New TEMPO-Appended 2,2'-Bipyridine-Based Eu(III), Tb(III), Gd(III) and Sm(III) Complexes: Synthesis, Photophysical Studies and Testing Photoluminescence-Based Bioimaging Abilities.

Linked to Alzheimer's disease (AD), amyloids and tau-protein are known to contain a large number of cysteine (Cys) residues. In addition, certain levels of some common biogenic thiols (cysteine (Cys), homocysteine (Hcy), glutathione (GSH), etc.) in biological fluids are closely related to AD as well as other diseases. Therefore, probes with a selective interaction with the above-mentioned thiols can be used for the monitoring and visualizing changes of (bio)thiols in the biological fluids as well as in the brain of animal models of Alzheimer's disease. In this study, new Eu(III), Tb(III), Gd(III) and Sm(III) complexes of 2,2'-bipyridine ligands containing TEMPO fragments as receptor units for (bio)thiols are reported. The presence of free radical fragments of the ligand in the complexes was proved by using the electronic paramagnetic resonance (EPR) method. Among all the complexes, the Eu(III) complex turned out to be the most promising one as luminescence- and spin-probe for the detection of biogenic thiols. The EPR and fluorescent titration methods showed the interaction of the resulting complex with free Cys and GSH in solution. To study the practical applicability of the probes for the monitoring of AD in-vivo, by using the above-mentioned Eu(III)-based probe, the staining of the brain of mice with amyloidosis and Vero cell cultures supplemented with the cysteine-enriched medium was studied as well as the fluorescence titration of Bovine Serum Albumin, BSA (as the model for the thiol moieties containing protein), was carried out. Based on the results of fluorescence titration, the formation of a non-covalent inclusion complex between the above-mentioned Eu(III) complex and BSA was suggested.

Powerful Potential of Polyfluoroalkyl-Containing 4-Arylhydrazinylidenepyrazol-3-ones for Pharmaceuticals.

4-Arylhydrazinylidene-5-(polyfluoroalkyl)pyrazol-3-ones (4-AHPs) were found to be obtained by the regiospecific cyclization of 2-arylhydrazinylidene-3-(polyfluoroalkyl)-3-oxoesters with hydrazines, by the azo coupling of 4-nonsubstituted pyrazol-5-oles with aryldiazonium chlorides or by the firstly discovered acid-promoted self-condensation of 2-arylhydrazinylidene-3-oxoesters. All the 4-AHPs had an acceptable ADME profile. Varying the substituents in 4-AHPs promoted the switching or combining of their biological activity. The polyfluoroalkyl residue in 4-AHPs led to the appearance of an anticarboxylesterase action in the micromolar range. An NH-fragment and/or methyl group instead of the polyfluoroalkyl one in the 4-AHPs promoted antioxidant properties in the ABTS, FRAP and ORAC tests, as well as anti-cancer activity against HeLa that was at the Doxorubicin level coupled with lower cytotoxicity against normal human fibroblasts. Some Ph-N-substituted 4-AHPs could inhibit the growth of N. gonorrhoeae bacteria at MIC 0.9 µg/mL. The possibility of using 4-AHPs for cell visualization was shown. Most of the 4-AHPs exhibited a pronounced analgesic effect in a hot plate test in vivo at and above the diclofenac and metamizole levels except for the ones with two chlorine atoms in the aryl group. The methylsulfonyl residue was proved to raise the anti-inflammatory effect also. A mechanism of the antinociceptive action of the 4-AHPs through blocking the TRPV1 receptor was proposed and confirmed using in vitro experiment and molecular docking.

Recruitment of macrophages and bone marrow stem cells to regenerating liver promoted by sodium phthalhydrazide in mice.

Pharmacological interventions which could be hepatoprotective, depending on bioavailability, anti-inflammatory and macrophage-targeting potential of drugs, are still at early preclinical stages. Existing evidence from many animal models of liver injury, as well as from human data, indicate that pharmacological and/or phytochemical interventions have limited impact on liver recovery. Recent studies on stem cell therapies focused on different cell subsets involved in tissue repair, including monocytes/macrophages and bone marrow cells migrating to the injured liver. Partial hepatectomy (PH) resulted in a rapid increase of monocytes/macrophages in bone marrow and liver, which could be further enhanced by prior treatment of animals with sodium phthalhydrazide. Increased number of proliferating Ki67+ hepatocytes, increased total protein and albumin content in regenerating liver, recruitment of CD172a+ macrophages and more differentiated CD45lowCD117+ bone marrow cells, could be further promoted by the treatment of animals with 2 mg/kg b.w. phthalhydrazide, considered immunomodulatory, antioxidant and macrophage-silencing. Phenotypic polarization of macrophages can possibly explain the macrophage reparative capacities, protective against liver injury. Enhanced macrophage cell recruitment from bone marrow to regenerating liver can be possibly one of important events in hepatic recovery.

Fluorescent boron complexes based on new N,O-chelates as promising candidates for flow cytometry.

This study presents the synthesis and optical properties of a new class of bright green-yellow fluorescent dyes with potential applications in bioimaging. A facile synthetic route via the chelation of aryl(hetaryl)aminoacryloylthiophene scaffolds with a BF2 fragment is presented. The photophysical properties of the dyes are attributed to the nature and position of electron-donating and electron-withdrawing substituents. Upon coordination to a BF2 fragment, characteristic emission was observed, with λem ranging from 503 to 543 nm and quantum yields of 0.14-0.42. Compared with parent aryl(hetaryl)aminoacryloylthiophenes, a significant red shift in absorption (up to 480 nm in solution) and emission (up to 543 nm in solution and 610 nm in the solid state) and high chemical stability and photostability were observed. The electron-accepting character of the substituents on the terminal aromatic ring or replacing this fragment with pyridine or pyrazine moieties resulted in increased quantum yields. To gain insight into the electronic structures and optical properties, quantum mechanical calculations were performed. The results of (TD-)DFT calculations supported the structural and spectroscopic data and showed the features of electronic distribution in the frontier molecular orbitals and active electrophilic and nucleophilic sites in the compounds investigated. Synthesized BF2 complexes are promising dyes for cell imaging and flow cytometry owing to their ready penetration and accumulation in cells.