Kink distortion of the pseudo-S4 axis in pseudotetrahedral [N2O2] bis-chelate cobalt(II) single-ion magnets leads to increased magnetic anisotropy.

Two new mononuclear cobalt(II) complexes with the general formula [Co(L1,2)2] (1 and 2) were synthesized using bidentate Schiff base ligands with NO donor set, namely, 2-(benzothiazole-2-ylimino)methyl-5-(diethylamino)phenol (HL1) and its methyl substituted derivative 2-(6-methylbenzothiazole-2-ylimino)methyl-5-(diethylamino)phenol (HL2). X-ray structure analysis reveals a distorted pseudotetrahedral coordination sphere at the cobalt(II) ion, that cannot be described by a simple twisting of the two ligand chelate planes with respect to each other, which would imply a rotation about the pseudo-S4 axis of the complex. Such a pseudo-rotation axis would approximately be colinear with the two vectors defined by the cobalt ion and the two centroids of the chelate ligands, where the angle κ between the two vectors would be 180° in an ideal pseudotetrahedral arrangement. For complexes 1 and 2, the observed distortion can be characterized by a significant bending at the cobalt ion with angles κ of 163.2° and 167.4°, respectively. Magnetic susceptibility and FD-FT THz-EPR measurements together with ab initio calculations reveal an easy-axis type of anisotropy for both complexes 1 and 2, with a spin-reversal barrier of 58.9 and 60.5 cm-1, respectively. For both compounds, frequency-dependent ac susceptibility measurements show an out-of-phase susceptibility under applied static fields of 40 and 100 mT, which can be analyzed in terms of Orbach and Raman processes within the observed temperature range.

Ruthenium(II)-Dithiocarbazates as Anticancer Agents: Synthesis, Solution Behavior, and Mitochondria-Targeted Apoptotic Cell Death.

The reaction of the Ru(PPh3 )3 Cl2 with HL1-3 -OH (-OH stands for the oxime hydroxyl group; HL1 -OH=diacetylmonoxime-S-benzyldithiocarbazonate; HL2 -OH=diacetylmonoxime-S-(4-methyl)benzyldithiocarbazonate; and HL3 -OH=diacetylmonoxime-S-(4-chloro)benzyl-dithiocarbazonate) gives three new ruthenium complexes [RuII (L1-3 -H)(PPh3 )2 Cl] (1-3) (-H stands for imine hydrogen) coordinated with dithiocarbazate imine as the final products. All ruthenium(II) complexes (1-3) have been characterized by elemental (CHNS) analyses, IR, UV-vis, NMR (1 H, 13 C, and 31 P) spectroscopy, HR-ESI-MS spectrometry and also, the structure of 1-2 was further confirmed by single crystal X-ray crystallography. The solution/aqueous stability, hydrophobicity, DNA interactions, and cell viability studies of 1-3 against HeLa, HT-29, and NIH-3T3 cell lines were performed. Cell viability results suggested 3 being the most cytotoxic of the series with IC50 6.9±0.2 µM against HeLa cells. Further, an apoptotic mechanism of cell death was confirmed by cell cycle analysis and Annexin V-FITC/PI double staining techniques. In this regard, the live cell confocal microscopy results revealed that compounds primarily target the mitochondria against HeLa, and HT-29 cell lines. Moreover, these ruthenium complexes elevate the ROS level by inducing mitochondria targeting apoptotic cell death.

Dithiocarbazate based oxidomethoxidovanadium(V) and mixed-ligand oxidovanadium(IV) complexes: Study of solution behavior, DNA binding, and anticancer activity.

In this work, one oxidomethoxidovanadium(V) [VVO(L)(OMe)] (1) and two mixed-ligand oxidovanadium(IV) [VIVO(L)(phen)] (2), and [VIVO(L)(bipy)] (3) complexes have been synthesized using a tridentate bi-negative ONS donor dithiocarbazate as main ligand, H2L [where, H2L = S-benzyl-3-(2-hydroxy-3-ethoxyphenyl)methylenedithiocarbazate] along with 1,10-phenanthroline (phen) (for 2) and 2,2'-bipyridine (bipy) (for 3) as co-ligands. The ligand and complexes have been characterised by FT-IR, UV-vis, NMR, and HR-ESI-MS techniques. Distorted square pyramidal for 1, and distorted octahedral geometry for 2 and 3 was confirmed by single crystal X-ray crystallography. The behavior of 1-3 in solution medium has been investigated through various physicochemical techniques. It is observed that 1 completely and 2-3 partially decomposes and converts into a penta-coordinated species, [VIVO(L)(DMSO/H2O)] after the release of the methoxido group (1) or breaking of the diimine based co-ligands (2 and 3) in DMSO/aqueous solution. Interestingly, in DMSO/aqueous solution, 1 gets completely reduced and converted into the corresponding oxidovanadium(IV) species. Interaction of 1-3 with calf thymus DNA (CT-DNA) was investigated and the results show, complex 2 exhibited the maximum binding constants, Kb = 7.12 × 104 M-1. The anticancer potential of 1-3 was evaluated by cell viability assay against human breast carcinoma cell, MCF-7, and noncancerous mouse embryonic cell, NIH-3T3 and 2 was found to be the most cytotoxic complex (IC50 = 6.73 ± 0.36 µM) in the series. In addition, 2 selectively inhibit colony formation compared to the rest complexes. Also, the cell cycle studies of the complexes were performed using flow cytometry analysis.

Evaluation of DNA/BSA interaction and in vitro cell cytotoxicity of µ2-oxido bridged divanadium(V) complexes containing ONO donor ligands.

Two new µ2-oxido bridged divanadium (V) complexes, [VV2O3(L1,2)2] (1 and 2) have been synthesized using bi-negative tridentate ONO-donor ligands, H2L1,2 (H2L1 = 4-tert-butyl-2-[[[3,5-di-tert-butyl-2-hydroxyphenyl]methylene]amino]phenol and H2L2 = 5-bromo-2-[[[4-(diethylamino)-2-hydroxyphenyl]methylene]amino]phenol). The synthesized ligands and complexes have been characterized through FT-IR, UV-vis, NMR, and HR-ESI-MS techniques. Single crystal X-ray crystallography data confirmed distorted square pyramidal geometry for both the complexes. The aqueous phase stability of these complexes has been evaluated through HR-ESI-MS in CH3CN:H2O (80:20) mixture. Thereafter their interaction with calf thymus DNA (CT-DNA) have been studied using electronic absorption and fluorescence spectroscopy, revealing an intercalation mode of binding, with binding constant in the order of 104 M-1. Moreover, bovine serum albumin (BSA) interaction of 1 and 2 has been evaluated via fluorescence quenching experiment, which suggests that the quenching mechanism is static (~1013 M-1) in nature. Additionally, the in vitro cytotoxicity of the complexes has been evaluated in human cervical cancer cells (HeLa) (IC50 = 13.57-16.62 µM) and normal mouse embryonic fibroblasts cells (NIH-3T3). The mechanism of cell death brought about by these complexes was studied by nuclear staining, cell cycle and Annexin V/PI double staining apoptotic assay. These studies indicate that 1 and 2 exert inhibitory effects on the S and G2M phase of cell cycle, which is an indication of apoptotic cell death. Also, a clonogenic assay was performed, which showed that the complexes could effectively inhibit colony formation.

New mixed ligand oxidovanadium(IV) complexes: Solution behavior, protein interaction and cytotoxicity.

Herein we report the synthesis of five new mononuclear mixed ligand oxidovanadium(IV) complexes [VIVO(L1-3)(LNN)] (1-5) with tridentate O,N,O-donor aroylhydrazones as main ligand (H2L1-3) and N,N-chelating 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen) as co-ligand (LNN). The complexes were characterized by elemental and thermogravimetric analysis (TGA), IR, UV-vis, and electron paramagnetic resonance (EPR) spectroscopy, electrospray ionization-mass spectrometry (ESI-MS) and cyclic voltammetry (CV). The structure of 1-5 was confirmed by single crystal X-ray analysis and also optimized by density functional theory (DFT) methods. At physiological pH an equilibrium [VIVO(L1-3)(LNN)] + H2O ⇄ [VIVO(L1-3)(H2O)] + LNN, shifted towards left, is established, with water molecule that could be replaced by the biomolecules of the organism. The studies on the interaction with two proteins, lysozyme (Lyz) chosen as a representative model of a small protein, and human serum albumin (HSA) show that two types of binding are possible: a non-covalent binding through the accessible residues on protein surface with [VIVO(L1-3)(LNN)] keeping its octahedral structure, and a covalent binding upon the replacement of water in [VIVO(L1-3)(H2O)] with His-N donors to form VIVO(L1-3)(HSA). In vitro cytotoxicity of ligands and complexes were screened against human cervical cancer (HeLa) (IC50 = 7.39-15.13 µM), colon cancer (HT-29) (IC50 = 11.04-28.20 µM) and mouse embryonic fibroblast (NIH-3T3) cell lines (IC50 = 62.22-87.75 µM) by MTT assay. Particularly, 5 showed higher cytotoxicity than cisplatin and cyclophosphamide, with an IC50 of 7.39 ± 1.21 µM and 11.04 ± 0.29 µM against HeLa and HT-29.

Mo(VI) Potential Metallodrugs: Explaining the Transport and Cytotoxicity by Chemical Transformations.

The transport and cytotoxicity of molybdenum-based drugs have been explained with the concept of chemical transformation, a very important idea in inorganic medicinal chemistry that is often overlooked in the interpretation of the biological activity of metal-containing systems. Two monomeric, [MoO2(L1)(MeOH)] (1) and [MoO2(L2)(EtOH)] (2), and two mixed-ligand dimeric MoVIO2 species, [{MoO2(L1-2)}2(µ-4,4'-bipy)] (3-4), were synthesized and characterized. The structures of the solid complexes were solved through SC-XRD, while their transformation in water was clarified by UV-vis, ESI-MS, and DFT. In aqueous solution, 1-4 lead to the penta-coordinated [MoO2(L1-2)] active species after the release of the solvent molecule (1 and 2) or removal of the 4,4'-bipy bridge (3 and 4). [MoO2(L1-2)] are stable in solution and react with neither serum bioligand nor cellular reductants. The binding affinity of 1-4 toward HSA and DNA were evaluated through analytical and computational methods and in both cases a non-covalent interaction is expected. Furthermore, the in vitro cytotoxicity of the complexes was also determined and flow cytometry analysis showed the apoptotic death of the cancer cells. Interestingly, µ-4,4'-bipy bridged complexes 3 and 4 were found to be more active than monomeric 1 and 2, due to the mixture of species generated, that is [MoO2(L1-2)] and the cytotoxic 4,4'-bipy released after their dissociation. Since in the cytosol neither the reduction of MoVI to MoV/IV takes place nor the production of reactive oxygen species (ROS) through Fenton-like reactions of 1-4 with H2O2 occurs, the mechanism of cytotoxicity should be attributable to the direct interaction with DNA that happens with a minor-groove binding which results in cell death through an apoptotic mechanism.

Water-Soluble Dioxidovanadium(V) Complexes of Aroylhydrazones: DNA/BSA Interactions, Hydrophobicity, and Cell-Selective Anticancer Potential.

Five new anionic aqueous dioxidovanadium(V) complexes, [{VO2L1,2}A(H2O)n]α (1-5), with the aroylhydrazone ligands pyridine-4-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)hydrazide (H2L1) and furan-2-carboxylic acid (3-ethoxy-2-hydroxybenzylidene)hydrazide (H2L2) incorporating different alkali metals (A = Na+, K+, Cs+) as countercation were synthesized and characterized by various physicochemical techniques. The solution-phase stabilities of 1-5 were determined by time-dependent NMR and UV-vis, and also the octanol/water partition coefficients were obtained by spectroscopic techniques. X-ray crystallography of 2-4 confirmed the presence of vanadium(V) centers coordinated by two cis-oxido-O atoms and the O, N, and O atoms of a dianionic tridentate ligand. To evaluate the biological behavior, all complexes were screened for their DNA/protein binding propensity through spectroscopic experiments. Finally, a cytotoxicity study of 1-5 was performed against colon (HT-29), breast (MCF-7), and cervical (HeLa) cancer cell lines and a noncancerous NIH-3T3 cell line. The cytotoxicity was cell-selective, being more active against HT-29 than against other cells. In addition, the role of hydrophobicity in the cytotoxicity was explained in that an optimal hydrophobicity is essential for high cytotoxicity. Moreover, the results of wound-healing assays indicated antimigration in case of HT-29 cells. Remarkably, 1 with an IC50 value of 5.42 ± 0.15 µM showed greater activity in comparison to cisplatin against the HT-29 cell line.

Probing CO Generation through Metal-Assisted Alcohol Dehydrogenation in Metal-2-(arylazo)phenol Complexes Using Isotopic Labeling (Metal = Ru, Ir): Synthesis, Characterization, and Cytotoxicity Studies.

The reaction of 2-{2-(benzo[1,3]dioxol-5-yl)- diazo}-4-methylphenol (HL) with [Ru(PPh3)3Cl2] in ethanol resulted in the carbonylated ruthenium complex [RuL(PPh3)2(CO)] (1), wherein metal-assisted decarbonylation via in situ ethanol dehydrogenation is observed. When the reaction was performed in acetonitrile, however, the complex [RuL(PPh3)2(CH3CN)] (2) was obtained as the main product, probably by trapping of a common intermediate through coordination of CH3CN to the Ru(II) center. The analogous reaction of HL with [Ir(PPh3)3Cl] in ethanol did not result in ethanol decarbonylation and instead gave the organoiridium hydride complex [IrL(PPh3)2(H)] (3). Unambiguous evidence for the generation of CO via ruthenium-assisted ethanol oxidation is provided by the synthesis of the 13C-labeled complex, [Ru(PPh3)2L(13CO)] (1A) using isotopically labeled ethanol, CH313CH2OH. To summarize all the evidence, a ruthenium-assisted mechanistic pathway for the decarbonylation and generation of alkane via alcohol dehydrogenation is proposed. In addition, the in vitro antiproliferative activity of complexes 1-3 was tested against human cervical (HeLa) and human colorectal adenocarcinoma (HT-29) cell lines. Complexes 1-3 showed impressive cytotoxicity against both HeLa (half-maximal inhibitory concentration (IC50) value of 3.84-4.22 µM) and HT-29 cancer cells (IC50 values between 3.3 and 4.5 µM). Moreover, the complexes were comparatively less toxic to noncancerous NIH-3T3 cells.

Metal-coordination driven intramolecular twisting: a turn-on fluorescent-redox probe for Hg2+ ions through the interaction of ferrocene nonbonding orbitals and dibenzylidenehydrazine.

A unique C2 symmetric azine bridged bi-ferrocenyl receptor (4) has been modelled and synthesized. In this work, we are able to synthetically regulate conjugation of the dibenzylidenehydrazine fluorophore unit to unexpectedly reveal metal-coordination driven intramolecular twisting. The present probe shows a dramatic turn-on fluorescence response with 91 fold increment of quantum yield along with 17 nm blue shift upon binding with Hg2+ ions selectively with a limit of detection as low as 15 nM. Upon Hg2+ recognition, the ferrocene/ferrocinium redox peak was anodically shifted by ΔE1/2 = 78 mV, indicating the formation of a new complex species. A plausible binding mode of Hg2+ ions with compound 4 has been proposed based on 1H NMR titration, a high-resolution mass spectrometry (HRMS) study and a density functional theory (DFT) study along with the Job's plot analysis. Interestingly, DFT calculations have revealed that the reason for fluorescence enhancement after coordination to Hg2+ ions is not due to conventional restricted C[double bond, length as m-dash]N isomerization or interrupted N-N single bond rotation rather it is due to the increase of the π ← π* transition at the expense of the n → π* (aromatic) transition of the free ligand. Furthermore, TD-DFT calculations of the first excited singlet state of 4 and [4·Hg2+] revealed the involvement of the aromatic π electrons with the vacant site of Hg2+ ions which may be further attributed to the fluorescence enhancement phenomenon. In addition, receptor 4 was successfully applied for the detection of Hg2+ ions in real samples.