using the SH-SY5Y cell line. Fluorescence spectroscopy investigated the early aggregation kinetics and dose-dependent characteristics of Aβ_1-42 with the complexes. Transmission electron microscopy confirmed the results. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and ¹H NMR spectroscopy examined the interaction with Aβ_1-16. Electrochemical analysis using square wave voltammetry monitored the interaction with Aβ_1-42. The synthesized complexes were active in inhibiting amyloid aggregation at a low molar ratio.

Acacetin (AC) is a natural polyphenol from the group of flavonoids. It is well established that the behavior of flavonoids depends on the presence of redox-active substances; therefore, we aim to investigate their biological activity following the interaction with Cu(II) ion. Our study demonstrates that AC can effectively bind Cu(II) ions, as confirmed by UV-Vis and EPR spectroscopy as well as DFT calculations. AC appears as a potent scavenger against the model ABTS radical cation by itself, but this ability is significantly limited upon Cu(II) coordination. The possible mild synergistic effect of AC in the presence of vitamin C and glutathione was also shown by the ABTS^•+ test. In contrast, an inhibitory effect was observed in the presence of Cu(II) ions. The equimolar addition of AC to the model Fenton-like system containing Cu(II) did not have a noticeable effect on the concentration of hydroxyl radicals produced, but in its excess the formation of ^•OH decreased, as proved by EPR spin trapping. Absorption titrations and gel electrophoresis revealed effective binding to calf thymus (CT)-DNA with a stronger interaction for the Cu(II)-AC complex. The detailed mode of binding to biomolecules was described using molecular docking and molecular dynamics. Obtained results indicate that the double helix of DNA unwinds after interaction with the Cu(II)-AC complex. Fluorescence spectroscopy, employing human serum albumin (HSA), suggested a potential transport capacity for both AC and its Cu(II) complex.

Here, we show that the replacement of the distal residues Asp and/or Arg of the DyP peroxidases from Bacillus subtilis and Pseudomonas putida results in functional enzymes, albeit with spectroscopically perturbed active sites. All the enzymes can be activated either by the addition of exogenous H₂O₂ or by in situ electrochemical generation of the reactive oxygen species (ROS) ^•OH, O₂^•- and H₂O₂. The latter method leads to broader and upshifted pH-activity profiles. Both WT enzymes exhibit a differential predominance of ROS involved in their electrochemical activation, which follows the order ^•OH > O₂^•- > H₂O₂ for BsDyP and O₂^•- > H₂O₂ > ^•OH for PpDyP. This ROS selectivity is preserved in mutants with unperturbed sites but is blurred out for distorted sites. The underlying molecular basis of the selectivity mechanisms is analysed through molecular dynamics simulations, which reveal distorted hydrogen bonding networks and higher throughput of the access tunnels in the variants exhibiting no selectivity. The electrochemical activation method provides superior performance for protein variants with a high prevalence of the alternative ^•OH and O₂^•- species. These results constitute a promising advance towards engineering DyPs for electrocatalytic applications.

Vanadium compounds (VCs) exhibit a broad range of pharmacological properties, with their most significant medical applications being in the treatment of cancer and diabetes. The therapeutic effects and mode of action of VCs may be associated with their ability to bind proteins and, consequently, understanding the VC-protein interaction is of paramount importance. Among the promising VCs, the V^VO₂ complex with the aroylhydrazone furan-2-carboxylic acid ((3-ethoxy-2-hydroxybenzylidene)hydrazide, hereafter denoted as VC1), deserves attention, since it exhibits cytotoxicity against various cancer cell lines, including HeLa. The interaction between VC1 and its analogue, denoted as VC2 (the dioxidovanadium(V) complex with (E)-N'-(1-(2-hydroxy-5-methoxyphenyl)ethylidene)furan-2-carbohydrazide), and hen egg white lysozyme (HEWL) was examined by UV-vis spectroscopy, fluorescence, circular dichroism, and X-ray crystallography. The interaction of VC1 and VC2 with HEWL does not alter the protein secondary and tertiary structure. Crystallographic studies indicate that the two metal complexes or V-containing fragments originating from VC1 and VC2 bind the protein via non-covalent interactions. Furthermore, when bound to HEWL, two VC1 molecules and two VC2 molecules form a supramolecular association stabilized by stacking interactions. This type of interaction could favour the binding of similar compounds to proteins and affect their biological activity.

The copper(II), cobalt(II), and zinc(II) complexes with 2-(1H-benzimidazol-2-ylmethylsulfanylmethyl)-1H-benzimidazole (tbb) and 2-[2-[2-(1H-benzimidazol-2-yl)ethylsulfanyl]ethyl]-1H-benzimidazole (tebb), [Cu(tbb)Cl₂] (1), [Co(tbb)Cl₂] (2), [Zn(tbb)Cl₂] (3), [Cu(tebb)Cl(H₂O)]Cl (4), [Co(tebb)Cl₂]_n·nCH₃OH (5) and [Zn(tebb)Cl(H₂O)]Cl (6), have been prepared and evaluated for antiproliferative activity. The structure of (4) was proved by X-ray diffraction crystallography. The coordination compounds were tested for their cytotoxic activities in cancer cell lines in vitro. The lower IC₅₀ values were obtained for Co(II), Cu(II), and Zn(II) complexes with tebb in comparison with tbb complexes. Complex 2 showed strong antiproliferative selectivity for leukemia CEM cells and nontoxicity towards other tested cell lines and normal human cells (BJ and RPE-1). Proapoptotic activity of 2 and 5 were weaker than positive control cisplatin, but the big advantage of these complexes was their zero-cytotoxicity for normal healthy cells in contrast to the high cytotoxicity of cisplatin. The activation of apoptotic initiation phase was detected in neuroblastoma cancer cell line SH-SY5Y where 5 was cytotoxic without fragmentation of cells. Interestingly, complexes 5, 6, and tebb, together with cisplatin, dramatically impaired the mitochondrial membrane potential of SH-SY5Y after 72 h. Taken together, we demonstrated that our compounds trigger apoptosis via the mitochondrial pathway.

Three stable oxidovanadium(IV) [V^IVOL^1-3] complexes (1-3) were synthesized through the incorporation of unsymmetrical salen ligands (H₂L^1-3). All the ligands are synthesized, and their vanadium compounds were thoroughly characterized by CHNS analysis, various spectroscopy methods (IR, UV-Vis, NMR spectroscopy), and HR-ESI-MS. The structures of 1-3 were validated through the single-crystal X-ray analysis. UV-Vis and HR-ESI-MS were used to determine the solution stability of the complexes in the aqueous phase, revealing their stability in aqueous/biological medium. Various spectroscopy techniques were used to study the DNA/BSA binding abilities, and the results indicate that 1-3 shows effective biomolecular interactions. The partition coefficient result indicates that 1-3 are highly hydrophobic and may easily permeate the cells. Finally, the in vitro anticancer properties of 1-3 were determined with two cancerous (HT-29 and A549), and the NIH-3T3 normal cell lines. Among the series, 3 is the most cytotoxic, with IC₅₀ values of 6.2 ± 0.2 and 5.3 ± 0.4 μM against HT-29 and A549 cell lines respectively. Moreover, the apoptotic cell death mechanism of 1-3 was assessed through DAPI, AO/EB, and double staining apoptosis experiments.