The Release of a Highly Cytotoxic Paullone Bearing a TEMPO Free Radical from the HSA Hydrogel: An EPR Spectroscopic Characterization.

This study shows the potential of a thermally induced human serum albumin (HSA) hydrogel to serve as a drug depot for sustained release of a highly cytotoxic modified paullone ligand bearing a TEMPO free radical (HL). The binding of HL to HSA was studied by electron paramagnetic resonance (EPR) spectroscopy and imaging. The EPR protocol was also implemented for the study of matrix degradation, and ligand diffusion rate, in two additional spin-labeled hydrogels, containing 5-doxylstearate and 3-carbamoyl-proxyl. The results showed that the hydrogel is an efficient HL reservoir as it retained 60% of the ligand during 11 days of dialysis in physiological saline. Furthermore, upon incubation with Colo 205 human colon adenocarcinoma cells for 3 days, the HL/HSA hydrogel did not exhibit cytotoxic activity, demonstrating that it is also an efficient ligand depot in the presence of living cells. It was observed that the percentage of HL release is independent of its initial concentration in the hydrogel, suggesting that HSA possesses a specific binding site for the ligand, most likely Sudlow site 2, as predicted by molecular docking. The intrinsic property of albumin to bind and transport various substances, including hydrophobic drugs, may be fine-tuned by appropriate physical/chemical hydrogel preparation procedures, providing optimal drug delivery.

Diastereomeric dinickel(II) complexes with non-innocent bis(octaazamacrocyclic) ligands: isomerization, spectroelectrochemistry, DFT calculations and use in catalytic oxidation of cyclohexane.

Diastereomeric dinickel(II) complexes with bis-octaazamacrocyclic 15-membered ligands [Ni(L1-3-L1-3)Ni] (4-6) have been prepared by oxidative dehydrogenation of nickel(II) complexes NiL1-3 (1-3) derived from 1,2- and 1,3-diketones and S-methylisothiocarbohydrazide. The compounds were characterized by elemental analysis, ESI mass spectrometry, and IR, UV-vis, 1H NMR, and 13C NMR spectroscopy. Single crystal X-ray diffraction (SC-XRD) confirmed the isolation of the anti and syn isomers of bis-octaazamacrocyclic dinickel(II) complexes 4a and 4s, the syn-configuration of 5s and the anti-configuration of the dinickel(II) complex 6a. Dimerization of prochiral nickel(II) complexes 1-3 generates two chiral centers at the bridging carbon atoms. The anti-complexes were isolated as meso-isomers (4a and 6a) and the syn-compounds as racemic mixtures of R,R/S,S-enantiomers (4s and 5s). The syn-anti isomerization (epimerization) of the isolated complexes in chloroform was disclosed. The isomerization kinetics of 5a was monitored at five different temperatures ranging from 20 °C to 50 °C by 1H NMR spectroscopy indicating the clean conversion of 5a into 5s. The activation barrier determined from the temperature dependence of the rate constants via the Eyring equation was found to be ΔH‡ = 114 ± 1 kJ mol-1 with activation entropy ΔS‡ = 13 ± 3 J K-1 mol-1. The complexes contain two low-spin nickel(II) ions in a square-planar coordination environment. The electrochemical behavior of 4a, 4s, 5s and 6a and the electronic structure of the oxidized species were studied by UV-vis-NIR-spectroelectrochemistry (SEC) and DFT calculations indicating the redox non-innocent behavior of the complexes. The dinickel(II) complexes 4a, 4s, 5s and 6a/6s were investigated as catalysts for microwave-assisted solvent-free oxidation of cyclohexane by tert-butyl hydroperoxide to produce a mixture of cyclohexanone and cyclohexanol (KA oil). The best value for KA oil yield (16%) was obtained with a mixture of 6a/6s after 2 h of microwave irradiation at 100 °C.

Nickel(II), Copper(II) and Palladium(II) Complexes with Bis-Semicarbazide Hexaazamacrocycles: Redox-Noninnocent Behavior and Catalytic Activity in Oxidation and C-C Coupling Reactions.

Nickel(II), copper(II), and palladium(II) complexes MLH, where M = Ni (1), Cu (2), Pd (3), and MLOMe, where M = Ni (4), Cu (5), Pd (6), have been prepared by reactions of NiCl2·6H2O, Cu(OAc)2·H2O, and PdCl2(MeCN)2 with 14-membered bis-semicarbazide hexaazamacrocycles H2LH and H2LOMe in dimethylformamide (DMF). The compounds were characterized by elemental analysis, ESI mass spectrometry, IR, UV-vis, and 1D (1H, 13C) and 2D (1H-1H COSY, 1H-1H TOCSY, 1H-1H NOESY, 1H-13C HSQC, 1H-13C HMBC) NMR spectra (1, 3, 4, and 6), and X-ray diffraction (2, 4-6). The complexes with MIIN4 coordination environment have S = 0, 1/2, 0 ground states for Ni, Cu, and Pd, respectively. The electrochemical behavior of 1-6 was investigated in detail. The electronic structures of 1e-oxidized species were studied by EPR, UV-vis-NIR spectroelectrochemistry, and DFT calculations, indicating the redox-noninnocent behavior of the ligands. Compounds 1-6 were tested in the oxidation of styrene and C-C coupling (Henry and Knoevenagel condensations). Compounds 2 and 5 selectively catalyze the microwave-assisted oxidation of neat styrene to benzaldehyde (up to 88% yield), whereas the 1 and 4 catalytic systems afforded up to 99% ß-nitroethanol yield with an appreciable diastereoselectivity toward the formation of the anti isomer.

Binding of a Fatty Acid-Functionalized Anderson-Type Polyoxometalate to Human Serum Albumin.

The Anderson-type hexamolybdoaluminate functionalized with lauric acid (LA), (TBA)3[Al(OH)3Mo6O18{(OCH2)3CNHCOC11H23}]·9H2O (TBA-AlMo6-LA, where TBA = tetrabutylammonium), was prepared via two synthetic routes and characterized by thermogravimetric and elemental analyses, mass spectrometry, IR and 1H NMR spectroscopy, and powder and single-crystal X-ray diffraction. The interaction of TBA-AlMo6-LA with human serum albumin (HSA) was investigated via fluorescence and circular dichroism spectroscopy. The results revealed that TBA-AlMo6-LA binds strongly to HSA (63% quenching at an HSA/TBA-AlMo6-LA ratio of 1:1), exhibiting static quenching. In contrast to TBA-AlMo6-LA, the nonfunctionalized polyoxometalate, Na3(H2O)6[Al(OH)6Mo6O18]·2H2O (AlMo6), showed weak binding toward HSA (22% quenching at a HSA/AlMo6 ratio of 1:25). HSA binding was confirmed by X-ray structure analysis of the HSA-Myr-AlMo6-LA complex (Myr = myristate). These results provide a promising lead for the design of novel polyoxometalate-based hybrids that are able to exploit HSA as a delivery vehicle to improve their pharmacokinetics and bioactivity.

Nickel(II) Complexes with Redox Noninnocent Octaazamacrocycles as Catalysts in Oxidation Reactions.

Nickel(II) complexes with 15-membered (1-5) and 14-membered (6) octaazamacrocyclic ligands derived from 1,2- and 1,3-diketones and S-methylisothiocarbohydrazide were prepared by template synthesis. The compounds were characterized by elemental analysis, electrospray ionization mass spectrometry, IR, UV-vis, 1H NMR spectroscopies, and X-ray diffraction. The complexes contain a low-spin nickel(II) ion in a square-planar coordination environment. The electrochemical behavior of 1-6 was investigated in detail, and the electronic structure of 1e-oxidized and 1e-reduced species was studied by electron paramagnetic resonance, UV-vis-near-IR spectroelectrochemistry, and density functional theory calculations indicating redox noninnocent behavior of the ligands. Compounds 1-6 were tested in the microwave-assisted solvent-free oxidation of cyclohexane by tert-butyl hydroperoxide to produce the industrially significant mixture of cyclohexanol and cyclohexanone (i.e., A/K oil). The results showed that the catalytic activity was affected by several factors, namely, reaction time and temperature or amount and type of catalyst. The best values for A/K oil yield (23%, turnover number of 1.1 × 102) were obtained with compound 6 after 2 h of microwave irradiation at 100 °C.

Iron(II) and copper(II) paratungstates B: a single-crystal X-ray diffraction study.

Paratungstate B is a common isopolytungstate (IPOT) built of the [W12O40(OH)2]10- anion and exhibits a cluster-like construction of 12 W-centred distorted octahedra. Due to a high surface charge density, the paratungstate anion acts as a multidentate ligand forming high-dimensional extended structures, which exhibit unique catalytic and magnetic properties. Two new paradodecatungstate B compounds decorated by iron(II) or copper(II), namely Na5Fe2.5[W12O40(OH)2]·36H2O (Na5Fe2.5paraB) and Na4Cu3[W12O40(OH)2]·28H2O (Na4Cu3paraB), have been synthesized by a convenient aqueous solution method, and structurally characterized by single-crystal and powder X-ray diffraction, IR spectroscopy, elemental analysis and thermogravimetric analysis. Both compounds crystallize in the triclinic P-1 space group. In both compounds, the [W12O40(OH)2]10- polyanion acts as a multidentate ligand that links transition-metal and sodium cations, forming a three-dimensional framework.

Structure-antiproliferative activity studies on l-proline- and homoproline-4-N-pyrrolidine-3-thiosemicarbazone hybrids and their nickel(ii), palladium(ii) and copper(ii) complexes.

Two water-soluble thiosemicarbazone-proline (H2L(1)) and thiosemicarbazone-homoproline hybrids (H2L(2)) were synthesised. By reaction of H2L(1) with NiCl2·6H2O, PdCl2 and CuCl2·2H2O in ethanol, the series of square-planar complexes [Ni(H2L(1))Cl]Cl·1.3H2O (1·1.3H2O), [Pd(H2L(1))Cl]Cl·H2O (2·H2O) and [Cu(H2L(1))Cl]Cl·0.7H2O (3·0.7H2O) was prepared, and starting from H2L(2) and CuCl2·2H2O in methanol, the complex [Cu(H2L(2))Cl2]·H2O (4·H2O) was obtained. The compounds have been characterised by elemental analysis, spectroscopic methods (IR, UV-vis and NMR spectroscopy), ESI mass spectrometry and single crystal X-ray crystallography (H2L(1), 1, 2 and 4). As a solid, 1 is diamagnetic, while it is paramagnetic in methanolic solution. The effective magnetic moment of 3.26 B.M. at room temperature indicates the change in coordination geometry from square-planar to octahedral upon dissolution. The in vitro anticancer potency of ligand precursors H2L(1) and H2L(2) and metal complexes 1-4 was studied in three human cancer cell lines (A549, CH1 and SW480) and in noncancerous murine embryonal fibroblasts (NIH/3T3), and the mechanism of cell death was also assayed by flow cytometry. Clear-cut structure-activity relationships have been established. The metal ions exert marked effects in a divergent manner: copper(ii) increases, whereas nickel(ii) and palladium(ii) decrease the cytotoxicity of the hybrids. The antiproliferative activity of H2L(1) and metal complexes 1-3 decreases in all three tumour cell lines in the following rank order: 3 > H2L(1) > 1 > 2. The role of square-planar geometry in the underlying mechanism of cytotoxicity of the metal complexes studied seems to be negligible, while structural modifications at the terminal amino group of thiosemicarbazide and proline moieties are significant for enhancing the antiproliferative activity of both hybrids and copper(ii) complexes.

A highly cytotoxic modified paullone ligand bearing a TEMPO free-radical unit and its copper(II) complex as potential hR2 RNR inhibitors.

A new paullone-TEMPO conjugate and its copper(II) complex inhibit RNR activity and show high antiproliferative activity in human cancer cell lines.

Ruthenium- and osmium-arene-based paullones bearing a TEMPO free-radical unit as potential anticancer drugs.

A modified paullone ligand bearing a TEMPO free-radical unit (HL) and its ruthenium(II) and osmium(II)-arene complexes [M(p-cymene)(HL)Cl]Cl·nH(2)O (M = Ru, Os) exhibit high antiproliferative activity in human cancer cell lines.