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Design and development of novel, low-cost and efficient electrocatalysts for oxygen evolution reaction (OER) in alkaline media is crucial for lowering the reaction overpotential and thus decreasing the energy input during the water electrolysis process. Herein, we present the synthesis of new 14-membered bis-thiosemicarbazide and bis-isothiosemicarbazide macrocycles and their nickel(II) complexes characterized by spectroscopic techniques ( 1 H and 13 C NMR, IR, UV-vis), electrospray ionization mass spectrometry, single crystal X-ray diffraction, scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX) and cyclic voltammetry. Finally, the activity of nickel(II) complexes towards OER is reported. NiIILSEt delivered a current density of 10 mA cm -2 at the lowest overpotential of 350 mV with the lowest Tafel slope of 93 mV dec -1 . The high performance of NiIILSEt might be attributed to its high surface area and thus abundant active sites with the observed low charge-transfer resistance enabling the effective current flow through the electrocatalyst. Square-planar coordination geometry and increment in Ni oxidation state are believed to favor its OER performance. Beside high activity towards OER, NiIILSEt demonstrated excellent long-term stability with continuous operation, advocating its possible application in commercial systems.

Quite recently we discovered that copper(II) complexes with isomeric morpholine-thiosemicarbazone hybrid ligands show good cytotoxicity in cancer cells and that the molecular target responsible for this activity might be tubulin. In order to obtain better lead drug candidates, we opted to exploit the power of coordination chemistry to (i) assemble structures with globular shape to better fit the colchicine pocket and (ii) vary the metal ion. We report the synthesis and full characterization of bis-ligand cobalt(III) and iron(III) complexes with 6-morpholinomethyl-2-formylpyridine 4 N -(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL1), 6-morpholinomethyl-2-acetylpyridine 4 N -(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL2), and 6-morpholinomethyl-2-formylpyridine 4 N -phenyl-3-thiosemicarbazone (HL3), and mono -ligand nickel(II), zinc(II) and palladium(II) complexes with HL1, namely [Co III (HL 1 )(L 1 )](NO 3 ) 2 (1), [Co III (HL 2 )(L 2 )](NO 3 ) 2 (2), [Co III (HL 3 )(L 3 )](NO 3 ) 2 (3), [Fe III (L 2 ) 2 ]NO 3 (4), [Fe III (HL 3 )(L 3 )](NO 3 ) 2 (5), [Ni II (L 1 )]Cl (6), [Zn(L 1 )Cl] (7) and [Pd II (HL 1 )Cl]Cl (8). We discuss the effect of the metal identity and metal complex stoichiometry on in vitro cytotoxicity and antitubulin activity. The high antiproliferative activity of complex 4 correlated well with inhibition of tubulin polymerization. Insights into the mechanism of antiproliferative activity were supported by experimental results and molecular docking calculations.

The development of copper(II) thiosemicarbazone complexes as potential anticancer agents, possessing dual functionality as inhibitors of R2 ribonucleotide reductase (RNR) and tubulin polymerization by binding at the colchicine site, presents a promising avenue for enhancing therapeutic effectiveness. Herein, we describe the syntheses and physicochemical characterization of four isomeric proligands H 2 L 3 - H 2 L 6 , with the methylmorpholine substituent at pertinent positions of the pyridine ring, along with their corresponding Cu(II) complexes 3 - 6 . Evidently, the position of the morpholine moiety and the copper(II) complex formation have marked effects on the in vitro antiproliferative activity in human uterine sarcoma MES-SA cells and the multidrug-resistant derivative MES-SA/Dx5 cells. Activity correlated strongly with quenching of the tyrosyl radical (Y • ) of mouse R2 RNR protein, inhibition of RNR activity in the cancer cells, and inhibition of tubulin polymerization. Insights into the mechanism of antiproliferative activity, supported by experimental results and molecular modeling calculations, are presented.

Cobalt complexes with multiproton- and multielectron-responsive ligands are of interest for challenging catalytic transformations. The chemical and redox noninnocence of pentane-2,4-dione bis( S -methylisothiosemicarbazone) (PBIT) in a series of cobalt complexes has been studied by a range of methods, including spectroscopy [UV-vis, NMR, electron paramagnetic resonance (EPR), X-ray absorption spectroscopy (XAS)], cyclic voltammetry, X-ray diffraction, and density functional theory (DFT) calculations. Two complexes [Co III (H 2 L SMe )I]I and [Co III ( L SMe )I 2 ] were found to act as precatalysts in a Wacker-type oxidation of olefins using phenylsilane, the role of which was elucidated through isotopic labeling. Insights into the mechanism of the catalytic transformation as well as the substrate scope of this selective reaction are described, and the essential role of phenylsilane and the noninnocence of PBIT are disclosed. Among the several relevant species characterized was an unprecedented Co(III) complex with a dianionic diradical PBIT ligand ([Co III (L SMe•• )I])., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The anti ( a ) to syn ( s ) isomerization pathway of the deprotonated form of the dimer with two nickel(II) 15-membered octaazamacrocyclic units connected via a carbon-carbon (C-C) σ bond was investigated. For the initial anti ( a ) structure, a deprotonation of one of the bridging ( sp 3 hybridized) carbon atoms is suggested to allow for an a to s geometry twist. A 360° scan around the bridging C-C dihedral angle was performed first to find an intermediate geometry. Subsequently, the isomerization pathway was explored via individual steps using a series of mode redundant geometry optimizations (internal coordinates potential energy surface scans) and geometry relaxations leading to the s structure. The prominent geometries (intermediates) of the isomerization pathway are chosen and compared to the a and s structures, and geometry relaxations of the protonated forms of selected intermediates are considered., Supplementary Information: The online version contains supplementary material available at 10.1007/s00214-024-03100-5., Competing Interests: Conflict of interestsThe authors declare that they have no conflict of interest., (© The Author(s) 2024.)

A series of four indolo[2,3- e ]benzazocines HL1-HL4 and two indolo[2,3- f ]benzazonines HL5 and HL6, as well as their respective copper(II) complexes 1-6, were synthesized and characterized by 1 H and 13 C NMR spectroscopy, ESI mass spectrometry, single crystal X-ray diffraction (SC-XRD) and combustion analysis (C, H, N). SC-XRD studies of precursors Vd, VIa·0.5MeOH, of ligands HL4 and HL6·DCM, and complexes 2·2DMF, 5·2DMF, 5'·iPrOH·MeOH provided insights into the energetically favored conformations of eight- and nine-membered heterocycles in the four-ring systems. In addition, proton dissociation constants (p K a ) of HL1, HL2 and HL5, complexes 1, 2 and 5, overall stability constants (log  β ) of 1, 2 and 5 in 30% (v/v) DMSO/H 2 O at 298 K, as well as thermodynamic solubility of HL1-HL6 and 1-6 in aqueous solution at pH 7.4 were determined by UV-vis spectroscopy. All compounds were tested for antiproliferative activity against Colo320, Colo205 and MCF-7 cell lines and showed IC 50 values in the low micromolar to sub-micromolar concentration range, while some of them (HL1, HL5 and HL6, 1, 2 and 6) showed remarkable selectivity towards malignant cell lines. Ethidium bromide displacement studies provided evidence that DNA is not the primary target for these drugs. Rather, inhibition of tubulin assembly is likely the underlying mechanism responsible for their antiproliferative activity. Tubulin disassembly experiments showed that HL1 and 1 are effective microtubule destabilizing agents binding to the colchicine site. This was also confirmed by molecular modelling investigations. To the best of our knowledge, complex 1 is the first reported transition metal complex to effectively bind to the tubulin-colchicine pocket.

An article was published in the journal "Current Pharmaceutical Design", Volume 9, No. 25, 2003, pp: 2078-2089 [1]. The first author is requesting an alteration in the name. Details of a correction are provided here. The original name published was Markus Galanski. The request is to change the name to Mathea Sophia Galanski. The original article can be found online at: https://www.eurekaselect.com/article/8545 We regret the error and apologize to readers., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Protein-based hydrogels have attracted growing attention for pharmaceutical and biomedical applications. Ovalbumin (OVA), the hen egg white albumin, possessing good foaming and gelling properties and being widely used in the food industry, has recently been indicated as a potential pharmaceutical vehicle. In this study, the binding and release properties of pure OVA hydrogels were investigated by electron paramagnetic resonance (EPR) spin labeling. The comparative analysis between OVA and serum albumin (SA) hydrogels revealed the same release kinetics of hydrophilic 3-carbamoyl-proxyl and 3-carboxy-proxyl, suggesting the diffusion-dominated release of small probes from both hydrogel types. The results obtained with the amphiphilic 16-doxylstearate (16-DS) indicate that OVA, unlike SAs, does not possess a specific fatty acid binding site. However, the OVA hydrogels were able to accommodate a two-fold excess of 16-DS, resulting from protein thermally induced conformational changes, as confirmed by Raman spectroscopy. Similarly, the hydrophobic modified paullone ligand HL , which was initially free in the OVA solution, was bound in the hydrogel. The hydrogels were found to retain a significant amount of 16-DS and HL after 7-day dialysis in physiological saline. The observed facilitated binding of amphiphilic/hydrophobic molecules in OVA hydrogels compared to the solution, and their sustained release, demonstrate the applicability of OVA hydrogels in pharmaceutics.

The search for new scaffolds of medicinal significance combined with molecular shape enhances their innovative potential and continues to attract the attention of researchers. Herein, we report the synthesis, spectroscopic characterization ( 1 H and 13 C NMR, UV-vis, IR), ESI-mass spectrometry, and single-crystal X-ray diffraction analysis of a new ring system of medicinal significance, 5,6,7,9-tetrahydro-8 H -indolo[3,2- e ]benzazocin-8-one, and a series of derived potential ligands ( HL 1 -HL 5 ), as well as ruthenium(II), osmium(II), and copper(II) complexes ( 1a , 1b , and 2-5 ). The stability of compounds in 1% DMSO aqueous solutions has been confirmed by 1 H NMR and UV-vis spectroscopy measurements. The antiproliferative activity of HL 1 -HL 5 and 1a , 1b , and 2-5 was evaluated by in vitro cytotoxicity tests against four cancer cell lines (LS-174, HCT116, MDA-MB-361, and A549) and one non-cancer cell line (MRC-5). The lead compounds HL 5 and its copper(II) complex 5 were 15× and 17×, respectively, more cytotoxic than cisplatin against human colon cancer cell line HCT116. Annexin V-FITC apoptosis assay showed dominant apoptosis inducing potential of both compounds after prolonged treatment (48 h) in HCT116 cells. HL 5 and 5 were found to induce a concentration- and time-dependent arrest of cell cycle in colon cancer cell lines. Antiproliferative activity of 5 in 3D multicellular tumor spheroid model of cancer cells (HCT116, LS-174) superior to that of cisplatin was found. Moreover, HL 5 and 5 showed notable inhibition potency against glycogen synthase kinases (GSK-3α and GSK-3β), tyrosine-protein kinase (Src), lymphocyte-specific protein-tyrosine kinase (Lck), and cyclin-dependent kinases (Cdk2 and Cdk5) (IC 50 = 1.4-6.1 μM), suggesting their multitargeted mode of action as potential anticancer drugs.

Unprecedented self-assembly of a novel 14-membered cyclic bis-thiosemicarbazone or/and a 28-membered cyclic tetrakis-thiosemicarbazone upon acid-promoted cyclooligomerization of 4-(4-thiosemicarbazido)butan-2-one hydrazone has been discovered. A thorough study of the influence of various factors on the direction of macrocyclization provided the optimal conditions for the highly selective formation of each of the macrocycles in excellent yields. Plausible pathways for macrocyclizations have been discussed. The macrocycle precursor was prepared by the reaction of readily available 4-isothiocyanatobutan-2-one with an excess of hydrazine.

In the title hydrated mol-ecular salt, [Cu(C 7 H 20 N 4 )(H 2 O) 2 ](C 8 H 4 O 4 )·H 2 O, the metal ion is coordinated by the two primary and two secondary N atoms of the amine ligand and the mutually trans O atoms of the water mol-ecules in a tetra-gonally distorted octa-hedral geometry. The average equatorial Cu-N bond lengths (2.013 and 2.026 Å for Cu-N prim and Cu-N sec , respectively) are substanti-ally shorter than the average axial Cu-O bond length (2.518 Å). The tetra-amine ligand adopts its energetically favored conformation with its five- and six-membered chelate rings in gauche and chair conformations, respectively. In the crystal, the N-H donor groups of the tetra-amine, the acceptor carboxyl-ate groups of the isophthalate dianion and both the coordinated water mol-ecules and the water mol-ecule of crystallization are involved in numerous N-H⋯O and O-H⋯O hydrogen bonds, resulting in the formation of electroneutral layers oriented parallel to the ac plane., (© Tsymbal et al. 2022.)

Indolo[3,2- d ][1]benzazepines (paullones), indolo[3,2- d ][2]benzazepines, and indolo[2,3- d ][2]benzazepines (latonduines) are isomeric scaffolds of current medicinal interest. Herein, we prepared a small library of novel indolo[3,2- d ][2]benzazepine-derived ligands HL 1 - HL 4 and copper(II) complexes 1 - 4 . All compounds were characterized by spectroscopic methods ( 1 H and 13 C NMR, UV-vis, IR) and electrospray ionization (ESI) mass spectrometry, while complexes 2 and 3 , in addition, by X-ray crystallography. Their purity was confirmed by HPLC coupled with high-resolution ESI mass spectrometry and/or elemental analysis. The stability of compounds in aqueous solutions in the presence of DMSO was confirmed by 1 H NMR and UV-vis spectroscopy measurements. The compounds revealed high antiproliferative activity in vitro in the breast cancer cell line MDA-MB-231 and hepatocellular carcinoma cell line LM3 in the low micromolar to nanomolar concentration range. Important structure-activity relationships were deduced from the comparison of anticancer activities of HL 1 - HL 4 and 1 - 4 with those of structurally similar paullone-derived ( HL 5 - HL 7 and 5 - 7 ) and latonduine-derived scaffolds ( HL 8 - HL 11 and 8 - 11 ). The high anticancer activity of the lead drug candidate 4 was linked to reactive oxygen species and endoplasmic reticulum stress induction, which were confirmed by fluorescent microscopy and Western blot analysis.

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.

The synthesis of new types of mono- and polynuclear ruthenium nitrosyl complexes is driving progress in the field of NO generation for a variety of applications. Light-induced Ru-NO bond dissociation in solution may involve transient linkage isomers MS1 (Ru-ON) and MS2 (Ru-η 2 -NO), which can be detected spectroscopically and analyzed computationally. The investigation of photoisomerization processes in the solid state may be useful for potential application of such complexes for data storage, photochromic or photomagnetic materials or even non-linear optics. Herein we describe the major developments in the synthesis of ruthenium nitrosyl complexes, their photoinduced linkage isomerization (PLI) processes, their NO release both in the solid state and in solution, and their application as potential anticancer drugs. Illustrative examples of such innovations made mainly in the last decade are provided.

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, 1 H NMR, and 13 C 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 1 H 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 Δ H ‡ = 114 ± 1 kJ mol -1 with activation entropy Δ S ‡ = 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.

The proton dissociation processes of two tridentate salicylidene aminoguanidine Schiff bases (SISC, Pro-SISC-Me), the solution stability and electrochemical properties of their Cu(II), Fe(II) and Fe(III) complexes were characterized using pH-potentiometry, cyclic voltammetry and UV-visible, 1 H NMR and electron paramagnetic resonance spectroscopic methods. The structure of the proline derivative (Pro-SISC-Me) was determined by X-ray crystallography. The conjugation of L-proline to the simplest salicylidene aminoguanidine Schiff base (SISC) increased the water solubility due to its zwitterionic structure in a wide pH range. The formation of mono complexes with both ligands was found in the case of Cu(II) and Fe(II), while bis complexes were also formed with Fe(III). In the complexes these tridentate ligands coordinate via the phenolato O, azomethine N and the amidine N, except the complex [Fe(III)L 2 ] + of Pro-SISC-Me in which the (O,N) donor atoms of the proline moiety are coordinated beside the phenolato O, confirmed by single crystal X-ray crystallographic analysis. This binding mode yielded a stronger Fe(III) preference for Pro-SISC-Me over Fe(II) in comparison to SISC. This finding is also reflected in the lower redox potential value of the iron-Pro-SISC-Me complexes. The ligands alone were not cytotoxic against human colon cancer cell lines, while complexation of SISC with Cu(II) resulted in moderate activity, unlike the case of its more hydrophilic counterpart.

A series of latonduine and indoloquinoline derivatives HL 1 - HL 8 and their copper(II) complexes ( 1-8 ) were synthesized and comprehensively characterized. The structures of five compounds ( HL 6 , [CuCl(L 1 )(DMF)]·DMF , [CuCl(L 2 )(CH 3 OH)] , [CuCl(L 3 )]·0.5H 2 O , and [CuCl 2 (H 2 L 5 )]Cl·2DMF ) were elucidated by single crystal X-ray diffraction. The copper(II) complexes revealed low micro- to sub-micromolar IC 50 values with promising selectivity toward human colon adenocarcinoma multidrug-resistant Colo320 cancer cells as compared to the doxorubicin-sensitive Colo205 cell line. The lead compounds HL 4 and 4 as well as HL 8 and 8 induced apoptosis efficiently in Colo320 cells. In addition, the copper(II) complexes had higher affinity to DNA than their metal-free ligands. HL 8 showed selective inhibition for the PIM-1 enzyme, while 8 revealed strong inhibition of five other enzymes, i.e., SGK-1, PKA, CaMK-1, GSK3β, and MSK1, from a panel of 50 kinases. Furthermore, molecular modeling of the ligands and complexes showed a good fit to the binding pockets of these targets.

Paullone isomers are known as inhibitors of tubulin polymerase and cyclin dependent kinases (Cdks), which are potential targets for cancer chemotherapy. Herein we report an efficient and clean pathway to the fourth isomer, which remained elusive so far, namely 7,8-dihydroindolo[2,3- d ][1]benzazepin-6(5 H )-one. Moreover, we demonstrate the generality of our pathway by synthesizing two closely related analogues, one containing a bromo substituent and the other one incorporating an 8-membered instead of a 7-membered ring. The key transformation in this four-step synthesis, with an overall yield of 29%, is the Fischer indole reaction of 2-nitrophenylacetyl acetoacetate with 1-benzyl-1-phenylhydrazine in acetic acid that delivers methyl 2-(1-benzyl-3-(2-nitrophenyl)-1 H -indol-2-yl)acetate in 55% yield., (Copyright © 2022, Kuznetcova et al.)

Indolo[2,3- d ]benzazepines (indololatonduines) are rarely discussed in the literature. In this project, we prepared a series of novel indololatonduine derivatives and their Ru II and Os II complexes and investigated their microtubule-targeting properties in comparison with paclitaxel and colchicine. Compounds were fully characterized by spectroscopic techniques ( 1 H NMR and UV-vis), ESI mass-spectrometry, and X-ray crystallography, and their purity was confirmed by elemental analysis. The stabilities of the compounds in DMSO and water were confirmed by 1 H and 13 C NMR and UV-vis spectroscopy. Novel indololatonduines demonstrated anticancer activity in vitro in a low micromolar concentration range, while their coordination to metal centers resulted in a decrease of cytotoxicity. The preliminary in vivo activity of the Ru II complex was investigated. Fluorescence staining and in vitro tubulin polymerization assays revealed the prepared compounds to have excellent microtubule-destabilizing activities, even more potent than the well-known microtubule-destabilizing agent colchicine.

The ruthenium nitrosyl moiety, {RuNO} 6 , is important as a potential releasing agent of nitric oxide and is of inherent interest in coordination chemistry. Typically, {RuNO} 6 is found in mononuclear complexes. Herein we describe the synthesis and characterization of several multimetal cluster complexes that contain this unit. Specifically, the heterotrinuclear μ 3 -oxido clusters [Fe 2 RuCl 4 (μ 3 -O)(μ-OMe)(μ-pz) 2 (NO)(Hpz) 2 ] ( 6 ) and [Fe 2 RuCl 3 (μ 3 -O)(μ-OMe)(μ-pz) 3 (MeOH)(NO)(Hpz)][Fe 2 RuCl 3 (μ 3 -O)(μ-OMe)(μ-pz) 3 (DMF)(NO)(Hpz)] ( 7 ·MeOH·2H 2 O) and the heterotetranuclear μ 4 -oxido complex [Ga 3 RuCl 3 (μ 4 -O)(μ-OMe) 3 (μ-pz) 4 (NO)] ( 8 ) were prepared from trans -[Ru(OH)(NO)(Hpz) 4 ]Cl 2 ( 5 ), which itself was prepared via acidic hydrolysis of the linear heterotrinuclear complex {[Ru(μ-OH)(μ-pz) 2 (pz)(NO)(Hpz)] 2 Mg} ( 4 ). Complex 4 was synthesized from the mononuclear Ru complexes (H 2 pz)[ trans -RuCl 4 (Hpz) 2 ] ( 1 ), trans -[RuCl 2 (Hpz) 4 ]Cl ( 2 ), and trans -[RuCl 2 (Hpz) 4 ] ( 3 ). The new compounds 4 - 8 were all characterized by elemental analysis, ESI mass spectrometry, IR, UV-vis, and 1 H NMR spectroscopy, and single-crystal X-ray diffraction, with complexes 6 and 7 being characterized also by temperature-dependent magnetic susceptibility measurements and Mössbauer spectroscopy. Magnetometry indicated a strong antiferromagnetic interaction between paramagnetic centers in 6 and 7 . The ability of 4 and 6 - 8 to form linkage isomers and release NO upon irradiation in the solid state was investigated by IR spectroscopy. A theoretical investigation of the electronic structure of 6 by DFT and ab initio CASSCF/NEVPT2 calculations indicated a redox-noninnocent behavior of the NO ancillary ligand in 6 , which was also manifested in TD-DFT calculations of its electronic absorption spectrum. The electronic structure of 6 was also studied by an X-ray charge density analysis.

The asymmetric unit of the title compound, trans -di-aqua-(1,4,8,11-tetra-aza-undecane-κ 4 N 1 , N 4 , N 8 , N 11 )nickel(II) bis-(pyridine-2,6-di-carboxyl-ato-κ 3 O 2 , N , O 6 )nickel(II) {[Ni( L )(H 2 O) 2 ][Ni(pdc) 2 ] where L = 1,4,8,11-tetra-aza-undecane (C 7 H 20 N 4 ) and pdc = the dianion of pyridine-2,6-di-carb-oxy-lic acid (C 7 H 3 NO 4 2- )} consists of an [Ni( L )(H 2 O) 2 ] 2+ complex cation and a [Ni(pdc) 2 ] 2- anion. The metal ion in the cation is coordinated by the four N atoms of the tetra-amine ligand and the mutually trans O atoms of the water mol-ecules in a tetra-gonally elongated octa-hedral geometry with the average equatorial Ni-N bond length slightly shorter than the average axial Ni-O bond [2.087 (4) versus 2.128 (4) Å]. The ligand L adopts its energetically favored conformation with five-membered and six-membered chelate rings in gauche and chair conformations, respectively. In the complex anion, the Ni II ion is coordinated by the two tridentate pdc 2- ligands via their carboxyl-ate and nitro-gen atom donors in a distorted octa-hedral trans -NiO 4 N 2 geometry with nearly orthogonal orientation of the planes defining the carboxyl-ate rings and the average Ni-N bond length [1.965 (4) Å] shorter than the average Ni-O bond distance [2.113 (7) Å]. In the crystal, the NH donor groups of the tetra-amine, the carb-oxy-lic groups of the pdc 2- anion and the coordinated water mol-ecules are involved in numerous N-H⋯O and O-H⋯O hydrogen bonds, leading to electroneutral sheets oriented parallel to the (001) plane., (© Andriichuk et al. 2021.)

The magnetism of a recently synthesized trans -[Os IV Cl 4 (κN 1 -Hind) 2 ] complex (5d 4 -system), where Hind = 2 H -indazole, was studied experimentally and theoretically. Relativistic CASSCF/CASPT2 calculations for this and model [Os IV Cl 6 ] 2- complexes were employed to understand the nature of the low-lying multiplets. It is found that despite strong metal-ligand covalency they are basically characterized by the total angular pseudo-momentum J̃ originating from the spin-orbit coupling of the ground-state spin S = 1 with the orbital pseudo-momentum L̃ = 1 of the Os IV ion. The strong spin-orbit interaction also preserves the dominant J̃ = 0 character of the non-magnetic ground state in the trans -[Os IV Cl 4 (κN 1 -Hind) 2 ] complex despite significant deviation of the ligand environment of Os IV from octahedral symmetry. At the same time the spin-orbit admixture of all multiplets arising from the t 2g 4 strong-field electronic configuration is indispensable for the correct description of magnetic properties of Os IV complexes. Moreover, based on ab initio calculations, we argue that the charge-transfer states play an important role in the magnetism of the present and probably other 5d complexes, a situation never encountered for 3d and 4f compounds.

Three new thiosemicarbazones (TSCs) HL 1 - HL 3 as triapine analogues bearing a redox-active phenolic moiety at the terminal nitrogen atom were prepared. Reactions of HL 1 - HL 3 with CuCl 2 ·2H 2 O in anoxic methanol afforded three copper(II) complexes, namely, Cu(HL 1 )Cl 2 ( 1 ), [ Cu(L 2 )Cl] ( 2' ), and Cu(HL 3 )Cl 2 ( 3 ), in good yields. Solution speciation studies revealed that the metal-free ligands are stable as HL 1 - HL 3 at pH 7.4, while being air-sensitive in the basic pH range. In dimethyl sulfoxide they exist as a mixture of E and Z isomers. A mechanism of the E/Z isomerization with an inversion at the nitrogen atom of the Schiff base imine bond is proposed. The monocationic complexes [Cu(L 1 - 3 )] + are the most abundant species in aqueous solutions at pH 7.4. Electrochemical and spectroelectrochemical studies of 1 , 2' , and 3 confirmed their redox activity in both the cathodic and the anodic region of potentials. The one-electron reduction was identified as metal-centered by electron paramagnetic resonance spectroelectrochemistry. An electrochemical oxidation pointed out the ligand-centered oxidation, while chemical oxidations of HL 1 and HL 2 as well as 1 and 2' afforded several two-electron and four-electron oxidation products, which were isolated and comprehensively characterized. Complexes 1 and 2' showed an antiproliferative activity in Colo205 and Colo320 cancer cell lines with half-maximal inhibitory concentration values in the low micromolar concentration range, while 3 with the most closely related ligand to triapine displayed the best selectivity for cancer cells versus normal fibroblast cells (MRC-5). HL 1 and 1 in the presence of 1,4-dithiothreitol are as potent inhibitors of mR2 ribonucleotide reductase as triapine.

Two 15-membered octaazamacrocyclic nickel(II) complexes are investigated by theoretical methods to shed light on their affinity forwards binding and reducing CO 2 . In the first complex 1 [ Ni II L ] 0 , the octaazamacrocyclic ligand is grossly unsaturated (π-conjugated), while in the second 1 [ Ni II LH ] 2+ one, the macrocycle is saturated with hydrogens. One and two-electron reductions are described using Mulliken population analysis, quantum theory of atoms in molecules, localized orbitals, and domain averaged fermi holes, including the characterization of the Ni-C CO2 bond and the oxidation state of the central Ni atom. It was found that in the [ NiLH ] complex, the central atom is reduced to Ni 0 and/or Ni I and is thus able to bind CO 2 via a single σ bond. In addition, the two-electron reduced 3 [ NiL ] 2- species also shows an affinity forwards CO 2 .

A series of thiosemicarbazone-coumarin hybrids ( HL 1 -HL 3 and H 2 L 4 ) has been synthesised in 12 steps and used for the preparation of mono- and dinuclear copper(II) complexes, namely Cu(HL 1 )Cl 2 ( 1 ), Cu(HL 2 )Cl 2 ( 2 ), Cu(HL 3 )Cl 2 ( 3 ) and Cu 2 (H 2 L 4 )Cl 4 ( 4 ), isolated in hydrated or solvated forms. Both the organic hybrids and their copper(II) and dicopper(II) complexes were comprehensively characterised by analytical and spectroscopic techniques, i.e., elemental analysis, ESI mass spectrometry, 1D and 2D NMR, IR and UV-vis spectroscopies, cyclic voltammetry (CV) and spectroelectrochemistry (SEC). Re-crystallisation of 1 from methanol afforded single crystals of copper(II) complex with monoanionic ligand Cu(L 1 )Cl , which could be studied by single crystal X-ray diffraction (SC-XRD). The prepared copper(II) complexes and their metal-free ligands revealed antiproliferative activity against highly resistant cancer cell lines, including triple negative breast cancer cells MDA-MB-231, sensitive COLO-205 and multidrug resistant COLO-320 colorectal adenocarcinoma cell lines, as well as in healthy human lung fibroblasts MRC-5 and compared to those for triapine and doxorubicin. In addition, their ability to reduce the tyrosyl radical in mouse R2 protein of ribonucleotide reductase has been ascertained by EPR spectroscopy and the results were compared with those for triapine.

The in situ spectroelectrochemical cyclic voltammetric studies of the antimony-monocapped nickel(II) and iron(II) tris-pyridineoximates with a labile triethylantimony cross-linking group and Zr(IV)/Hf(IV) phthalocyaninate complexes were performed in order to understand the nature of the redox events in the molecules of heterodinuclear zirconium(IV) and hafnium(IV) phthalocyaninate-capped derivatives. Electronic structures of their 1e-oxidized and 1e-electron-reduced forms were experimentally studied by electron paramagnetic resonance (EPR) spectroscopy and UV-vis-near-IR spectroelectrochemical experiments and supported by density functional theory (DFT) calculations. The investigated hybrid molecular systems that combine a transition metal (pseudo)clathrochelate and a Zr/Hf-phthalocyaninate moiety exhibit quite rich redox activity both in the cathodic and in the anodic region. These binuclear compounds and their precursors were tested as potential catalysts in oxidation reactions of cyclohexane and the results are discussed.

Recognition of elements of protein tertiary structure is crucial for biotechnological and biomedical tasks; this makes the development of optical sensors for certain protein surface elements important. Herein, we demonstrated the ability of iron(II) clathrochelates ( 1 - 3 ) functionalized with mono-, di- and hexa-carboxyalkylsulfide to induce selective circular dichroism (CD) response upon binding to globular proteins. Thus, inherently CD-silent clathrochelates revealed selective inducing of CD spectra when binding to human serum albumin (HSA) ( 1 , 2 ), beta-lactoglobuline ( 2 ) and bovine serum albumin (BSA) ( 3 ). Hence, functionalization of iron(II) clathrochelates with the carboxyalkylsulfide group appears to be a promising tool for the design of CD-probes sensitive to certain surface elements of proteins tertiary structure. Additionally, interaction of 1 - 3 with proteins was also studied by isothermal titration calorimetry, protein fluorescence quenching, electrospray ionization mass spectrometry (ESI-MS) and computer simulations. Formation of both 1:1 and 1:2 assemblies of HSA with 1 - 3 was evidenced by ESI-MS. A protein fluorescence quenching study suggests that 3 binds with both BSA and HSA via the sites close to Trp residues. Molecular docking calculations indicate that for both BSA and HSA, binding of 3 to Site I and to an "additional site" is more favorable energetically than binding to Site II.

Thiosemicarbazones continue to attract the interest of researchers as potential anticancer drugs. For example, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, or triapine, is the most well-known representative of this class of compounds that has entered multiple phase I and II clinical trials. Two new triapine derivatives HL 1 and HL 2 were prepared by condensation reactions of 2-pyridinamidrazone and S-methylisothiosemicarbazidium chloride with 3- N -( tert -butyloxycarbonyl) amino-pyridine-2-carboxaldehyde, followed by a Boc-deprotection procedure. Subsequent reaction of HL 1 and HL 2 with CuCl 2 ·2H 2 O in 1:1 molar ratio in methanol produced the complexes [Cu II (HL 1 )Cl 2 ]·H 2 O ( 1·H 2 O ) and [Cu II (HL 2 )Cl 2 ] ( 2 ). The reaction of HL 2 with Fe(NO 3 ) 3 ∙9H 2 O in 2:1 molar ratio in the presence of triethylamine afforded the complex [Fe III (L 2 ) 2 ]NO 3 ∙0.75H 2 O ( 3∙0.75H 2 O ), in which the isothiosemicarbazone acts as a tridentate monoanionic ligand. The crystal structures of HL 1 , HL 2 and metal complexes 1 and 2 were determined by single crystal X-ray diffraction. The UV-Vis and EPR spectroelectrochemical measurements revealed that complexes 1 and 2 underwent irreversible reduction of Cu(II) with subsequent ligand release, while 3 showed an almost reversible electrochemical reduction in dimethyl sulfoxide (DMSO). Aqueous solution behaviour of HL 1 and 1, as well as of HL 2 and its complex 2 , was monitored as well. Complexes 1 - 3 were tested against ovarian carcinoma cells, as well as noncancerous embryonic kidney cells, in comparison to respective free ligands, triapine and cisplatin. While the free ligands HL 1 and HL 2 were devoid of antiproliferative activity, their respective metal complexes showed remarkable antiproliferative activity in a micromolar concentration range. The activity was not related to the inhibition of ribonucleotide reductase (RNR) R2 protein, but rather to cancer cell homeostasis disturbance-leading to the disruption of cancer cell signalling.

A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([H 2 L R ]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HL R )Cl]Cl ( 1 - 4 ) were synthesised with the aim to study (i) their antiproliferative activity in cancer cells and, (ii) for the first time for thiosemicarbazones, the interaction with membrane transport proteins, specifically organic cation transporters OCT1-3. The compounds were comprehensively characterised by analytical, spectroscopic and X-ray diffraction methods. The highest cytotoxic effect was observed in the neuroblastoma cell line SH-5YSY after 24 h exposure and follows the rank order: 3 > 2 > 4 > cisplatin > 1 >>[H 2 L R ]Cl. The copper(II) complexes showed marked interaction with OCT1-3, comparable to that of well-known OCT inhibitors (decynium 22, prazosin and corticosterone) in the cell-based radiotracer uptake assays. The work paves the way for the development of more potent and selective anticancer drugs and/or OCT inhibitors., Competing Interests: The authors declare no conflict of interest.

Nickel(II), copper(II), and palladium(II) complexes ML H , where M = Ni ( 1 ), Cu ( 2 ), Pd ( 3 ), and ML OMe , where M = Ni ( 4 ), Cu ( 5 ), Pd ( 6 ), have been prepared by reactions of NiCl 2 ·6H 2 O, Cu(OAc) 2 ·H 2 O, and PdCl 2 (MeCN) 2 with 14-membered bis-semicarbazide hexaazamacrocycles H 2 L H and H 2 L OMe in dimethylformamide (DMF). The compounds were characterized by elemental analysis, ESI mass spectrometry, IR, UV-vis, and 1D ( 1 H, 13 C) and 2D ( 1 H- 1 H COSY, 1 H- 1 H TOCSY, 1 H- 1 H NOESY, 1 H- 13 C HSQC, 1 H- 13 C HMBC) NMR spectra ( 1 , 3 , 4 , and 6 ), and X-ray diffraction ( 2 , 4 - 6 ). The complexes with M II N 4 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% β-nitroethanol yield with an appreciable diastereoselectivity toward the formation of the anti isomer.

A series of 2-phenyl and 2-pyridyl tris-benzimidazole ligands was reacted with the [Ru(p-cymene)Cl2]2 dimer to yield the corresponding neutral cyclometallated and cationic organoruthenium(ii) complexes. All of the synthesized compounds were characterized using an array of spectroscopic and analytical techniques, including 1H, 13C nuclear magnetic resonance (NMR), infrared spectroscopy and mass spectrometry. The trinuclear compounds were screened for their cytotoxicy against the MCF-7 breast cancer cell line and the triple negative MDA-MB-231 breast cancer cell line at concentrations of 10 and 20 μM. Overall, the 2-pyridyl ligands 10 and 11, and their corresponding trinuclear complexes [16][PF6]3 and [17][PF6]3, show the most promising activity as these compounds significantly reduce the percentage cell survival of MCF-7 and MDA-MB-231 breast cancer cell lines at the aforementioned fixed concentrations. It was observed that 10 and [16][PF6]3 show potency greater than that of cisplatin against the MCF-7 breast cancer cell line, and [17][PF6]3 shows potency comparable to that of cisplatin against the MCF-7 cell line. Additionally, the synthesized compounds were observed to have relatively low cytotoxicty towards MCF-12A breast epithelial cells and relatively higher selectivity towards MCF-7 breast cancer cells compared to cisplatin.

The asymmetric unit of the title com-pound, catena -poly[[[(perchlorato-κ O )copper(II)]-μ-3-(3-carb-oxy-prop-yl)-1,5,8,12-tetra-aza-3-azonia-cyclo-tetra-decane-κ 4 N 1 , N 5 , N 8 , N 12 ] bis-(per-chlorate)], {[Cu(C 13 H 30 N 5 O 2 )(ClO 4 )](ClO 4 ) 2 } n , (I), consists of a macrocyclic cation, one coordinated per-chlorate anion and two per-chlorate ions as counter-anions. The metal ion is coordinated in a tetra-gonally distorted octa-hedral geometry by the four secondary N atoms of the macrocyclic ligand, the mutually trans O atoms of the per-chlorate anion and the carbonyl O atom of the protonated carb-oxy-lic acid group of a neighbouring cation. The average equatorial Cu-N bond lengths [2.01 (6) Å] are significantly shorter than the axial Cu-O bond lengths [2.379 (8) Å for carboxyl-ate and average 2.62 (7) Å for disordered per-chlorate]. The coordinated macrocyclic ligand in (I) adopts the most energetically favourable trans -III conformation with an equatorial orientation of the substituent at the protonated distal 3-position N atom in a six-membered chelate ring. The coordination of the carb-oxy-lic acid group of the cation to a neighbouring com-plex unit results in the formation of infinite chains running along the b -axis direction, which are cross-linked by N-H⋯O hydrogen bonds between the secondary amine groups of the macrocycle and O atoms of the per-chlorate counter-anions to form sheets lying parallel to the (001) plane. Additionally, the extended structure of (I) is consolidated by numerous intra- and interchain C-H⋯O contacts., (© Tsymbal et al. 2019.)

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, 1 H 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 × 10 2 ) were obtained with compound 6 after 2 h of microwave irradiation at 100 °C.

Four Schiff bases derived from 7-hydrazin-yl-5,8-dihydroindolo[2,3-d][2]benzazepin-(6H)-one and its bromo-substituted analogue (HL1-HL4) and four copper(ii) complexes 1-4 have been synthesised and fully characterised by standard spectroscopic methods (1H and 13C NMR, UV-vis), ESI mass spectrometry, single crystal X-ray diffraction and spectroelectrochemistry. In addition, two previously reported complexes with paullone ligands 5 and 6 were prepared and studied for comparison reasons. The CuII ion in 1-4 is five-coordinate and adopts a square-pyramidal or slightly distorted square-pyramidal coordination geometry. The ligands HL1-4 act as tridentate, the other two coordination places are occupied by two chlorido co-ligands. The organic ligands in 2 and 3 are bound tighter to copper(ii) when compared to related paullone ligands in 5 and 6. The new compounds show very strong cytotoxic activity against human colon adenocarcinoma doxorubicin-sensitive Colo 205 and multidrug resistant Colo 320 cancer cell lines with IC50 values in the low micromolar to nanomolar concentration range.

The asymmetric units of the title compounds, trans -di-aqua-(3-benzyl-1,3,5,8,12-penta-aza-cyclo-tetra-decane-κ 4 N 1 , N 5 , N 8 , N 12 )copper(II) isophthalate monohydrate, [Cu(C 16 H 29 N 5 )(H 2 O) 2 ](C 8 H 4 O 4 )·H 2 O, (I), and trans -di-aqua-[3-(pyridin-3-ylmeth-yl)-1,3,5,8,12-penta-aza-cyclo-tetra-decane-κ 4 N 1 , N 5 , N 8 , N 12 ]copper(II) iso-phthalate 0.9-hydrate, [Cu(C 15 H 28 N 6 )(H 2 O) 2 ](C 8 H 4 O 4 )·0.9H 2 O, (II) consist of one di-aqua macrocyclic cation, one di-carboxyl-ate anion and uncoordinated water mol-ecule(s). In each compound, the metal ion is coordinated by the four secondary N atoms of the macrocyclic ligand and the mutually trans O atoms of the water mol-ecules in a tetra-gonally distorted octa-hedral geometry. The average equatorial Cu-N bond lengths are significantly shorter than the average axial Cu-O bond lengths [2.020 (9) versus 2.495 (12) Å and 2.015 (4) versus 2.507 (7) Å for (I) and (II), respectively]. The coordinated macrocyclic ligand in the cations of both compounds adopts the most energetically favorable trans -III conformation. In the crystals, the complex cations and counter-anions are connected via hydrogen-bonding inter-actions between the N-H groups of the macrocycles and the O-H groups of coordinated water mol-ecules as the proton donors and the O atoms of the carboxyl-ate as the proton acceptors. Additionally, as a result of O-H⋯O hydrogen bonding with the coordinated and water mol-ecules of crystallization, the isophthalate dianions form layers lying parallel to the (01) and (100) planes in (I) and (II), respectively.

Three dimanganese(iii) complexes have been synthesised and fully characterised by standard spectroscopic methods and spectroelectrochemistry. Each MnIII ion is chelated by a salen type ligand (H2L), but there is variation in the bridging group: LMn(OOCCH[double bond, length as m-dash]CHCOO)MnL, LMn(OOCC6H4COO)MnL, and LMn(OOCC6H4C6H4COO)MnL. X-ray diffraction revealed an axial compression of each six-coordinate high-spin d4 MnIII ion, which is a Jahn-Teller-active ion. Temperature dependent magnetic susceptibility and variable temperature-variable field (VTVH) magnetisation measurements, as well as high-frequency and -field EPR (HFEPR) spectroscopy were used to accurately describe the magnetic properties of the complexes, not only the single-ion spin Hamiltonian parameters: g-values and zero-field splitting (ZFS) parameters D and E, but also the exchange interaction constant J between the two ions, which has been seldom determined for a di-MnIII complex, particularly when there is more than a single bridging atom. Quantum chemical calculations reproduced well the electronic and geometric structure of these unusual complexes, and, in particular, their electronic absorption spectra along with the spin Hamiltonian and exchange parameters.

The asymmetric unit of the title compound, trans -di-aqua-(3,10-dimethyl-1,3,5,8,10,12-hexa-aza-cyclo-tetra-decane-κ 4 N 1 , N 5 , N 8 , N 12 )copper(II) 4,4'-methyl-ene-bis(3-hy-droxy-naphthalene-2-carboxyl-ate), [Cu(C 10 H 26 N 6 )(H 2 O) 2 ](C 23 H 14 O 6 ) {[Cu( L )(H 2 O) 2 ](pam), where L = 3,10-dimethyl-1,3,5,8,10,12-hexa-aza-cyclo-tetra-decane and pam = dianion of pamoic acid} consists of two independent halves of the [Cu( L )(H 2 O) 2 ] 2+ cation and one di-carboxyl-ate anion. The Cu II atoms, lying on inversion centres, are coordinated by the four secondary N atoms of the macrocyclic ligands and the mutually trans O atoms of the water mol-ecules in a tetra-gonally elongated octa-hedral geometry. The average equatorial Cu-N bond length is significantly shorter than the average axial Cu-O bond length [2.007 (10) and 2.486 (18) Å, respectively]. The macrocyclic ligand in the complex cations adopts the most energetically stable trans -III conformation. The complex cations and anions are connected via hydrogen-bonding inter-actions between the N-H groups of the macrocycles and the O-H groups of coordinated water mol-ecules as the proton donors and the O atoms of the carboxyl-ate as the proton acceptors into layers lying parallel to the (11) plane.

Six morpholine-(iso)thiosemicarbazone hybrids HL 1 -HL 6 and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L 1-6 )Cl] (1-6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2-5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC 50 values at 2-5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction.

With the aim of enhancing the biological activity of ruthenium-nitrosyl complexes, new compounds with four equatorially bound indazole ligands, namely, trans-[RuCl(Hind) 4 (NO)]Cl 2 ·H 2 O ([3]Cl 2 ·H 2 O) and trans-[RuOH(Hind) 4 (NO)]Cl 2 ·H 2 O ([4]Cl 2 ·H 2 O), have been prepared from trans-[Ru(NO 2 ) 2 (Hind) 4 ] ([2]). When the pH-dependent solution behavior of [3]Cl 2 ·H 2 O and [4]Cl 2 ·H 2 O was studied, two new complexes with two deprotonated indazole ligands were isolated, namely [RuCl(ind) 2 (Hind) 2 (NO)] ([5]) and [RuOH(ind) 2 (Hind) 2 (NO)] ([6]). All prepared compounds were comprehensively characterized by spectroscopic (IR, UV-vis, 1 H NMR) techniques. Compound [2], as well as [3]Cl 2 ·2(CH 3 ) 2 CO, [4]Cl 2 ·2(CH 3 ) 2 CO, and [5]·0.8CH 2 Cl 2 , the latter three obtained by recrystallization of the first isolated compounds (hydrates or anhydrous species) from acetone and dichloromethane, respectively, were studied by X-ray diffraction methods. The photoinduced release of NO in [3]Cl 2 and [4]Cl 2 was investigated by cyclic voltammetry and resulting paramagnetic NO species were detected by EPR spectroscopy. The quantum yields of NO release were calculated and found to be low (3-6%), which could be explained by NO dissociation and recombination dynamics, assessed by femtosecond pump-probe spectroscopy. The geometry and electronic parameters of Ru species formed upon NO release were identified by DFT calculations. The complexes [3]Cl 2 and [4]Cl 2 showed considerable antiproliferative activity in human cancer cell lines with IC 50 values in low micromolar or submicromolar concentration range and are suitable for further development as potential anticancer drugs. p53-dependence of Ru-NO complexes [3]Cl 2 and [4]Cl 2 was studied and p53-independent mode of action was confirmed. The effects of NO release on the cytotoxicity of the complexes with or without light irradiation were investigated using NO scavenger carboxy-PTIO.

X- and Q-band electron paramagnetic resonance (EPR) spectroscopy was used to characterize polycrystalline Cu(II) complexes that contained sodium 5-sulfonate salicylaldehyde thiosemicarbazones possessing a hydrogen, methyl, ethyl, or phenyl substituent at the terminal nitrogen. The ability of thiosemicarbazone proligands to generate superoxide radical anions and hydroxyl radicals upon their exposure to UVA irradiation in aerated aqueous solutions was evidenced by the EPR spin trapping technique. The UVA irradiation of proligands in neutral or alkaline solutions and dimethylsulfoxide (DMSO) caused a significant decrease in the absorption bands of aldimine and phenolic chromophores. Mixing of proligand solutions with the equimolar amount of copper(II) ions resulted in the formation of 1:1 Cu(II)-to-ligand complex, with the EPR and UV-Vis spectra fully compatible with those obtained for the dissolved Cu(II) thiosemicarbazone complexes. The formation of the complexes fully inhibited the photoinduced generation of reactive oxygen species, and only subtle changes were found in the electronic absorption spectra of the complexes in aqueous and DMSO solutions upon UVA steady-state irradiation. The dark redox activity of copper(II) complexes and proligand/Cu(II) aqueous solutions towards hydrogen peroxide which resulted in the generation of hydroxyl radicals, was confirmed by spin trapping experiments., Competing Interests: The authors declare no conflict of interest.

The monomeric (PdL·2H 2 O) and dimeric (Pd 2 L 2 ·7H 2 O) palladium(II) complexes of N,N'-bis(2-aminoethyl)oxamide (H 2 L) were isolated, and their structures were established by single-crystal X-ray diffraction. Both compounds display identical cis-(2N amide + 2N amine ) coordination environments of the metal ion. The dimer, representing a combination of two PdL species with an open lateral chelate ring, has an "open clamshell"-like structure. The intramolecular metal-metal separation in Pd 2 L 2 (3.215 Å) is slightly shorter than the sum of the van der Waals radii of the palladium(II) atoms. The dimeric complex is relatively stable to dissociation, and its spectral features in aqueous solutions have been compared to those of the monomeric complex. A 1 H NMR spectroscopic study revealed the presence of the dynamic conformational exchange process assigned to a turning of the dimeric molecule "inside out" with an activation energy of 65 kJ/mol. Cyclic voltammetry of PdL in perchlorate-, chloride-, and sulfate-containing electrolytes revealed two-electron oxidation of the palladium center. For the dimeric complex similar, though irreversible, oxidation to the palladium(IV) state was observed in NaCl electrolyte. At the same time, in NaClO 4 or Na 2 SO 4 solutions oxidation of Pd 2 L 2 occurs in two distinct steps. The first step is quasi-reversible and can be assigned to the formation of species in an intermediate Pd III Pd III state. Monomeric palladium(IV) complex Pd IV LCl 2 was generated via chemical oxidation of Pd II L by peroxodisulfate in the presence of chloride ions and structurally characterized. The related M II L complexes (M = Pd, Ni, Cu) showed low cytotoxicity in human cancer cell lines AGS (gastric adenocarcinoma) and HCT116 (colorectal carcinoma) with IC 50 values from 204 to 525 μM, while the proligand H 2 L was devoid of antiproliferative activity (IC 50 > 1000 μM).

The relationship between cis-trans isomerism and anticancer activity has been mainly addressed for square-planar metal complexes, in particular, for platinum(ii), e.g., cis- and trans-[PtCl 2 (NH 3 ) 2 ], and a number of related compounds, of which, however, only cis-counterparts are in clinical use today. For octahedral metal complexes, this effect of geometrical isomerism on anticancer activity has not been investigated systematically, mainly because the relevant isomers are still unavailable. An example of such an octahedral complex is trans-[RuCl 4 (Hind) 2 ] - , which is in clinical trials now as its indazolium (KP1019) or sodium salt (NKP1339), but the corresponding cis-isomers remain inaccessible. We report the synthesis of Na[cis-Os III Cl 4 (κN2-1H-ind) 2 ]·(Na[1]) suggesting a route to the cis-isomer of NKP1339. The procedure involves heating (H 2 ind)[Os IV Cl 5 (κN1-2H-ind)] in a high boiling point organic solvent resulting in an Anderson rearrangement with the formation of cis-[Os IV Cl 4 (κN2-1H-ind) 2 ] ([1]) in high yield. The transformation is accompanied by an indazole coordination mode switch from κN1 to κN2 and stabilization of the 1H-indazole tautomer. Fully reversible spectroelectrochemical reduction of [1] in acetonitrile at 0.46 V vs. NHE is accompanied by a change in electronic absorption bands indicating the formation of cis-[Os III Cl 4 (κN2-1H-ind) 2 ] - ([1] - ). Chemical reduction of [1] in methanol with NaBH 4 followed by addition of nBu 4 NCl afforded the osmium(iii) complex nBu 4 N[cis-Os III Cl 4 (κN2-1H-ind) 2 ] (nBu 4 N[1]). A metathesis reaction of nBu 4 N[1] with an ion exchange resin led to the isolation of the water-soluble salt Na[1]. The X-ray diffraction crystal structure of [1]·Me 2 CO was determined and compared with that of trans-[Os IV Cl 4 (κN2-1H-ind) 2 ]·2Me 2 SO (2·2Me 2 SO), also prepared in this work. EPR spectroscopy was performed on the Os III complexes and the results were analyzed by ligand-field and quantum chemical theories. We furthermore assayed effects of [1] and Na[1] on cell viability and proliferation in comparison with trans-[Os IV Cl 4 (κN1-2H-ind) 2 ] [3] and cisplatin and found a strong reduction of cell viability at concentrations between 30 and 300 μM in different cancer cell lines (HT29, H446, 4T1 and HEK293). HT-29 cells are less sensitive to cisplatin than 4T1 cells, but more sensitive to [1] and Na[1], as shown by decreased proliferation and viability as well as an increased late apoptotic/necrotic cell population.

A new high-spin d 4 roughly trigonal-bipyramidal (TBP) manganese(iii) complex with a salen type ligand (H 2 L), namely MnL(NCS)·0.4H 2 O, has been synthesised and characterised by elemental analysis, ESI mass spectrometry, IR and UV-vis spectroscopy, and spectroelectrochemistry. X-ray diffraction analysis revealed an axial compression of the approximate TBP. Temperature dependent magnetic susceptibility and variable-temperature variable-field (VTVH) magnetisation measurements, as well as high-frequency and -field EPR (HFEPR) spectroscopy, were used to accurately describe the magnetic properties of this complex and, in particular, determine the spin Hamiltonian parameters: g-values and the zero-field splitting (ZFS) parameters D and E. The HFEPR spectra allowed the extraction of fourth order ZFS parameters. Quantum chemical calculations reproduced well the electronic and geometric structures of this unusual complex and, in particular, its electronic absorption spectrum along with the spin Hamiltonian parameters.

We report on the investigation of Bismuth-doped pure silica glass without other co-dopant by the tech- nique of magnetic circular dichroism (MCD), which allows the direct probing of the ground state of optical centres. Taking into account the results of conventional optical spectroscopy, we show that the observed MCD bands belong to the centre responsible for the red photoluminescence in this material. Measurements of the temperature and field dependences indicate that the MCD effect is caused by the even-electron system. This, however, opposes the widespread opinion that Bi 2+ ions are the origin of red photoluminescence in Bismuth-doped silica glasses. On the other hand, the lasing centre responsi- ble for the near infrared photoluminescence does not exhibit any magnetic optical activity connected to its ground state. As a consequence, we conclude that the ground state of lasing centre is a magnetic singlet with the effective spin S = 0.

A series of water-soluble sodium salts of 3-formyl-4-hydroxybenzenesulfonic acid thiosemicarbazones (or sodium 5-sulfonate-salicylaldehyde thiosemicarbazones) containing different substituents at the terminal nitrogen atom (H, Me, Et, Ph) and their copper(ii) complexes have been prepared and characterised by elemental analysis, spectroscopic techniques (IR, UV-vis, 1 H NMR), ESI mass spectrometry, X-ray crystallography and cyclic voltammetry. The proligands and their copper(ii) complexes exhibit moderate water solubility and good stability in aqueous environment, determined by investigating their proton dissociation and complex formation equilibria. The copper(ii) complexes showed moderate anticancer activity in established human cancer cell lines, while the proligands were devoid of cytotoxicity. The anticancer activity of the copper(ii) complexes correlates with their ability to induce ROS accumulation in cells, consistent with their redox potentials within the biological window, triggering the activation of antioxidation defense mechanisms in response to the ROS insult. These studies pave the way for the investigation of ROS-inducing copper(ii) complexes as prospective antiproliferative agents in cancer chemotherapy.

As ribonucleotide reductase (RNR) plays a crucial role in nucleic acid metabolism, it is an important target for anticancer therapy. The thiosemicarbazone Triapine is an efficient R2 inhibitor, which has entered ∼20 clinical trials. Thiosemicarbazones are supposed to exert their biological effects through effectively binding transition-metal ions. In this study, six iminodiacetate-thiosemicarbazones able to form transition-metal complexes, as well as six dicopper(II) complexes, were synthesized and fully characterized by analytical, spectroscopic techniques (IR, UV-vis; 1 H and 13 C NMR), electrospray ionization mass spectrometry, and X-ray diffraction. The antiproliferative effects were examined in several human cancer and one noncancerous cell lines. Several of the compounds showed high cytotoxicity and marked selectivity for cancer cells. On the basis of this, and on molecular docking calculations one lead dicopper(II) complex and one thiosemicarbazone were chosen for in vitro analysis as potential R2 inhibitors. Their interaction with R2 and effect on the Fe(III) 2 -Y· cofactor were characterized by microscale thermophoresis, and two spectroscopic techniques, namely, electron paramagnetic resonance and UV-vis spectroscopy. Our findings suggest that several of the synthesized proligands and copper(II) complexes are effective antiproliferative agents in several cancer cell lines, targeting RNR, which deserve further investigation as potential anticancer drugs.

A new iron(iii)-centred ferric wheel Fe⊂{Fe 6 } of the formula [Fe 7 (H 2 L) 6 (NCS) 6 ](ClO 4 ) 3 ·10H 2 O, where H 4 L = N,N'-bis(3-carboxylsalicylidene)-1,3-bis(3-aminopropyl)tetramethyldisiloxane, was synthesised and fully characterised. 57 Fe Mössbauer spectra indicate the presence of high spin (S = 5/2) Fe 3+ cations adopting a slightly different coordination environment in agreement with the X-ray diffraction structure. There are competing antiferromagnetic exchange interactions along the rim (J 1 = -1.00 cm -1 ) and the radius (J 2 = -1.46 cm -1 ) of the wheel.

Six dinuclear vanadium(V) complexes have been synthesized: NH4[(VO2)2((H)LH)] (NH4[1]), NH4[(VO2)2((t-Bu)LH)] (NH4[2]), NH4[(VO2)2((Cl)LH)] (NH4[3]), [(VO2)(VO)((H)LH)(CH3O)] (4), [(VO2)(VO)((t-Bu)LH)(C2H5O)] (5), and [(VO2)(VO)((Cl)LH)(CH3O)(CH3OH/H2O)] (6) (where (H)LH4 = 1,5-bis(2-hydroxybenzaldehyde)carbohydrazone, (t-Bu)LH4 = 1,5-bis(3,5-di-tert-butyl-2-hydroxybenzaldehyde)carbohydrazone, and (Cl)LH4 = 1,5-bis(3,5-dichloro-2-hydroxybenzaldehyde)carbohydrazone). The structures of NH4[1] and 4-6 have been determined by X-ray diffraction (XRD) analysis. In all complexes, the triply deprotonated ligand accommodates two V ions, using two different binding sites ONN and ONO separated by a diazine unit -N-N-. In two pockets of NH4[1], two identical VO2(+) entities are present, whereas, in those of 4-6, two different VO2(+) and VO(3+) are bound. The highest oxidation state of V ions was corroborated by X-ray data, indicating the presence of alkoxido ligand bound to VO(3+) in 4-6, charge density measurements on 4, magnetic susceptibility, NMR spectroscopy, spectroelectrochemistry, and density functional theory (DFT) calculations. All four complexes characterized by XRD form dimeric associates in the solid state, which, however, do not remain intact in solution. Compounds NH4[1], NH4[2], and 4-6 were applied as alternative selective homogeneous catalysts for the industrially significant oxidation of cyclohexane to cyclohexanol and cyclohexanone. The peroxidative (with tert-butyl hydroperoxide, TBHP) oxidation of cyclohexane was performed under solvent-free and additive-free conditions and under low-power microwave (MW) irradiation. Cyclohexanol and cyclohexanone were the only products obtained (high selectivity), after 1.5 h of MW irradiation. Theoretical calculations suggest a key mechanistic role played by the carbohydrazone ligand, which can undergo reduction, instead of the metal itself, to form an active reduced form of the catalyst.

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.

Overall binding affinity of sodium or indazolium cis/trans-[MCl4(1H-indazole)(NO)] (M = Ru, Os) complexes towards human serum albumin (HSA) and high molecular mass components of the blood serum was monitored by ultrafiltration. HSA was found to be mainly responsible for the binding of the studied ruthenium and osmium complexes. In other words, this protein can provide a depot for the compounds and can affect their biodistribution and transport processes. In order to elucidate the HSA binding sites tryptophan fluorescence quenching studies and displacement reactions with the established site markers warfarin and dansylglycine were performed. Conditional stability constants for the binding to sites I and II on HSA were computed showing that the studied ruthenium and osmium complexes are able to bind into both sites with moderately strong affinity (logK' = 4.4-5.1). Site I is slightly more favored over site II for all complexes. No significant differences in the HSA binding properties were found for these metal complexes demonstrating negligible influence of the type of counterion (sodium vs indazolium), the metal ion center identity (Ru vs. Os) or the position of the nitrosyl group on the binding event. Electron paramagnetic resonance spin labeling of HSA revealed that indazolium trans-[RuCl4(1H-indazole)(NO)] and long-chain fatty acids show competitive binding to HSA. Moreover, this complex has a higher affinity for site I, but when present in excess, it is able to bind to site II as well, and displace fatty acids., (Copyright © 2016 Elsevier Inc. All rights reserved.)