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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 vitroantiproliferative 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 [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]).

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.

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–HL4and 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 2and 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–HL4and 1–4with those of structurally similar paullone-derived (HL5–HL7and 5–7) and latonduine-derived scaffolds (HL8–HL11and 8–11). The high anticancer activity of the lead drug candidate 4was linked to reactive oxygen species and endoplasmic reticulum stress induction, which were confirmed by fluorescent microscopy and Western blot analysis.

A series of latonduine and indoloquinoline derivatives HL1–HL8and 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 IC50values with promising selectivity toward human colon adenocarcinoma multidrug-resistant Colo320 cancer cells as compared to the doxorubicin-sensitive Colo205 cell line. The lead compounds HL4and 4as well as HL8and 8induced apoptosis efficiently in Colo320 cells. In addition, the copper(II) complexes had higher affinity to DNA than their metal-free ligands. HL8showed selective inhibition for the PIM-1 enzyme, while 8revealed 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.

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 RuIIand OsIIcomplexes 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 vitroin a low micromolar concentration range, while their coordination to metal centers resulted in a decrease of cytotoxicity. The preliminary in vivoactivity of the RuIIcomplex was investigated. Fluorescence staining and in vitrotubulin 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}6is 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 4was 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 4–8were all characterized by elemental analysis, ESI mass spectrometry, IR, UV–vis, and 1H NMR spectroscopy, and single-crystal X-ray diffraction, with complexes 6and 7being characterized also by temperature-dependent magnetic susceptibility measurements and Mössbauer spectroscopy. Magnetometry indicated a strong antiferromagnetic interaction between paramagnetic centers in 6and 7. The ability of 4and 6–8to 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 6by DFT and ab initioCASSCF/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 6was also studied by an X-ray charge density analysis.

Three new thiosemicarbazones (TSCs) HL1–HL3as triapine analogues bearing a redox-active phenolic moiety at the terminal nitrogen atom were prepared. Reactions of HL1–HL3with 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–HL3at pH 7.4, while being air-sensitive in the basic pH range. In dimethyl sulfoxide they exist as a mixture of Eand Zisomers. A mechanism of the E/Zisomerization 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 3confirmed 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 HL1and HL2as well as 1and 2′afforded several two-electron and four-electron oxidation products, which were isolated and comprehensively characterized. Complexes 1and 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 3with the most closely related ligand to triapine displayed the best selectivity for cancer cells versus normal fibroblast cells (MRC-5). HL1and 1in the presence of 1,4-dithiothreitol are as potent inhibitors of mR2 ribonucleotide reductase as triapine.

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)2with 14-membered bis-semicarbazide hexaazamacrocycles H2LHand H2LOMein 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 MIIN4coordination environment have S= 0, 1/2, 0 ground states for Ni, Cu, and Pd, respectively. The electrochemical behavior of 1–6was 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 1–6were tested in the oxidation of styrene and C–C coupling (Henry and Knoevenagel condensations). Compounds 2and 5selectively catalyze the microwave-assisted oxidation of neat styrene to benzaldehyde (up to 88% yield), whereas the 1and 4catalytic systems afforded up to 99% β-nitroethanol yield with an appreciable diastereoselectivity toward the formation of the antiisomer.

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 1–6was 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 1–6were 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 6after 2 h of microwave irradiation at 100 °C.

A novel proligand HLHhas been prepared from 2-pyridinamidrazone and 6-(morpholinomethyl)pyridine-2-carboxaldehyde. Subsequently, starting from HLHand CuCl2·2H2O in the presence of triethylamine, a series of homo- and heterometallic complexes with [CuICl2]−as counteranion, namely mononuclear complex [CuIICl(HLOMe)][CuICl2] (1), dinuclear Ru(II)–Cu(II) complex [CuIIRuII(η6-p-cymene)Cl2(LH)][CuICl2]·1.5H2O (2·1.5H2O), Os(II)–Cu(II) complex [CuIIOsII(η6-p-cymene)Cl2(LH)][CuICl2]·H2O (3·H2O), and tetranuclear complex [CuII4(L1)2(L2)2Cl2]·5MeOH (4·5MeOH), where HLOMe, L1, and L2are Schiff base ligands derived from HLH, were synthesized. The structures of metal complexes were established by X-ray diffraction. Complexes 1–3demonstrated quasireversible one-electron reduction of Cu(II) in complex cations and one-electron oxidation of [CuICl2]−counterion, confirmed by UV–vis and EPR spectroelectrochemical measurements. They exhibited moderate antiproliferative activity against ovarian carcinoma and cervical adenocarcinoma cell lines in a micromolar concentration range, which was superior to the activity of HLH, CuCl2, and [CuICl2]−. The observed anticancer effects might be related to the ability of novel complexes to generate ROS, which was established by spin trapping experiments in cell-free media as well as by confocal microscopic imaging in ovarian carcinoma cells.

endo-Tricyclo[3.2.1.02,4]oct-8-ylidene is a foiled carbene reaction intermediate. It was generated by thermolyzing Δ3-1,3,4-oxadiazoline precursors dissolved in benzaldehyde and acetophenone. The products appear to stem from direct insertion of the carbene’s divalent C atom into the α-bonds of the carbonyl compounds; however, this is only superficial. The strict stereochemistry observed is due to the topologies of the reaction intermediates of the proposed two-step mechanism. Bimolecular nucleophilic addition generates bent 1,3-zwitterions. The neutral reaction intermediates undergo pinacolic rearrangements to form the observed adducts. Product ratios reflect the migratory aptitudes of the carbonyl compounds’ α-substituents. The carbene reaction was modeled using DFT. The singlet carbene’s bicoordinate C atom bends 31° toward the endo-fused cyclopropane bond, elongating it to r= 1.69 Å. The resulting trishomocyclopropyl HOMO{−1} is a three-center two-electron bond responsible for the electron-deficient carbene’s nucleophilicity. Its calculated properties are consistent with this assertion: (1) singlet–triplet (ΔES–T) energy gap of −25 kcal/mol, (2) gas-phase proton affinity (PA) value of 272 kcal/mol, (3) hard and soft acid and base (HSAB) ΔNvalue of −0.2 in its initial reaction with the carbonyl compounds, and (4) negative frontier orbital interaction values ΔΔE(PhC(O)H) = −4.38 eV and ΔΔE(PhC(O)Me) = −3.97 eV.

Six morpholine-(iso)thiosemicarbazone hybrids HL1–HL6and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L1–6)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 2–5were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureuswith MIC50values at 2–5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2and 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)]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·H2Oand [4]Cl2·H2Owas 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]Cl2and [4]Cl2was 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]Cl2and [4]Cl2showed considerable antiproliferative activity in human cancer cell lines with IC50values in low micromolar or submicromolar concentration range and are suitable for further development as potential anticancer drugs. p53-dependence of Ru–NO complexes [3]Cl2and [4]Cl2was 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.

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 NaClO4or Na2SO4solutions oxidation of Pd2L2occurs in two distinct steps. The first step is quasi-reversible and can be assigned to the formation of species in an intermediate PdIIIPdIIIstate. Monomeric palladium(IV) complex PdIVLCl2was 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 IC50values from 204 to 525 μM, while the proligand H2L was devoid of antiproliferative activity (IC50> 1000 μM).

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.

Six dinuclear vanadium(V) complexes have been synthesized: NH4[(VO2)2(HLH)] (NH4[1]), NH4[(VO2)2(t-BuLH)] (NH4[2]), NH4[(VO2)2(ClLH)] (NH4[3]), [(VO2)(VO)(HLH)(CH3O)] (4), [(VO2)(VO)(t-BuLH)(C2H5O)] (5), and [(VO2)(VO)(ClLH)(CH3O)(CH3OH/H2O)] (6) (where HLH4= 1,5-bis(2-hydroxybenzaldehyde)carbohydrazone, t-BuLH4= 1,5-bis(3,5-di-tert-butyl-2-hydroxybenzaldehyde)carbohydrazone, and ClLH4= 1,5-bis(3,5-dichloro-2-hydroxybenzaldehyde)carbohydrazone). The structures of NH4[1] and 4–6have 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 VO3+are bound. The highest oxidation state of V ions was corroborated by X-ray data, indicating the presence of alkoxido ligand bound to VO3+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 4–6were 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.

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.