Hydrolytic activity of new bioinspired MnIIIMnII and FeIIIMnII complexes as mimetics of PAPs: Biological and environmental interest.

Coordination compounds that mimic Purple Acid Phosphatases (PAPs) have drawn attention in the bioinorganic field due to their capacity to cleave phosphodiester bonds. However, their catalytic activity upon phosphate triesters is still unexplored. Thus, we report the synthesis and characterization of two binuclear complexes, [MnIIMnIII(L1)(OAc)2]BF4 (1) and [MnIIFeIII(L1)(OAc)2]BF4 (2) (H2L1 = 2-[N,N-bis-(2- pyridilmethyl)aminomethyl]-4-methyl-6-[N-(2-hydroxy-3-formyl-5-methylbenzyl)-N-(2-pyridylmethyl)aminomethyl]phenol), their hydrolytic activity and antioxidant potential. The complexes were fully characterized, including the X-Ray diffraction (XRD) of 1. Density functional theory (DFT) calculations were performed to better understand their electronic and structural properties and phosphate conjugates. The catalytic activity was analyzed for two model substrates, a diester (BDNPP) and a triester phosphate (DEDNPP). The results suggest enhancement of the hydrolysis reaction by 170 to 1500 times, depending on the substrate and complex. It was possible to accompany the catalytic reaction of DEDNPP hydrolysis by phosphorus nuclear magnetic resonance (31P NMR), showing that both 1 and 2 are efficient catalysts. Moreover, we also addressed that 1 and 2 present a relevant antioxidant potential, protecting the yeast Saccharomyces cerevisiae, used as eukaryotic model of study, against the exposure of cells to acute oxidative stress.

A heterotrinuclear bioinspired coordination complex capable of binding to DNA and emulation of nuclease activity.

The investigation of compounds capable of strongly and selectively interacting with DNA comprises a field of research in constant development. In this work, we demonstrate that a trinuclear coordination complex based on a dinuclear Fe(III)Zn(II) core designed for biomimicry of the hydrolytic enzyme kidney bean purple acid phosphatase, containing an additional pendant arm coordinating a Pd(II) ion, has the ability to interact with DNA and to promote its hydrolytic cleavage. These results were found through analysis of plasmid DNA interaction and cleavage by the trinuclear complex 1 and its derivatives 2 and 3, in addition to the analysis of alteration in the DNA structure in the presence of the complexes through circular dichroism and DNA footprinting techniques. The suggested covalent interaction of the palladium-containing complex with DNA was analysed using an electrophoretic mobility assay, circular dichroism, high resolution gel separation techniques and kinetic analysis. This is a new and promising metal complex targeted to nucleic acids and acting in two separate ways: strong DNA interaction and hydrolytic cleavage.

New AlIIIZnII and AlIIICuII dinuclear complexes: Phosphatase-like activity and cytotoxicity.

Herein, we report the synthesis and characterization of the first two AlIII(µ-OH)MII (M = Zn (1) and Cu (2)) complexes with the unsymmetrical ligand H2L{2-[[(2-hydroxybenzyl)(2-pyridylmethyl)]aminomethyl]-6-bis(pyridylmethyl)aminomethyl}-4-methylphenol. The complexes were characterized through elemental analysis, X-ray crystallography, IR spectroscopy, mass spectrometry and potentiometric titration. In addition, complex 2 was characterized by electronic spectroscopy. Kinetics studies on the hydrolysis of the model substrate bis(2,4-dinitrophenyl)phosphate by 1 and 2 show Michaelis-Menten behavior, with 1 being slightly more active (8.31%) than 2 (at pH 7.0). The antimicrobial effect of the compounds was studied using four bacterial strains (Staphylococcus aureus, Pseudomonas aeuruginosa, Shigella sonnei and Shigella dysenteriae) and for both complexes the inhibition of bacterial growth was superior to that caused by sulfapyridine, but inferior to that of tetracycline. The dark cytotoxicity and photocytotoxicity (under UV-A light) of the complexes in a chronic myelogenous leukemia cell line were investigated. Complexes 1 and 2 exhibited significant cytotoxic activity against K562 cells, which undergoes a 2-fold increase on applying 5 min of irradiation with UV-A light. Complex 2 was more effective and a good correlation between cytotoxicity and intracellular concentration was observed, the intracellular copper concentration required to inhibit 50% of cell growth being 3.5 × 10-15 mol cell-1.

Chitosan functionalized with heptadentate dinucleating ligand applied to removal of nickel, copper and zinc.

The preconcentration of metal ions present at low concentration levels in aqueous systems and the selective removal of potentially toxic metals are important applications of adsorption processes. In this study, a heptadentate dinucleating ligand was anchored to chitosan for use in adsorption studies on Zn(II), Cu(II) and Ni(II) ions. The novel adsorbent was characterized by 13C NMR and FT-IR spectroscopy, TGA and BET surface area analysis. The degree of substitution of the ligand in chitosan, obtained from CHN analysis, was 0.73. The adsorption kinetics followed a pseudo-second-order model. The rate constants and the adsorption capacities for multicomponent systems decreased in the order Cu(II) >> Ni(II) ∼ Zn(II), indicating the preferential adsorption of Cu(II). For Cu(II) ions, the Langmuir model provided the best fitting to the experimental data, and the monolayer Cu(II) adsorption capacity was 0.404 mmol g-1, while the linear isotherm described Zn(II) and Ni(II) ion adsorption.

Dinuclear copper(II) complexes with derivative triazine ligands as biomimetic models for catechol oxidases and nucleases.

The research reported herein focuses on the synthesis of two new Cu(II) complexes {[Cu2(2-X-4,6-bis(di-2-picolylamino)-1,3,5-triazine], with X = butane-1,4-diamine (2) or N-methylpyrenylbutane-1,4-diamine (3)}, the latter with a pyrene group as a possible DNA intercalating agent. The structure of complex (3) was determined by X-ray crystallography and shows the dinuclear {CuII(µ-OCH3)2CuII} unit in which the CuII···CuII distance of 3.040 Å is similar to that of 2.97 Å previously found for 1, which contains a {CuII(µ-OH)2CuII} structural unit. Complexes (2) and (3) were also characterized in spectroscopic and electrochemical studies, and catecholase-like activity were performed for both complexes. The kinetic parameters obtained for the oxidation of the model substrate 3,5-di-tert-butylcatechol revealed that the insertion of the spacer butane-1,4-diamine and the pyrene group strongly contributes to increasing the catalytic efficiency of these systems. In fact, Kass becomes significantly higher, indicating that these groups influence the interaction between the complex and the substrate. These complexes also show DNA cleavage under mild conditions with moderate reaction times. The rate of cleavage (kcat) indicated that the presence of butane-1,4-diamine and pyrene increased the activity of both complexes. The reaction mechanism seems to have oxidative and hydrolytic features and the effect of DNA groove binding compounds and circular dichroism indicate that all complexes interact with plasmid DNA through the minor groove. High-resolution DNA cleavage assays provide information on the interaction mechanism and for complex (2) a specificity for the unpaired hairpin region containing thymine bases was observed, in contrast to (3).

Targeting an Artificial Metal Nuclease to DNA by a Simple Chemical Modification and Its Drastic Effect on Catalysis.

A novel metal complex was synthesized containing a purine derived ligand in order to increase its binding to DNA. We observed a huge increase in nuclease activity and, quite interestingly, an improvement on DNA sequence selectivity. A potential site of specific cleavage in the presence of a reductant in the reaction medium is suggested. We were able to synthesize a novel metal nuclease with improved activity on DNA, and with sequence specificity when exposed to a coreactant, this opens up new possibilities to create site specific and redox status modulated artificial nucleases.

SOD activity of new copper II complexes with ligands derived from pyridoxal and toxicity in Caenorhabditis elegans.

This work presents the synthesis, characterization of copper(II) complexes (C1-C6) and the potential of these compounds to mimic the catalytic activity of the enzyme superoxide dismutase (SOD). The copper(II)complexes were obtained by reaction between the aldol condensation between substituted aromatic hydrazides and aromatic aldehydes (salicylic aldehyde and pyridoxal hydrochloride), forming two new ligands (L1 to L6), resulting in new dimeric dicopper (II) complexes (C1 and C2), new three monomeric CuII derivatives (C3, C4 and C6) and a polymeric complex (C5). The CuII complexes were fully characterized by X-ray diffraction, spectroscopic and electrochemical analysis. Subsequently, CuII derivatives were evaluated for their antioxidant activities, using the NBT (Nitro blue tetrazolium chloride) photoreduction methodology. After evaluating the antioxidant activity in vitro, it was observed that the best inhibition rates of the superoxide ion are associated to the C4 and C5 complexes. Computational analysis via molecular docking and quantum chemical calculation (Fukui map) offered a molecular level explanation on the biological activity of CuII complexes. Additionally, cytotoxicity of C1-C6 was tested in the first time in vivo in nematodes Caenorhabditis elegans, corroborating with the results identified for C4 and C5.

Guanidine- and purine-functionalized ligands of FeIIIZnII complexes: effects on the hydrolysis of DNA.

In this paper, the catalytic effects of aminoguanidine and aminopurine groups in the second sphere of a FeIIIZnII complex that mimics the active site of the metallohydrolase purple acid phosphatase (PAP) are investigated, with a particular view on DNA as substrate. The ligand 3-(((3-((bis(2-(pyridin-2-yl)ethyl)amino)methyl)-2-hydroxy-5-methylbenzyl)(pyridin-2-ylmethyl)amino)meth-yl)-2 hydroxy-5-methylbenzaldehyde-(H2L1bpea) was synthesized and its complex [(OH)FeIII(µ-OH)ZnII(H2O)(L1bpea)](ClO4) was used as a base for comparison with similar complexes previously published in the literature. Subsequent modifications were conducted in the aldehyde group, where aminoguanidine (amig) and aminopurine (apur) were used as side chain derivatives. The complexes [(OH)FeIII(µ-OH)ZnII(H2O)(L1bpea)](ClO4) (1), [(OH)FeIII(µ-OH)ZnII(H2O)(L1bpea-amig)](ClO4) (2) and [(OH)FeIII(µ-OH)ZnII(H2O)(L1bpea-apur)](ClO4) (3) were characterized by spectroscopic methods (infrared, UV-Vis) and ESI-MS spectrometry. Density functional theory (DFT) was also used to better understand the structure of the complexes. The hydrolytic activity of complexes 1, 2 and 3 was analyzed using both the model substrate 2,4-BDNPP (bis-(2,4-dinitrophenyl)phosphate) and DNA. Complexes 2 and 3, containing the derivatized ligands, have a significantly higher association constant (Kassoc≅ 1/KM) for the activated substrate 2,4-BDNPP compared to complex 1. The catalytic efficiency (kcat/KM) is also higher due to hydrogen bonds and/or π-stacking interactions between the substrate and the aminoguanidine or aminopurine groups present in 2 and 3, respectively. In the DNA cleavage assays, all complexes were able to cleave DNA, with 1 and 2 having higher catalytic activity than 3. In addition, when compared to previously analyzed complexes, complex 2 is one of the most active, having a kcat of 0.21 h-1.

Synthesis, characterization and biological evaluation of new manganese metal carbonyl compounds that contain sulfur and selenium ligands as a promising new class of CORMs.

Three new manganese carbonyl compounds with heavy atom donors were synthesized and their potential use as photoCORMS was evaluated. Interestingly, all compounds had an elusive binding mode, in which the ligands adopted a κ2-X coordination (where X = S or Se), confirmed both by X-ray crystallography and IR spectroscopy. The stability of the title compounds in the dark was determined by monitoring the changes in the UV spectra of the compounds in both dichloromethane and acetonitrile. These studies show that in coordinating solvents there is an exchange of the bromide bonded to the metal centre by a solvent molecule, which is evidenced by the changes in the UV and IR spectra and by DFT analysis. EDA and natural bond order analyses were conducted to evaluate the influence of the heavy atom donors in the first coordination sphere of the compounds. Photoexcitation at 380 nm demonstrated that all compounds showed release of all three COs, as seen in the photoproducts detected by IR spectroscopy. Furthermore, CO release was observed when the photoCORMs were incubated with living cells, and we observed a CO-dependent inhibition of cell viability.

Second-Sphere Effects in Dinuclear FeIIIZnII Hydrolase Biomimetics: Tuning Binding and Reactivity Properties.

Herein, we report the synthesis and characterization of two dinuclear FeIIIZnII complexes [FeIIIZnIILP1] (1) and [FeIIIZnIILP2] (2), in which LP1 and LP2 are conjugated systems containing one and two pyrene groups, respectively, connected via the diamine -HN(CH2)4NH- spacer to the well-known N5O2-donor H2L ligand (H2L = 2-bis{[(2-pyridylmethyl)aminomethyl]-6-[(2-hydroxybenzyl)(2-pyridylmethyl)]aminomethyl}-4-methylphenol). The complex [FeIIIZnIIL1] (3), in which H2L was modified to H2L1, with a carbonyl group attached to the terminal phenol group, was included in this study for comparison purposes.1 Both complexes 1 and 2 were satisfactorily characterized in the solid state and in solution. Extended X-ray absorption fine structure data for 1 and 3 in an acetonitrile solution show that the multiply bridged structure seen in the solid state of 3 is retained in solution. Potentiometric and UV-vis titration of 1 and 2 show that electrostatic interaction between the protonated amino groups and coordinated water molecules significantly decreases the pKa of the iron(III)-bound water compared to those of 3. On the other hand, catalytic activity studies using 1 and 2 in the hydrolysis of the activated substrate bis(2,4-dinitrophenyl)phosphate (BDNPP) resulted in a significant increase in the association of the substrate (Kass ≅ 1/KM) compared to that of 3 because of electrostatic and hydrophobic interactions between BDNPP and the side-chain diaminopyrene of the ligands H2LP1 and H2LP2. In addition, the introduction of the pyrene motifs in 1 and 2 enhanced their activity toward DNA and as effective antitumor drugs, although the biochemical mechanism of the latter effect is currently under investigation. These complexes represent interesting examples of how to promote an increase in the activity of traditional artificial metal nucleases by introducing second-coordination-sphere effects.

Synthesis and characterization of FeIII(µ-OH)ZnII complexes: effects of a second coordination sphere and increase in the chelate ring size on the hydrolysis of a phosphate diester and DNA.

The synthesis and characterization of three ligands and their respective heterobinuclear FeIIIZnII complexes were carried out, with the goal of mimicking the active site of purple acid phosphatases (PAPs). The ligand 2-hydroxy-3-(((2-hydroxy-5-methyl-3-(((2-(pyridin-2-yl)ethyl)(pyridin-2-ylmethyl)amino)methyl)benzyl)(pyridin-2ylmethyl)amino)methyl)-5-methylbenzaldehyde (H2L2) was synthesized and its complex (FeIIIZnIIL2) was used as a basis for comparison with similar complexes previously published in the literature. Subsequent modifications were conducted in the aldehyde group, where 1,2-ethanediamine and 1,4-diaminobutane were used as side chain derivatives. The compounds FeIIIZnIIL2 (1), FeIIIZnIIL2-et (2) and FeIIIZnIIL2-but (3) were characterized by spectroscopic methods (infrared and UV-Vis) and ESI-MS spectrometry. Theoretical calculations were performed to provide insights into the complex structures with FeIIIZnII structures. The hydrolytic activity was analyzed both with the model substrate 2,4-BDNPP and with DNA catalyzed by complexes 1, 2 and 3.

Photoactive meso-tetra(4-pyridyl)porphyrin-tetrakis-[chloro(2,2'bipyridine)platinum(ii) derivatives recognize and cleave DNA upon irradiation.

In this work, we evaluate the interaction of the peripheral Pt(bpy)Cl+ substituted porphyrins, H2PtPor and ZnPtPor with DNA using UV-vis, emission fluorescence, CD spectroscopy, and DNA melting properties altered by the Pt(ii)-porphyrinoid compounds. Additionally, we observe the ability of these porphyrin derivatives to generate 1O2 and to efficiently photocleave plasmid DNA upon visible light irradiation based on a mixed (oxidative/hydrolytic) mechanism.

Dopamine polymerization promoted by a catecholase biomimetic CuII(µ-OH)CuII complex containing a triazine-based ligand.

We describe herein the catecholase-like catalytic activity and dopamine polymerization by using a dinuclear [LCuII(µ-OH)2CuII](ClO4)2 (1) complex where L is the dinucleating triazine-based ligand 6-chloro-N2,N2,N4,N4-tetrakis(pyridin-2-ylmethyl)-1,3,5-triazine-2,4-diamine. The kinetic parameters (kcat = 0.318 s-1, KM = 1.6 × 10-3 mol L-1, and kcat/KM = 198.8 L s-1 mol-1), mechanistic insights into the oxidation of 3,5-di-tert-butyl catechol and early characterization of poly(dopamine) are presented.

meso-Mono-[4-(1,4,7-triazacyclononanyl)]-tri(phenyl)]porphyrin and the respective zinc(ii)-complex: complete characterization and biomolecules binding abilities.

We aimed to synthesize a new series of triazacyclononanyl-porphyrins (4 and 5) with the potential ability to bind DNA. For this, the free-base porphyrin 4 and the corresponding Zn(ii)-complex 5 were synthesized by the Schiff base formation reaction. The binding ability of the porphyrin derivatives 4 and 5 with DNA from calf-thymus was studied by UV-vis and emission spectroscopy. Detailed analysis of the results suggests that the interaction of these systems most probably occurs through π-stacking and secondary hydrogen interaction surface binding with ct-DNA. Moreover, we also demonstrate the substantial ability of porphyrins 4 and 5 to generate (1)O2 and to photocleave plasmid DNA after irradiation.

Synthesis, characterization, hydrolase and catecholase activity of a dinuclear iron(III) complex: Catalytic promiscuity.

Herein, we report the synthesis and characterization of the new di-iron(III) complex [(bbpmp)(H2O)(Cl)Fe(III)(µ-Ophenoxo)Fe(III)(H2O)Cl)]Cl (1), with the symmetrical ligand 2,6-bis{[(2-hydroxybenzyl)(pyridin-2-yl)methylamino]methyl}-4-methylphenol (H3bbpmp). Complexes 2 with the unsymmetrical ligand H2bpbpmp - {2-[[(2-hydroxybenzyl)(2-pyridylmethyl)]aminomethyl]-6-bis(pyridylmethyl) aminomethyl}-4-methylphenol and 3 with the ligand L(1)=4,11-dimethyl-1,8-bis{2-[N-(di-2-pyridylmethyl)amino]ethyl}cyclam were included for comparison purposes. Complex 1 was characterized through elemental analysis, X-ray crystallography, magnetochemistry, electronic spectroscopy, electrochemistry, mass spectrometry and potentiometric titration. The magnetic data show a very weak antiferromagnetic coupling between the two iron centers of the dinuclear complex 1 (J=-0.29cm(-1)). Due to the presence of labile coordination sites in both iron centers the hydrolysis of both the diester model substrate 2,4-BDNPP and DNA was studied in detail. Complex 1 was also able to catalyze the oxidation of the substrate 3,5-di-tert-butylcatechol (3,5-DTBC) to give the corresponding quinone, and thus it can be considered as a catalytically promiscuous system.

Study of the antimicrobial activity of metal complexes and their ligands through bioassays applied to plant extracts

The appearance of resistant bacteria was found to reduce the efficiency of antimicrobial therapies with the current antibiotics, thereby increasing the need for more efficient drugs for the treatment of infections. Several studies have demonstrated an increase in antimicrobial activity following the interaction of several compounds with metal ions. The present study used a methodology adapted for antimicrobial bioassays using plant extracts, in compliance with the standards of the Clinical and Laboratory Standards Institute against Gram-positive and Gram-negative bacteria. The results obtained were considered appropriate for determining MIC, MBC as for performing antimicrobial sensitivity testing with good efficiency and reproducibility. The bacteria Pseudomonas fluorescens exhibited high sensitivity to the tested compounds, being efficient to evaluate the antibacterial activity. The bioassays with the metal complexes of flavonoid quercetin and Ga(III) ions, and synthetic ligand H2bbppd and Cu(II) ions showed a greater inhibitory effect than their individual ligands, thus, the addition indicated an increase in the antimicrobial activity after the coordination. Both metal complexes exhibit good antimicrobial performances, such as low minimum inhibitory concentration (MIC ≤ 250 µg/ml), bactericidal effect and a broad activity spectrum, which qualify these compounds as suitable candidates to the next step of drugs fabrication. Nevertheless, further studies on the mechanism of growth inhibition and toxicity are needed, in order to evaluate the potential of therapeutic application.

New La(III) complex immobilized on 3-aminopropyl-functionalized silica as an efficient and reusable catalyst for hydrolysis of phosphate ester bonds.

Described herein is the synthesis, structure, and monoesterase and diesterase activities of a new mononuclear [La(III)(L(1))(NO3)2] (1) complex (H2L(1) = 2-bis[{(2-pyridylmethyl)-aminomethyl}-6-[N-(2-pyridylmethyl) aminomethyl)])-4-methyl-6-formylphenol) in the hydrolysis of 2,4-bis(dinitrophenyl)phosphate (2,4-BDNPP). When covalently linked to 3-aminopropyl-functionalized silica, 1 undergoes disproportionation to form a dinuclear species (APS-1), whose catalytic efficiency is increased when compared to the homogeneous reaction due to second coordination sphere effects which increase the substrate to complex association constant. The anchored catalyst APS-1 can be recovered and reused for subsequent hydrolysis reactions (five times) with only a slight loss in activity. In the presence of DNA, we suggest that 1 is also converted into the dinuclear active species as observed with APS-1, and both were shown to be efficient in DNA cleavage.

Correlation between DNA interactions and cytotoxic activity of four new ternary compounds of copper(II) with N-donor heterocyclic ligands.

Four new ternary complexes of copper(II) were synthesized and characterized: [Cu(hyd)(bpy)(acn)(ClO4)](ClO4)] (1), [Cu(hyd)(phen)(acn)(ClO4)](ClO4)] (2), [Cu(Shyd)(bpy)(acn)(ClO4)](ClO4)] (3) and [Cu(Shyd)(phen)(acn)(ClO4)](ClO4)] (4), in which acn=acetonitrile; hyd=2-furoic acid hydrazide, bpy=2,2-bipyridine; phen=1,10-phenanthroline and Shyd=2-thiophenecarboxylic acid hydrazide. The cytotoxic activity of the complexes in a chronic myelogenous leukemia cell line was investigated. All complexes are able to enter cells and inhibit cellular growth in a concentration-dependent manner, with an activity higher than that of the corresponding free ligands. The substitution of Shyd for hyd increases the activity, while the substitution of bpy for phen renders the complex less active. Therefore, the most potent complex is 4 with an IC50 value of 1.5±0.2µM. The intracellular copper concentration needed to inhibit 50% of cell growth is approximately 7×10(-15)mol/cell. It is worth notifying that a correlation between cytotoxic activity, DNA binding affinity and DNA cleavage was found: 1<3<2<4.

Second-coordination-sphere effects increase the catalytic efficiency of an extended model for Fe(III)M(II) purple acid phosphatases.

Herein we describe the synthesis of a new heterodinuclear Fe(III)Cu(II) model complex for the active site of purple acid phosphatases and its binding to a polyamine chain, a model for the amino acid residues around the active site. The properties of these systems and their catalytic activity in the hydrolysis of bis(2,4-dinitrophenyl)phosphate are compared, and conclusions regarding the effects of the second coordination sphere are drawn. The positive effect of the polymeric chain on DNA hydrolysis is also described and discussed.