Synthesis and biological evaluation of salophen nickel(II) and cobalt(III) complexes as potential anticancer compounds.

Recent in vitro investigations of N,N'-bis(salicylidene)-1,2-phenylenediamine (SAP) iron(III) complexes substituted with alkyl (ethyl, propyl, butyl) carboxylates at position 4 in tumor and leukemia cells revealed strong cytotoxic activity. In continuation of this study, analogous nickel(II) and cobalt(III) complexes were synthesized and tested in HL-60 leukemia, and cisplatin-sensitive and -resistant A2780 ovarian cancer cell lines. The biological activity depended on the extent of cellular uptake and the formation of reactive oxygen species (ROS). Inactive [(Ni(II)SAP] complexes (1-3) only marginally accumulated in tumor cells and did not induce ROS. The cellular uptake of [Co(III)SAP]Cl complexes (4-6) into the cells depended on the length of the ester alkyl chain (ethyl, 4 < propyl, 5 < butyl, 6). The cytotoxicity correlated with the presence of ROS. The low cytotoxic complex 4 induced only few ROS, while 5 and 6 caused a good to outstanding antiproliferative activity, exerted high ROS generation, and induced cell death after 48 h. Necrostatin-1 prevented the biological effects, proving necroptosis as part of the mode of action. Interestingly, the effects of 5 and 6 were not reversed by Ferrostatin-1, but even enhanced upon simultaneous application to the tumor cells.

Ni(II)-Salophen-Comprehensive Analysis on Electrochemical and Spectral Characterization and Biological Studies.

New aspects of the Ni(II)-salophen complex and salophen ligand precursor were found during deep electrochemical and optical characterization, as well as biological studies for new pharmacological applications. Physicochemical and spectroscopic methods (1H- and 13C-NMR, FT-IR and UV-Vis, electrospray ionization mass spectroscopy, thermogravimetric analysis, and molar conductance measurements) were also used to prove that the salophen ligand acts as a tetradentate and coordinates to the central metal through nitrogen and oxygen atoms. The electrochemical behavior of the free Schiff salophen ligand (H2L) and its Ni(II) complex (Ni(II)L) was deeply studied in tetrabutylammonium perchlorate solutions in acetonitrile via CV, DPV, and RDE. Blue films on the surfaces of the electrodes as a result of the electropolymerization processes were put in evidence and characterized via CV and DPV. (H2L) and Ni(II)L complexes were tested for their antimicrobial, antifungal, and antioxidant activity, showing good antimicrobial and antifungal activity against several bacteria and fungi.

Excited state dynamics of Zn-salophen complexes.

Zn-salophen complexes are a promising class of fluorescent chemosensors for nucleotides and nucleic acids. We have investigated, by means of steady state UV-Vis, ultrafast transient absorption, fluorescence emission and time dependent density functional theory (TD-DFT) the behavior of the excited states of a salicylidene tetradentate Schiff base (Sal), its Zn(II) coordination compound (Zn-Sal) and the effect of the interaction between Zn-Sal and adenosine diphosphate (ADP). TD-DFT shows that the deactivation of the excited state of Sal occurs through torsional motion, due to its rotatable bonds and twistable angles. Complexation with Zn(II) causes rigidity so that the geometry changes in the excited states with respect to the ground state structure are minimal. By addition of ADP to a freshly prepared Zn-Sal ethanol solution, a longer relaxation constant, in comparison to Zn-Sal, was measured, indicative of the interaction between Zn-Sal and ADP. After a few days, the Zn-Sal-ADP solution displayed the same static and dynamic behavior of a solution containing only the Sal ligand, demonstrating that the coordination of the ADP anion to Zn(II)leads to the demetallation of the Sal ligand. Fluorescence measurements also revealed an enhanced fluorescence at 375 nm following the addition of ADP to the solution, caused by the presence of 2,3-diamino naphthalene that is formed by demetallation and partial decomposition of the Sal ligand. The efficient fluorescence of this species at 375 nm could be selectively detected and used as a probe for the detection of ADP in solution.

A Simple and Efficient Mechanochemical Route for the Synthesis of Salophen Ligands and of the Corresponding Zn, Ni, and Pd Complexes.

A number of salophen ligands and their Zn, Ni, and Pd complexes were synthesized by an efficient one-pot mechanosynthesis protocol. The reaction products were characterized by means of complementary solid-state techniques, i.e., powder X-ray diffraction, single-crystal X-ray diffraction, and solid-state NMR spectroscopy. Four new crystal structures of metal salophen complexes as DMSO solvates are here reported. The described simple and relatively fast (about 1 h for all derivatives) procedure is a good alternative to classical methods performed in organic solvents.

Vanadium: History, chemistry, interactions with α-amino acids and potential therapeutic applications.

In the last 30 years, since the discovery that vanadium is a cofactor found in certain enzymes of tunicates and possibly in mammals, different vanadium-based drugs have been developed targeting to treat different pathologies. So far, the in vitro studies of the insulin mimetic, antitumor and antiparasitic activity of certain compounds of vanadium have resulted in a great boom of its inorganic and bioinorganic chemistry. Chemical speciation studies of vanadium with amino acids under controlled conditions or, even in blood plasma, are essential for the understanding of the biotransformation of e.g. vanadium antidiabetic complexes at the physiological level, providing clues of their mechanism of action. The present article carries out a bibliographical research emphaticizing the chemical speciation of the vanadium with different amino acids and reviewing also some other important aspects such as its chemistry and therapeutical applications of several vanadium complexes.

Phenoxyaluminum(salophen) Scaffolds: Synthesis, Electrochemical Properties, and Self-Assembly at Surfaces of Multifunctional Systems.

Salophens and Salens are Schiff bases generated through the condensation of two equivalents of salicylaldehyde with either 1,2-phenylenediamines or aliphatic diamines, respectively. Both ligands have been extensively exploited as key building blocks in coordination chemistry and catalysis. In particular, their metal complexes have been widely used for various catalytical transformations with high yield and selectivity. Through the modification of the phenol unit it is possible to tune the steric hindrance and electronic properties of Salophen and Salen. The introduction of long aliphatic chains in salicylaldehydes can be used to promote their self-assembly into ordered supramolecular structures on solid surfaces. Herein, we report a novel method towards the facile synthesis of robust and air-stable [Al(Salophen)] derivatives capable of undergoing spontaneous self-assembly at the graphite/solution interface forming highly-ordered nanopatterns. The new synthetic approach relies on the use of [MeAlIII (Salophen)] as a building unit to introduce, via a simple acid/base reaction with functionalized acidic phenol derivatives, selected frameworks integrating multiple functions for efficient surface decoration. STM imaging at the solid/liquid interface made it possible to monitor the formation of ordered supramolecular structures. In addition, the redox properties of the Salophen derivatives functionalized with ferrocene units in solution and on surface were unraveled by cyclic voltammetry. The use of a five-coordinate aluminum alkyl Salophen precursor enables the tailoring of new Salophen molecules capable of undergoing controlled self-assembly on HOPG, and thereby it can be exploited to introduce multiple functionalities with subnanometer precision at surfaces, ultimately forming ordered functional patterns.

Solution and Solid-State Studies on the Halide Binding Affinity of Perfluorophenyl-Armed Uranyl-Salophen Receptors Enhanced by Anion-π Interactions.

The enhancement of the binding between halide anions and a Lewis acidic uranyl-salophen receptor has been achieved by the introduction of pendant electron-deficient arene units into the receptor skeleton. The association and the occurrence of the elusive anion-π interaction with halide anions (as tetrabutylammonium salts) have been demonstrated in solution and in the solid state, providing unambiguous evidence on the interplay of the concerted interactions responsible for the anion binding.

Cu (II) Chemosensor Based on a Fluorogenic Bodipy-Salophen Combination: Sensitivity and Selectivity Studies.

A new fluorescent chemosensor (Bodipy-S) derived from Bodipy and Salophen was developed. After the characterization of all compounds, the behavior of the chemosensor Bodipy-S toward p, d and f block-metal ions was investigated by UV-vis and fluorescence spectroscopy. This chemosensor can selectively detect to Cu (II) in methanol-aqueous solution based on chelation enhanced fluorescence (CHEF) and it almost exhibit to a fluorescence quenching effect with 20-fold. The binding constant of the fluorophore was interpreted by using of the Stern-Volmer method and the complex stoichiometry was defined by using Job's plot. Moreover, the effect of pH was performed by the fluorescence intensities of Bodipy-S in presence of Cu(II) ions. The chemosensor can be successfully used to the detection of Cu(II) in most areas.

Resonance light scattering detection of fructose bisphosphates using uranyl-salophen complex-modified gold nanoparticles as optical probe.

In this paper, we report a resonance light scattering (RLS) method for the determination of fructose bisphosphates (FBPs) in water solution using fructose 1,6-bisphosphate (F-1,6-BP) as a model analyte without the procedure of extracting target analyte. The method used a type of modified gold nanoparticles (GNPs) as optical probe. The modified GNPs are uranyl-salophen-cysteamine-GNPs (U-Sal-Cy-GNPs) which are obtained through the acylation reaction of carboxylated salophen with cysteamine-capped GNPs (Cy-GNPs) to form Sal-Cy-GNPs and then the chelation reaction of uranyl with tetradentate ligand salophen in the Sal-Cy-GNPs. A FBP molecule is used easily to connect two U-Sal-Cy-GNPs to cause the aggregation of the GNPs by utilizing the specific affinity of uranyl-salophen complex to phosphate group, resulting in the production of strong RLS signal from the system. The amount of FBPs can be determined through detecting the RLS intensity change of the system. A linear range was found to be 2.5 to 75 nmol/L with a detection limit of 0.91 nmol/L under optimal conditions. The method has been successfully used to determine FBPs in real samples with the recoveries of 96.5-103.5 %.

Innovative Application of Salophen Derivatives in Organic Electronics as a Composite Film with a Poly(3,4-Ethylenedioxythiophene)-poly(styrenesulfonate) Matrix.

In this work, we present the innovative synthesis of salophen (acetaminosalol) derivatives in a solvent-free environment by high-speed ball milling, using a non-conventional activation method, which allowed obtaining compounds in a shorter time and with a better yield. Furthermore, for the first time, the salophen derivatives were deposited as composite films, using a matrix of poly 3,4-ethylene dioxythiophene:polystyrene sulfonate (PEDOT:PSS) polymer. Significant findings include the transformation from the benzoid to the quinoid form of PEDOT post-IPA treatment, as evidenced by Raman spectroscopy. SEM analysis revealed the formation of homogeneous films, and AFM provided insights into the changes in surface roughness and morphology post-IPA treatment, which may be crucial for understanding potential applications in electronics. The optical bandgap ranges between 2.86 and 3.2 eV for PEDOT:PSS-salophen films, placing them as organic semiconductors. The electrical behavior of the PEDOT:PSS-salophen films undergoes a transformation with the increase in voltage, from ohmic to space charge-limited conduction, and subsequently to constant current, with a maximum of 20 mA. These results suggest the possible use of composite films in organic electronics.

Improving CO2 electroconversion by customizing the hydroxyl microenvironment around a semi-open Co-N2O2 configuration.

Constructing local microenvironments is one of the important strategies to improve the electrocatalytic performances, such as in electrochemical CO2 reduction (ECR). However, effectively customizing these microenvironments remains a significant challenge. Herein, utilizing carbon nanotube (CNT) heterostructured semi-open Co-N2O2 catalytic configurations (Co-salophen), we have demonstrated the role of the local microenvironment on promoting ECR through regulating the location of hydroxyl groups. Concretely, compared with the maximum Faradaic efficiency (FE) of 62% for carbon monoxide (CO) presented by Co-salophen/CNT without a hydroxyl microenvironment, the designed Co-salophen-OH3/CNT, featuring hydroxyl groups at the Co-N2O2 structural opening, shows remarkable CO2-to-CO electroreduction activity across a wide potential window, with the FE of CO up to 95%. In particular, through the deuterium kinetic isotope experiments and theoretical calculations, we decoded that the hydroxyl groups act as a proton relay station, promoting the efficient transfer of protons to the Co-N2O2 active sites. The finding demonstrates a promising molecular design strategy for enhancing electrocatalysis.

Diversifying the functions of heme proteins with non-porphyrin cofactors.

Heme proteins perform diverse biochemical functions using a single iron porphyrin cofactor. This versatility makes them attractive platforms for the development of new functional proteins. While directed evolution and metal substitution have expanded the properties, reactivity, and applications of heme proteins, the incorporation of porphyrin analogs remains an underexplored approach. This review discusses the replacement of heme with non-porphyrin cofactors, such as porphycene, corrole, tetradehydrocorrin, phthalocyanine, and salophen, and the attendant properties of these conjugates. While structurally similar, each ligand exhibits distinct optical and redox properties, as well as unique chemical reactivity. These hybrids serve as model systems to elucidate the effects of the protein environment on the electronic structure, redox potentials, optical properties, or other features of the porphyrin analog. Protein encapsulation can confer distinct chemical reactivity or selectivity of artificial metalloenzymes that cannot be achieved with the small molecule catalyst alone. Additionally, these conjugates can interfere with heme acquisition and uptake in pathogenic bacteria, providing an inroad to innovative antibiotic strategies. Together, these examples illustrate the diverse functionality that can be achieved by cofactor substitution. The further expansion of this approach will access unexplored chemical space, enabling the development of superior catalysts and the creation of heme proteins with emergent properties.

Modulating carbon dioxide activation on carbon nanotube immobilized salophen complexes by varying metal centers for efficient electrocatalytic reduction.

Electrocatalytic CO2 reduction (ECR) into valuable chemicals, especially driven by renewable energy, presents a promising pattern to realize carbon neutrality. Site-isolated metal complexes flourish in the area of ECR as single-atom-like catalysts because of their competent and tailorable activity. In this study, salophen-based metal (Fe, Co, Ni and Cu) complexes were anchored onto carbon nanotubes (CNTs) to construct efficient catalysts for electrochemically converting CO2 to CO. Both experimental and theoretical results verified that CO2 activation was the rate-determining step for the catalytic performance of these hybrid molecular catalysts. The coordinate activation ability can be manipulated by varying the metal centers. The as-synthesized Fe-salophen hybrid CNT (Fe-salophen/CNT) shows the best activity and selectivity of -13.24 mA·cm-2 current density with 86.8% Faradaic efficiency for generating CO (FECO) at -0.76 V vs. RHE in aqueous solution, whereas Cu-salophen/CNT only achieved a -2.22 mA·cm-2 current density and 57.9% FECO under the same reaction conditions. These distinct catalytic performances resulted from the different coordination activation abilities of CO2 on various metal centers.

Complexation and enantioselectivity of novel bridge-like uranyl- 2-((1Z,9Z)-9-(2-Hydroxyphenyl)-3,5,6,8-tetrahydrobenzo[h][1,4,7,10] dioxadiazacyclododecin-2-yl)-5-methoxyphenol with chiral organophosphorus pesticide enantiomers of R/S-malathions.

Designing new uranyl complexes with enantioselectivity is of great significance for the identification and separation of enantiomers of chiral pesticides. In this paper, a new asymmetric rigid uranyl-2-((1Z,9Z)-9-(2-Hydroxyphenyl)-3,5,6,8-tetrahydrobenzo[h][1,4,7,10] dioxadiaza-cyclododecin-2-yl)-5-methoxyphenol(Uranyl-HTDM) was designed, we used Uranyl-HTDM as a receptor to selectively coordinate with the guests of the chiral organophosphorus pesticide R/S-malathions(R/S-MLTs) to explore the receptor's enatioselectivity recognition of the chiral guests of R/S-MLTs. Density functional theory (DFT) method was used to comprehensively study the complexation mode of the receptor with enantiomers. The results showed that the U of Uranyl-HTDM could coordinate with both the thiophosphoryl sulfur and carbonyl oxygens of R/S-MLTs in different environments, respectively. The thermodynamics calculations further indicated that the receptor could selectively recognize the thiophosphoryl sulfur and carbonyl oxygen atoms of R/S-malathions, and the complexation abilities of Uranyl-HTDM to the R/S-malathions under different solvents were not the same. The smaller the polarity of solvents, the stronger the complexation ability of Uranyl-HTDM with R-malathion, toluene was an ideal solvent with large △G change and enatioselectivity coefficient of 99.55%. The study provides useful references for the design of new uranyl-salophens and for the experimental study on the molecular recognition of chiral organophosphorus pesticides.

A Newly Designed Water Soluble Uranyl-Salophen Complex for Anion Recognition.

A novel water-soluble uranyl-salophen (salophen=N,N'-disalicylidene-o-phenylenediaminate) complex was obtained. Solubility was achieved in aqueous methyl-ß-cyclodextrin solutions, taking advantage of the host-guest interactions established with the adamantyl moieties present on the ligand skeleton. Such an approach facilitates the synthesis of the receptor and the purification processes and, in perspective, can be definitely applicable to other molecular scaffolds. UV/Vis titration experiments demonstrate that the capacity of the uranyl-salophen core to behave as a receptor for anions is retained in water and appears comparable with that previously reported for other water-soluble uranyl-salophen systems. Hence the presence of cyclodextrins does not interfere with molecular recognition processes.

Chromium-Salophen as a Soluble or Silica-Supported Co-Catalyst for the Fixation of CO2 Onto Styrene Oxide at Low Temperatures.

Addition of a soluble or a supported CrIII-salophen complex as a co-catalyst greatly enhances the catalytic activity of Bu4NBr for the formation of styrene carbonate from styrene epoxide and CO2. Their combination with a very low co-catalyst:Bu4NBr:styrene oxide molar ratio = 1:2:112 (corresponding to 0.9 mol% of CrIII co-catalyst) led to an almost complete conversion of styrene oxide after 7 h at 80°C under an initial pressure of CO2 of 11 bar and to a selectivity in styrene carbonate of 100%. The covalent heterogenization of the complex was achieved through the formation of an amide bond with a functionalized {NH2}-SBA-15 silica support. In both conditions, the use of these CrIII catalysts allowed excellent conversion of styrene already at 50°C (69 and 47% after 24 h, respectively, in homogeneous and heterogeneous conditions). Comparison with our previous work using other metal cations from the transition metals particularly highlights the preponderant effect of the nature of the metal cation as a co-catalyst in this reaction, that may be linked to its calculated binding energy to the epoxides. Both co-catalysts were successfully reused four times without any appreciable loss of performance.

Efficient Nitrate Reduction over Novel Covalent Ag-Salophen Polymer-Derived "Vein-Leaf-Apple"-like Ag@Carbon Structures.

Efficient electrocatalysts for nitrate reduction reaction (NO3--RR) that could selectively transfer nitrate into harmless nitrogen are required for water-denitrification treatment. The most widely used electrodes for NO3--RR including noble metals, transition metals, and their alloys still face many challenges such as lower selectivity and efficiency, high cost, and easy corrosion properties. Metallic Ag with acceptable cost possesses strong corrosion resistance in electrolysis, but its activity is often incompetent for NO3--RR. In this work, Ag nanoparticles with a lower loading content (1.99 wt %) on a nitrogen-doped carbon support was successfully used as the robust electrocatalyst for NO3--RR in a Cl--free neutral solution. This Ag@carbon catalyst exhibited an impressive electrochemical performance for NO3--RR, with a NO3--N conversion yield of 53% and a N2-N selectivity of 97% at a low electrolysis overpotential (-0.29 V vs RHE). In particular, the prepared Ag@carbon showed better stability and no secondary Ag ion pollution in electrolysis. Its impressive electrocatalytic performance was attributed to the unique "vein-leaf-apple"-like Ag@carbon structures, prepared by thermal conversion of Ag-salophen polymers@CNTs. CNTs served as veins to enhance the electron transportation in electrocatalysts. Salophen polymer-derived mesoporous N-doped carbon plates acted as leaves to concentrate NO3- from the electrolyte. Like apples on trees, Ag nanoparticles of about 10-20 nm highly dispersed on carbons selectively converted NO3--N into N2-N. It opens up a cost-acceptable and corrosion-resistant Ag-less electrocatalytic pathway for NO3--RR, and the special "vein-leaf-apple"-like Ag@carbon structure could enhance the electrolytic efficiency and N2-N selectivity for NO3--RR.

An unsymmetrical dinuclear scandium complex comprising salophen ligands [H2salophen = N,N'-bis-(salicyl-idene)-1,2-phenyl-enedi-amine].

Treatment of scandium nitrate tetra-hydrate with the tetra-dentate ligand H2salophen [N,N'-bis-(salicyl-idene)-1,2-phenyl-enedi-amine] afforded the yellow dinuclear complex Sc(NO3)2(µ-salophen)Sc(salophen)(EtOH) or [Sc2(C20H14N2O2)2(NO3)2(C2H6O)] (systematic name: (ethanol-κO)bis-(nitrato-κ2 O,O'){µ-2,2'-[1,2-phenyl-enebis(nitrilo-methanylyl-idene)]diphenolato-κ4 N,N',O,O':κ2 O,O'}{2,2'-[1,2-phenyl-enebis(nitrilo-methanylyl-idene)]diphenolato-κ4 O,N,N',O'}discandium). In this compound, one salophen ligand displays a bridging coordination via the two oxygen atoms, while the other salophen ligand is attached to only one Sc center. This arrangement is stabilized by a hydrogen-bonded EtOH co-ligand, and by π-π stacking inter-actions between the two salophen ligands.

Symmetrical bis-salophen probe serves as a selectively and sensitively fluorescent switch of gallium ions in living cells and zebrafish.

The semi-metallic element gallium has repeatedly shown bio-activities in preclinical and clinical studies. Gallium derivatives have already entered clinical trials for treatment of various refractory malignancies. To better monitor or track the status of administered gallium compound, herein a novel fluorescent probe N,N',N'',N'''-Tetrakis(2-hydroxybenzylidene)biphenyl-3,3',4,4'-tetramine (bis-salophen) has been designed and synthesized. The bis-salophen probe was found to recognize gallium ions (Ga3+) with high selectivity and sensitivity over other cations via fluorescence "turn on" strategy. The spectroscopy results exhibited a 1:2 stoichiometry for probe and Ga3+, and the association constant and limit of detection were calculated as 8.85 × 106 M-1 and 13.0 nM, respectively. Additionally, base on spectroscopy and theoretical research, the mechanism of Ga3+ sensing action was explored by density functional theory (DFT), which indicated suppression of photoinduced electron transfer (PET) action along with the interruption of π-conjugation between salicylaldehyde and 3,3-diaminobenzidine backbone by Ga3+ ions. Furthermore, the biological applicability of bis-salophen probe were evaluated in various normal and cancer cell lines, results have shown that this probe is highly selective and sensitive for cancer cells. Finally, zebrafish imaging confirmed and indicated that the probe is also capable of examining Ga3+ ions. Collectively, these results suggest that we have successfully developed a novel probe for selective and sensitive detection of Ga3+ ions both in living cells and zebrafish. We expect that our work here will shed light on future development of Ga3+ detecting probes and wider application in the filed of biology and medicine shall be anticipated.

Electronic and magnetic properties of the [Ni(salophen)]: An experimental and DFT study.

The effect of the coordination of a Ni(II) ion on the electronic and magnetic properties of the ligand salophen were experimentally and theoretically evaluated. The complex [Ni(salophen)] was synthesized and characterized through FTIR and an elemental analysis. Spectral data obtained using DMSO as a solvent showed that the ligand absorption profile was significantly disturbed after the coordination of the metal atom. In addition to a redshift of the salophen ligand absorption bands, mainly composed by π → π∗ electronic transitions, additional bands of around 470 nm were observed, resulting in a partial metal-to-ligand charge transfer. Furthermore, a significant increment of its band intensities was observed, favoring a more intense absorption in a broader range of the visible spectrum, which is a desired characteristic for applications in the field of organic electronics. This finding is related to an increment of the planarity and consequent electron delocalization of the macrocycle in the complex, which was estimated by the calculation of the current strengths at the PBE0/cc-pVTZ (Dyall.v3z for Ni(II)) level.