Journal of Biological Inorganic Chemistry最新文献

Platinum-based drugs are widely recognized efficient anti-tumor agents, but faced with multiple undesirable effects. Here, four dinuclear platinum(II) complexes, [{Pt(1,2-pn)Cl}₂(μ-pydz)]Cl₂ (C1), [{Pt(ibn)Cl}₂(μ-pydz)]Cl₂ (C2), [{Pt(1,3-pn)Cl}₂(μ-pydz)]Cl₂ (C3) and [{Pt(1,3-pnd)Cl}₂(μ-pydz)]Cl₂ (C4), were designed (pydz is pyridazine, 1,2-pn is ( ±)-1,2-propylenediamine, ibn is 1,2-diamino-2-methylpropane, 1,3-pn is 1,3-propylenediamine, and 1,3-pnd is 1,3-pentanediamine). Interactions and binding ability of C1–C4 complexes with calf thymus DNA (CT-DNA) has been monitored by viscosity measurements, UV–Vis, fluorescence emission spectroscopy and molecular docking. Binding affinities of C1–C4 complexes to the bovine serum albumin (BSA) has been monitored by fluorescence emission spectroscopy. The tested complexes exhibit variable cytotoxicity toward different mouse and human tumor cell lines. C2 shows the most potent cytotoxicity, especially against mouse (4T1) and human (MDA-MD468) breast cancer cells in the dose- and time-dependent manner. C2 induces 4T1 and MDA-MD468 cells apoptosis, further documented by the accumulation of cells at sub-G1 phase of cell cycle and increase of executive caspase 3 and caspase 9 levels in 4T1 cells. C2 exhibits anti-proliferative effect through the reduction of cyclin D3 and cyclin E expression and elevation of inhibitor p27 level. Also, C2 downregulates c-Myc and phosphorylated AKT, oncogenes involved in the control of tumor cell proliferation and death. In order to measure the amount of platinum(II) complexes taken up by the cells, the cellular platinum content were quantified. However, C2 failed to inhibit mouse breast cancer growth in vivo. Chemical modifications of tested platinum(II) complexes might be a valuable approach for the improvement of their anti-tumor activity, especially effects in vivo.

Graphical abstract

Dinuclear platinum(II) complex [{Pt(ibn)Cl}₂(μ-pydz)]Cl₂ shows anti-tumor activity, triggers the apoptosis and reduces the proliferation of mouse breast cancer cells in vitro. However, its inhibitory effect on tumor growth in vivo is absent.

In the search for improved and safer gadolinium-based magnetic resonance imaging (MRI) contrast agents, macrocyclic cyclodextrins (CDs) attract great interest. Our group previously synthesized a cyclodextrin-based ligand with 1,2,3-triazolmethyl residues conjugated to β-CD, called β-CD(A), which efficiently chelates Gd(III) ions. To probe the local structure around the Gd(III) ion in the 1:1 Gd(III): β-CD(A) complex in aqueous solution (pH 5.5), we used extended X-ray absorption fine structure (EXAFS) spectroscopy. Least-squares curve fitting of the Gd L₃-edge EXAFS spectrum revealed 5 Gd–O (4 COO⁻ and 1 H₂O) and 4 Gd–N (from two imino and two 1,2,3-triazole groups) bonds around the Gd(III) ion with average distances 2.36 and 2.56 ± 0.02 Å, respectively. A similar EXAFS spectrum was obtained from an aqueous solution of the clinically used MRI contrast agent Na[Gd(DOTA)(H₂O)], also 9-coordinated in its first shell. Careful analysis revealed that the mean Gd–N distance is shorter in the Gd(III): β-CD(A) (1:1) complex, indicating stronger Gd–N bonding and stronger Gd(III) complex formation than with the DOTA⁴⁻ ligand. This is consistent with the lower free Gd³⁺ concentration found previously for the Gd(III): β-CD(A) (1:1) complex than for the [Gd(DOTA)(H₂O)]⁻ complex, and shows its potential as an MRI probe.

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EXAFS spectroscopy revealed a similar Gd(III) 9-coordination although slightly stronger for a modified β-cyclodextrin: Gd(III) 1:1 complex, [Gd(LH₄)]⁷⁻, in aqueous solution than for the clinically used MRI contrast agent Na[Gd(DOTA)(H₂O)].

Positron emission tomography (PET) imaging of Aβ plaques, is recognized as a tool for the diagnosis of Alzheimer’s disease. As a contribution to the development of new strategies for early diagnosis of the disease, using PET medical imaging technique, a new copper complex, the [Cu(TE1PA-ONO)]⁺ was synthesized in ten steps. The key step of our strategy is the coupling of a monopicolinate-N-alkylated cyclam-based ligand with a moiety capable of recognizing Aβ plaques via a successful and challenging Buchwald-Hartwig coupling reaction. To our knowledge, it is the first time that such a strategy is used to functionalize polyazamacrocyclic derivatives. The thermodynamic stability constants determined in MeOH/H₂O solvent indicate that the attachment of this moiety does not weaken the chelating properties of TE1PA-ONO ligand in relation to parent HTE1PA. The novel complex described here is able to recognize amyloid plaques in brain sections from Alzheimer's disease patients and shows low toxicity to human neuronal cells.

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The cellular accumulation and the underlying mechanisms for the two ruthenium-based anticancer complexes [Ru^II(cym)(HQ)Cl] 1 (cym = η⁶-p-cymene, HQ = 8-hydroxyquinoline) and [Ru^II(cym)(PCA)Cl]Cl 2 (PCA = N-fluorophenyl-2-pyridinecarbothioamide) were investigated in HCT116 human colorectal carcinoma cells. The results showed that the cellular accumulation of both complexes increased over time and with higher concentrations, and that 2 accumulates in greater quantities in cells than 1. Inhibition studies of selected cellular accumulation mechanisms indicated that both 1 and 2 may be transported into the cells by both passive diffusion and active transporters, similar to cisplatin. Efflux experiments indicated that 1 and 2 are subjected to efflux through a mechanism that does not involve p-glycoprotein, as addition of verapamil did not make any difference. Exploring the influence of the Cu transporter by addition of CuCl₂ resulted in a higher accumulation of 1 and 2 whilst the amount of Pt detected was slightly reduced when cells were treated with cisplatin. Complexes 1 and 2 were further explored in zebrafish where accumulation and distribution were determined with ICP-MS and LA-ICP-MS. The results correlated with the in vitro observations and zebrafish treated with 2 showed higher Ru contents than those treated with 1. The distribution studies suggested that both complexes mainly accumulated in the intestines of the zebrafish.

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Three new dinuclear gold(I) complexes (1–3) containing a carbene (1,3-Bis(2,6-di-isopropylphenyl)imidazol-2-ylidene (IPr)) and diphosphane ligands [bis(1,2-diphenylphosphano)ethane (Dppe), bis(1,3-diphenylphosphano)propane (Dppp) and bis[2-(dicyclohexylphosphano)ethyl]amine (DCyPA)], were synthesized and characterized by elemental analysis and, ESI–MS, mid FT-IR and NMR spectroscopic methods. The structures of complexes 2 and 3 were determined by X-ray crystallography, which revealed that the complexes are dinuclear having gold(I) ions linearly coordinated. The anticancer activities of the complexes (1–3) were evaluated in lung (A549), breast (MC-F7), prostate (PC-3), osteosarcoma (MG-63) and ovarian (A2780 and A2780cis) cancer models. Growth inhibition by the new complexes was higher than cisplatin in all cell lines tested. The mechanism of action of complex 3 was investigated in A549 cells using 2-dimensional (2D) models and 3D-multicellular tumor spheroids. Treatment of A549 cells with complex 3 caused: the induction of apoptosis and the generation of reactive oxygen species; the cell cycle arrest in the G0/G1 phase; the inhibition of both the proteasome and the NF-kB activity; the down-regulation of lung cancer stem cell markers (NOTCH1, CD133, ALDH1 and CD44). Complex 3 was more active than cisplatin also in 3D models of A549 lung cancer cells.

Grahical abstract

Circular permutation (CP) is a technique by which the primary sequence of a protein is rearranged to create new termini. The connectivity of the protein is altered but the overall protein structure generally remains unperturbed. Understanding the effect of CP can help design robust proteins for numerous applications such as in genetic engineering, optoelectronics, and improving catalytic activity. Studies on different protein topologies showed that CP usually affects protein stability as well as unfolding rates. Though a significant number of proteins contain metals or other cofactors, reports of metalloprotein CPs are rare. Thus, we chose a bacterial metalloprotein, azurin, and its CP within the metal-binding site (cpF114). We studied the stabilities, folding, and unfolding rates of apo- and Zn²⁺-bound CP azurin using fluorescence and circular dichroism. The introduced CP had destabilizing effects on the protein. Also, the folding of the Zn²⁺-CP protein was much slower than that of the Zn²⁺-WT or apo-protein. We compared this study to our previously reported azurin-cpN42, where we had observed an equilibrium and kinetic intermediate. cpF114 exhibits an apparent two-state equilibrium unfolding but has an off-pathway kinetic intermediate. Our study hinted at CP as a method to modify the energy landscape of proteins to alter their folding pathways. WT azurin, being a faster folder, may have evolved to optimize the folding rate of metal-bound protein compared to its CPs, albeit all of them have the same structure and function. Our study underscores that protein sequence and protein termini positions are crucial for metalloproteins.

Graphical abstract

TOC Figure. (Top) Zn²⁺-azurin WT structure (PDB code: 1E67) and 2-D topology diagram of Zn²⁺-cpF114 azurin. (Bottom) Cartoon diagram representing folding (red arrows) and unfolding (blue arrows) of apo- and Zn²⁺- WT and cpF114 azurins. The width of the arrows represents the rate of the corresponding processes.

In this study, a series of N-functionalized benzimidazole silver(I) complexes were prepared and characterized by FT-IR, ¹H, ¹³C{¹H} NMR spectroscopy, and elemental analysis. Synthesized N-benzylbenzimidazole silver(I) complexes were evaluated for their antimicrobial activities against bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and the fungal strains Candida albicans and Candida glabrata. The results indicated that N-alkylbenzimidazole silver(I) complexes exhibited good antimicrobial activity compared to N-alkylbenzimidazole derivatives. Especially, complex 2e presented perfect antimicrobial activity than the other complexes. The characterized molecules were optimized by DFT-based calculation methods and the optimized molecules were analyzed in detail by molecular docking methods against bacterial DNA-gyrase and CYP51. The amino acid residues detected for both target molecules are consistent with expectations, and the calculated binding affinities and inhibition constants are promising for further studies.

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A series of N-alkylbenzimidazole silver(I) complexes were synthesized and fully characterized by means of 1H NMR, 13C NMR, and FT-IR spectroscopies. Synthesized N-alkylbenzimidazole silver(I) complexes were investigated for their antimicrobial activities against bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and the fungal strains Candida albicans and Candida glabrata. All complexes showed better activity according to Ampicilin against Pseudomonas aeruginosa. The molecules which were firstly optimized by DFT-based calculation methods were also analyzed by molecular docking methods against DNA gyrase of E. Coli and CYP51. 338 × 190 mm (96 × 96 DPI)

In this work, two analogous coumarin-thio and semicarbazone hybrid compounds were prepared and evaluated as a potential antichagasic agents. Furthermore, palladium and platinum complexes with the thiosemicarbazone derivative as ligand (L1) were obtained in order to establish the effect of metal complexation on the antiparasitic activity. All compounds were fully characterized both in solution and in solid state including the resolution of the crystal structure of the palladium complex by X-ray diffraction methods. Unexpectedly, all experimental and theoretical characterizations in the solid state, demonstrated that the obtained palladium and platinum complexes are structurally different: [PdCl(L1)] and [PtCl₂(HL1)]. All the studied compounds lower the proliferation of the amastigote form of Trypanosoma cruzi while some of them also have an effect on the trypomastigote stage. Additionally, the compounds inhibit T. cruzi release from host cells in variable extents. The Pd compound presented a remarkable profile in all the in vitro experiments, and it showed no toxicity for mammalian cells in the assayed concentrations. In this sense, in vivo experiments were performed for this compound using an acute model of Chagas disease. Results showed that the complex significantly lowered the parasite count in the mice blood with no significant toxicity.

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Trace elements within the brain are important for proper neurological function, but their imbalance has been rarely investigated in glioblastoma. This study enrolled a total of 14 patients with glioblastoma, and the tumor and peritumoral brain tissues were collected while undergoing surgery. The concentrations of Mg, Ca, Cr, Mn, Fe, Co, Cu, Zn, Se, As, Cd, Tl and Pb were determined using a well-evaluated ICP-MS method. The Cu- and Cd-binding proteomes were further analyzed using the anatomic transcriptional atlas from Ivy GAP. Histological evaluation was based on rubeanic acid staining and immunohistochemistry, respectively. The 13 trace element concentrations were obtained, and the highest were Ca, Mn, Fe, Zn and Cu, ranging from a few to dozens of ug/g. Correlation analysis suggested the existence of two intra-correlated clusters: essential metals (Cu–Ca–Zn–Mg) and heavy metals (Pb–As–Cd–Tl–Co–Cr–Mn). Compared to the tumor samples, significantly higher levels of Cu and Cd were observed in the peritumoral region. Further analysis of the Cu- and Cd-binding proteins from the anatomic view suggested that DBH and NOS1 were obviously increased in the leading edge than the central tumor region. Consistent with the above findings, histological evaluation of Cu and DBH further confirmed more copper and DBH expressions in the peritumoral area compared to the tumor core. Trace elements differ in tumor and peritumoral brain zone in glioblastoma, which may associate with tumor angiogenesis.

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