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.

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.

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.

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.

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.

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.

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.

Triapine Analogues and Their Copper(II) Complexes: Synthesis, Characterization, Solution Speciation, Redox Activity, Cytotoxicity, and mR2 RNR Inhibition.

Three new thiosemicarbazones (TSCs) HL1-HL3 as triapine analogues bearing a redox-active phenolic moiety at the terminal nitrogen atom were prepared. Reactions of HL1-HL3 with CuCl2·2H2O in anoxic methanol afforded three copper(II) complexes, namely, Cu(HL1)Cl2 (1), [Cu(L2)Cl] (2'), and Cu(HL3)Cl2 (3), in good yields. Solution speciation studies revealed that the metal-free ligands are stable as HL1-HL3 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(L1-3)]+ 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 HL1 and HL2 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). HL1 and 1 in the presence of 1,4-dithiothreitol are as potent inhibitors of mR2 ribonucleotide reductase as triapine.

Ni Oxidation State and Ligand Saturation Impact on the Capability of Octaazamacrocyclic Complexes to Bind and Reduce CO2.

Two 15-membered octaazamacrocyclic nickel(II) complexes are investigated by theoretical methods to shed light on their affinity forwards binding and reducing CO2. In the first complex 1[NiIIL]0, the octaazamacrocyclic ligand is grossly unsaturated (π-conjugated), while in the second 1[NiIILH]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-CCO2 bond and the oxidation state of the central Ni atom. It was found that in the [NiLH] complex, the central atom is reduced to Ni0 and/or NiI and is thus able to bind CO2 via a single σ bond. In addition, the two-electron reduced 3[NiL]2- species also shows an affinity forwards CO2.

Spectroelectrochemical Properties and Catalytic Activity in Cyclohexane Oxidation of the Hybrid Zr/Hf-Phthalocyaninate-Capped Nickel(II) and Iron(II) tris-Pyridineoximates and Their Precursors.

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.

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

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

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

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

Palladium Complexes of N,N'-Bis(2-aminoethyl)oxamide (H2L): Structural (PdIIL, PdII2L2, and PdIVLCl2), Electrochemical, Dynamic 1H NMR, and Cytotoxicity Studies.

The monomeric (PdL·2H2O) and dimeric (Pd2L2·7H2O) palladium(II) complexes of N,N'-bis(2-aminoethyl)oxamide (H2L) were isolated, and their structures were established by single-crystal X-ray diffraction. Both compounds display identical cis-(2Namide + 2Namine) 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 Pd2L2 (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 1H 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 NaClO4 or Na2SO4 solutions oxidation of Pd2L2 occurs in two distinct steps. The first step is quasi-reversible and can be assigned to the formation of species in an intermediate PdIIIPdIII state. Monomeric palladium(IV) complex PdIVLCl2 was generated via chemical oxidation of PdIIL by peroxodisulfate in the presence of chloride ions and structurally characterized. The related MIIL complexes (M = Pd, Ni, Cu) showed low cytotoxicity in human cancer cell lines AGS (gastric adenocarcinoma) and HCT116 (colorectal carcinoma) with IC50 values from 204 to 525 µM, while the proligand H2L was devoid of antiproliferative activity (IC50 > 1000 µM).

NO Releasing and Anticancer Properties of Octahedral Ruthenium-Nitrosyl Complexes with Equatorial 1 H-Indazole Ligands.

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)]Cl2·H2O ([3]Cl2·H2O) and trans-[RuOH(Hind)4(NO)]Cl2·H2O ([4]Cl2·H2O), have been prepared from trans-[Ru(NO2)2(Hind)4] ([2]). When the pH-dependent solution behavior of [3]Cl2·H2O and [4]Cl2·H2O 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, 1H NMR) techniques. Compound [2], as well as [3]Cl2·2(CH3)2CO, [4]Cl2·2(CH3)2CO, and [5]·0.8CH2Cl2, 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]Cl2 and [4]Cl2 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]Cl2 and [4]Cl2 showed considerable antiproliferative activity in human cancer cell lines with IC50 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]Cl2 and [4]Cl2 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.

Copper(II) Thiosemicarbazone Complexes and Their Proligands upon UVA Irradiation: An EPR and Spectrophotometric Steady-State Study.

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.

New Iminodiacetate-Thiosemicarbazone Hybrids and Their Copper(II) Complexes Are Potential Ribonucleotide Reductase R2 Inhibitors with High Antiproliferative Activity.

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; 1H and 13C 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.

Vanadium(V) Complexes with Substituted 1,5-bis(2-hydroxybenzaldehyde)carbohydrazones and Their Use As Catalyst Precursors in Oxidation of Cyclohexane.

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.

Anti-Stokes photoluminescence in Ga/Bi co-doped sol-gel silica glass.

Unusual temperature dependence of the anti-Stokes photoluminescence (ASPL) at 734 nm was found in Ga/Bi co-doped sol-gel silica glass. While in the temperature range of 450-873 K, the behavior of ASPL is completely determined by the thermal population of the excited state levels, its intensity is continuously increasing with decreasing temperature in the range of 77-430 K. By measuring the pump power dependence of ASPL at 300 K, we show that the latter can be described via the two-step intracenter excitation process and subsequent relaxation. Based on the measurements of temperature dependence of the excitation spectra of near infrared band (at 1140 nm) and that corresponding to the ASPL (at 734 nm), we propose a simple rate equation model to explain the unusual behavior of ASPL.

Heteropentanuclear Oxalato-Bridged nd-4f (n=4, 5) Metal Complexes with NO Ligand: Synthesis, Crystal Structures, Aqueous Stability and Antiproliferative Activity.

A series of heteropentanuclear oxalate-bridged Ru(NO)-Ln (4d-4f) metal complexes of the general formula (nBu4N)5[Ln{RuCl3(µ-ox)(NO)}4], where Ln=Y (2), Gd (3), Tb (4), Dy (5) and ox=oxalate anion, were obtained by treatment of (nBu4N)2[RuCl3(ox)(NO)] (1) with the respective lanthanide salt in 4:1 molar ratio. The compounds were characterized by elemental analysis, IR spectroscopy, electrospray ionization (ESI) mass spectrometry, while 1, 2, and 5 were in addition analyzed by X-ray crystallography, 1 by Ru K-edge XAS and 1 and 2 by (13)C NMR spectroscopy. X-ray diffraction showed that in 2 and 5 four complex anions [RuCl3(ox)(NO)](2-) are coordinated to Y(III) and Dy(III), respectively, with formation of [Ln{RuCl3(µ-ox)(NO)}4](5-) (Ln=Y, Dy). While Y(III) is eight-coordinate in 2, Dy(III) is nine-coordinate in 5, with an additional coordination of an EtOH molecule. The negative charge is counterbalanced by five nBu4N(+) ions present in the crystal structure. The stability of complexes 2 and 5 in aqueous medium was monitored by UV/Vis spectroscopy. The antiproliferative activity of ruthenium-lanthanide complexes 2-5 were assayed in two human cancer cell lines (HeLa and A549) and in a noncancerous cell line (MRC-5) and compared with those obtained for the previously reported Os(NO)-Ln (5d-4f) analogues (nBu4N)5[Ln{OsCl3(ox)(NO)}4] (Ln=Y (6), Gd (7), Tb (8), Dy (9)). Complexes 2-5 were found to be slightly more active than 1 in inhibiting the proliferation of HeLa and A549 cells, and significantly more cytotoxic than 5d-4f metal complexes 6-9 in terms of IC50 values. The highest antiproliferative activity with IC50 values of 20.0 and 22.4 µM was found for 4 in HeLa and A549 cell lines, respectively. These cytotoxicity results are in accord with the presented ICP-MS data, indicating five- to eightfold greater accumulation of ruthenium versus osmium in human A549 cancer cells.