Copper(II) Complexes with Isomeric Morpholine-Substituted 2-Formylpyridine Thiosemicarbazone Hybrids as Potential Anticancer Drugs Inhibiting Both Ribonucleotide Reductase and Tubulin Polymerization: The Morpholine Position Matters.

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 H2L3-H2L6, 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.

Chemical and Redox Noninnocence of Pentane-2,4-dione Bis(S-methylisothiosemicarbazone) in Cobalt Complexes and Their Application in Wacker-Type Oxidation.

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 [CoIII(H2LSMe)I]I and [CoIII(LSMe)I2] 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 ([CoIII(LSMe••)I]).

Isomerization pathway of a C-C sigma bond in a bis(octaazamacrocycle)dinickel(II) complex activated by deprotonation: a DFT study.

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 (sp3 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.

Indolo[2,3-e]benzazocines and indolo[2,3-f]benzazonines and their copper(II) complexes as microtubule destabilizing agents.

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 1H and 13C 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 (pKa) of HL1, HL2 and HL5, complexes 1, 2 and 5, overall stability constants (log ß) of 1, 2 and 5 in 30% (v/v) DMSO/H2O 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 IC50 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.

Enriching Chemical Space of Bioactive Scaffolds by New Ring Systems: Benzazocines and Their Metal Complexes as Potential Anticancer Drugs.

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 (1H and 13C 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-8H-indolo[3,2-e]benzazocin-8-one, and a series of derived potential ligands (HL1-HL5), 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 1H NMR and UV-vis spectroscopy measurements. The antiproliferative activity of HL1-HL5 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 HL5 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. HL5 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, HL5 and 5 showed notable inhibition potency against glycogen synthase kinases (GSK-3α and GSK-3ß), tyrosine-protein kinase (Src), lymphocyte-specific protein-tyrosine kinase (Lck), and cyclin-dependent kinases (Cdk2 and Cdk5) (IC50 = 1.4-6.1 µM), suggesting their multitargeted mode of action as potential anticancer drugs.

Different Modes of Acid-Promoted Cyclooligomerization of 4-(4-Thiosemicarbazido)butan-2-one Hydrazone: 14-Membered versus 28-Membered Polyazamacrocycle Formation.

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.

Synthesis and crystal structure of trans-di-aqua(1,4,8,11-tetra-aza-undeca-ne)copper(II) isophthalate monohydrate.

In the title hydrated mol-ecular salt, [Cu(C7H20N4)(H2O)2](C8H4O4)·H2O, 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 Šfor Cu-Nprim and Cu-Nsec, 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.

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.

Elucidation of Structure-Activity Relationships in Indolobenzazepine-Derived Ligands and Their Copper(II) Complexes: the Role of Key Structural Components and Insight into the Mechanism of Action.

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 HL1-HL4 and copper(II) complexes 1-4. All compounds were characterized by spectroscopic methods (1H and 13C 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 1H 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 HL1-HL4 and 1-4 with those of structurally similar paullone-derived (HL5-HL7 and 5-7) and latonduine-derived scaffolds (HL8-HL11 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.

Solution Equilibrium Studies on Salicylidene Aminoguanidine Schiff Base Metal Complexes: Impact of the Hybridization with L-Proline on Stability, Redox Activity and Cytotoxicity.

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, 1H 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)L2]+ 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.

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.

Ruthenium-nitrosyl complexes as NO-releasing molecules, potential anticancer drugs, and photoswitches based on linkage isomerism.

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-η2-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.

Highly Antiproliferative Latonduine and Indolo[2,3-c]quinoline Derivatives: Complex Formation with Copper(II) Markedly Changes the Kinase Inhibitory Profile.

A series of latonduine and indoloquinoline derivatives HL1-HL8 and their copper(II) complexes (1-8) were synthesized and comprehensively characterized. The structures of five compounds (HL6, [CuCl(L1)(DMF)]·DMF, [CuCl(L2)(CH3OH)], [CuCl(L3)]·0.5H2O, and [CuCl2(H2L5)]Cl·2DMF) were elucidated by single crystal X-ray diffraction. The copper(II) complexes revealed low micro- to sub-micromolar IC50 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 HL4 and 4 as well as HL8 and 8 induced apoptosis efficiently in Colo320 cells. In addition, the copper(II) complexes had higher affinity to DNA than their metal-free ligands. HL8 showed selective inhibition for the PIM-1 enzyme, while 8 revealed strong inhibition of five other enzymes, i.e., SGK-1, PKA, CaMK-1, GSK3ß, 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.

Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction.

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(5H)-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)-1H-indol-2-yl)acetate in 55% yield.

Inhibition of Microtubule Dynamics in Cancer Cells by Indole-Modified Latonduine Derivatives and Their Metal Complexes.

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 RuII and OsII complexes and investigated their microtubule-targeting properties in comparison with paclitaxel and colchicine. Compounds were fully characterized by spectroscopic techniques (1H 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 1H and 13C 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 RuII 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 in Clusters: Trinuclear Linear µ-Hydroxido Magnesium(II)-Diruthenium(II), µ3-Oxido Trinuclear Diiron(III)-Ruthenium(II), and Tetranuclear µ4-Oxido Trigallium(III)-Ruthenium(II) Complexes.

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 µ3-oxido clusters [Fe2RuCl4(µ3-O)(µ-OMe)(µ-pz)2(NO)(Hpz)2] (6) and [Fe2RuCl3(µ3-O)(µ-OMe)(µ-pz)3(MeOH)(NO)(Hpz)][Fe2RuCl3(µ3-O)(µ-OMe)(µ-pz)3(DMF)(NO)(Hpz)] (7·MeOH·2H2O) and the heterotetranuclear µ4-oxido complex [Ga3RuCl3(µ4-O)(µ-OMe)3(µ-pz)4(NO)] (8) were prepared from trans-[Ru(OH)(NO)(Hpz)4]Cl2 (5), which itself was prepared via acidic hydrolysis of the linear heterotrinuclear complex {[Ru(µ-OH)(µ-pz)2(pz)(NO)(Hpz)]2Mg} (4). Complex 4 was synthesized from the mononuclear Ru complexes (H2pz)[trans-RuCl4(Hpz)2] (1), trans-[RuCl2(Hpz)4]Cl (2), and trans-[RuCl2(Hpz)4] (3). The new compounds 4-8 were all characterized by elemental analysis, ESI mass spectrometry, IR, UV-vis, and 1H 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.

Spectroscopic Characterization of the Binding and Release of Hydrophilic, Hydrophobic and Amphiphilic Molecules from Ovalbumin Supramolecular Hydrogels.

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.

Crystal structure of trans-di-aqua-(1,4,8,11-tetra-aza-undeca-ne)nickel(II) bis-(pyridine-2,6-di-carboxyl-ato)nickel(II).

The asymmetric unit of the title compound, trans-di-aqua-(1,4,8,11-tetra-aza-undecane-κ4 N 1,N 4,N 8,N 11)nickel(II) bis-(pyridine-2,6-di-carboxyl-ato-κ3 O 2,N,O 6)nickel(II) {[Ni(L)(H2O)2][Ni(pdc)2] where L = 1,4,8,11-tetra-aza-undecane (C7H20N4) and pdc = the dianion of pyridine-2,6-di-carb-oxy-lic acid (C7H3NO4 2-)} consists of an [Ni(L)(H2O)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 NiII ion is coordinated by the two tridentate pdc2- ligands via their carboxyl-ate and nitro-gen atom donors in a distorted octa-hedral trans-NiO4N2 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 pdc2- 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.

Towards understanding the magnetism of Os(IV) complexes: an ab initio insight.

The magnetism of a recently synthesized trans-[OsIVCl4(κN1-Hind)2] complex (5d4-system), where Hind = 2H-indazole, was studied experimentally and theoretically. Relativistic CASSCF/CASPT2 calculations for this and model [OsIVCl6]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 OsIV ion. The strong spin-orbit interaction also preserves the dominant J̃ = 0 character of the non-magnetic ground state in the trans-[OsIVCl4(κN1-Hind)2] complex despite significant deviation of the ligand environment of OsIV from octahedral symmetry. At the same time the spin-orbit admixture of all multiplets arising from the t2g4 strong-field electronic configuration is indispensable for the correct description of magnetic properties of OsIV 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.

Coumarin-Based Triapine Derivatives and Their Copper(II) Complexes: Synthesis, Cytotoxicity and mR2 RNR Inhibition Activity.

A series of thiosemicarbazone-coumarin hybrids (HL1-HL3 and H2L4) has been synthesised in 12 steps and used for the preparation of mono- and dinuclear copper(II) complexes, namely Cu(HL1)Cl2 (1), Cu(HL2)Cl2 (2), Cu(HL3)Cl2 (3) and Cu2(H2L4)Cl4 (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(L1)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.