The influence of thioether-substituted ligands in dicopper(II) complexes: Enhancing oxidation and biological activities.

This paper describes the synthesis, structural analysis, as well as the magnetic and spectroscopic characterizations of three new dicopper(II) complexes with dinucleating phenol-based ligands containing different thioether donor substituents: aromatic (1), aliphatic (2) or thiophene (3). Temperature-dependent magnetometry reveals the presence of antiferromagnetic coupling for 1 and 3 (J = -2.27 cm-1 and -5.01 cm-1, respectively, H = -2JS1S2) and ferromagnetic coupling for 2 (J = 5.72 cm-1). Broken symmetry DFT calculations attribute this behavior to a major contribution from the dz2 orbitals for 1 and 3, and from the dx2-y2 orbitals for 2, along with the p orbitals of the oxygens. The bioinspired catalytic activities of these complexes related to catechol oxidase were studied using 3,5-di-tert-butylcatechol as substrate. The order of catalytic rates for the substrate oxidation follows the trend 1 > 2 > 3 with kcat of (90.79 ± 2.90) × 10-3 for 1, (64.21 ± 0.99) × 10-3 for 2 and (14.20 ± 0.32) × 10-3 s-1 for 3. The complexes also cleave DNA through an oxidative mechanism with minor-groove preference, as indicated by experimental and molecular docking assays. Antimicrobial potential of these highly active complexes has shown that 3 inhibits both Staphylococcus aureus bacterium and Epidermophyton floccosum fungus. Notably, the complexes were found to be nontoxic to normal cells but exhibited cytotoxicity against epidermoid carcinoma cells, surpassing the activity of the metallodrug cisplatin. This research shows the multifaceted properties of these complexes, making them promising candidates for various applications in catalysis, nucleic acids research, and antimicrobial activities.

Spectroscopical and Molecular Studies of Four Manganese(I) PhotoCORMs with Bioinspired Ligands Containing Non-Coordinated Phenol Groups.

Carbonyl compounds are widely explored in medicinal inorganic chemistry and have drawn attention due to their signaling functions in homeostasis. Carbon-monoxide-releasing molecules (CORMs) were developed with the purpose of keeping the CO inactive until its release in the intracellular environment, considering its biological relevance. However, for therapeutic applications, the mechanisms of photorelease and which electronic and structural variations influence its rates must be fully understood. In this work, four ligands containing a pyridine, a secondary amine, and a phenolic group with different substituents were used to prepare new Mn(I) carbonyl compounds. Structural and physicochemical characterization of these complexes was carried out and confirmed the proposed structures. X-ray diffractometry structures obtained for the four organometallic compounds revealed that the substituents in the phenolic ring promote only negligible distortions in their geometry. Furthermore, UV-Vis and IR kinetics showed the direct dependence of the electron-withdrawing or donating ability of the substituent group, indicating an influence of the phenol ring on the CO release mechanism. These differences in properties were also supported by theoretical studies at the DFT, TD-DFT, and bonding situation analyses (EDA-NOCV). Two methods were used to determine the CO release constants (kCO,old and kCO,new), where Mn-HbpaBr (1) had the greatest kCO by both methods (Kco,old = 2.36 × 10-3 s-1 and kCO,new = 2.37 × 10-3 s-1). Carbon monoxide release was also evaluated using the myoglobin assay, indicating the release of 1.248 to 1.827 carbon monoxides upon light irradiation.

Synthesis, characterization and cytotoxicity of copper (II) complex containing a 2H-benzo[e][1,3]oxazin derivative.

A new cis-dihalo copper(II) complex, [CuII(HLbz)(Cl)2].CH3CN (1), where HLbz = (S)-2-(((2-(2-(pyridin-2-yl)-2H-benzo[e][1,3]oxazin-3(4H)-yl)ethyl)amino)methyl)phenol), was isolated by reacting copper(II) chloride dihydrate and the H2L ligand (H2L = 2,2'-((2-(pyridin-2-yl)imidazolidine-1,3-diyl)bis(methylene))diphenol) in a MeOH/CH3CN (1:3 v/v) mixture. The complex formation occurred via the ligand modification during complexation, producing a unique structure containing 2H-benzo[e][1,3]oxazin, as observed from the single crystal X-ray structure determination. The complex was characterized by elemental analysis, potentiometric titration, spectroscopic techniques (UV-Vis, FT-IR) and conductance measurements. Complex 1 inhibits the growth of myelogenous leukemia cells with an IC50 of 17.3 µmol L-1.

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.

Enhancing the phosphorescence decay pathway of Cu(I) emitters - the role of copper-iodide moiety.

Speeding up the phosphorescence channel in luminescent copper(I) complexes has been extremely challenging due to the copper atoms relatively low spin-orbit coupling constant compared to heavier metals such as iridium. Here, we report the synthesis and characterization of three mononuclear copper(I) complexes with diimines, triphenylphosphine, and iodide ligands to evaluate the effect of the copper-iodide (Cu-I) moiety into the phosphorescence decay pathway. Temperature-dependent photophysical studies revealed combined thermally activated delayed fluorescence and phosphorescence emission, with a phosphorescence decay rate of the order of 104 s-1. Density functional theory calculations indicate very high spin-orbit coupling matrix elements between the low-lying states of these complexes. Compared to the classical [Cu(phen)(POP)]+, our results demonstrate that Cu-I is a versatile moiety to speed up the phosphorescence decay pathway in about one order of magnitude, and it can be prepared by a simplified synthetic route with few synthetic steps. Furthermore, the SOC matrix elements and the phosphorescence decay rates of these complexes are comparable to those of extensively applied coordination complexes based on heavier metals, making them a promising alternative as active layers of organic light-emitting diodes.

Chromogenic chemodosimeter based on a silylated azo compound detects cyanide in water and cassava.

A novel silylated azo compound was synthesized and fully characterized. This compound was used in a chromogenic chemodosimeter approach for the highly selective detection of cyanide (CN-) in acetonitrile/water and in an aqueous micellar system. The anion breaks the Si-O bond, delivering a dye and causing a change in the color of the solution (from yellow to blue). The chemodosimeter was employed for the naked-eye and quantitative detection of CN- in tap water and cassava roots.

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.

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).

An unusual partial occupancy of labile chloride and aqua ligands in cocrystallized isomers of a nickel(II) complex bearing a tripodal N4-donor ligand.

A novel Ni2+ complex with the N4-donor tripodal ligand bis[(1-methyl-1H-imidazol-2-yl)methyl][2-(pyridin-2-yl)ethyl]amine (L), namely, aqua{bis[(1-methyl-1H-imidazol-2-yl-κN3)methyl][2-(pyridin-2-yl-κN)ethyl]amine-κN}chloridonickel(II) perchlorate, [NiCl(C17H22N6)(H2O)]ClO4 or [NiCl(H2O)(L)Cl]ClO4 (1), was synthesized and characterized by spectroscopic and spectrometric methods. The crystal structure of 1 reveals an interesting and unusual cocrystallization of isomeric complexes, which are crystallographically disordered with partial occupancy of the labile cis aqua and chloride ligands. The Ni2+ centre exhibits a distorted octahedral environment, with similar bond lengths for the two Ni-N(imidazole) bonds. The bond length increases for Ni-N(pyridine) and Ni-N(amine), which is in agreement with literature examples. The bond lengths of the disordered labile sites are also in the expected range and the Ni-Cl and Ni-O bond lengths are comparable with similar compounds. The electronic, redox and solution stability behaviour of 1 were also evaluated, and the data obtained suggest the maintenance of structural integrity, with no sign of demetalation or decomposition under the studied conditions.

Crystal structure of 5-(4-tert-but-oxy-phen-yl)-3-(4-n-octyloxyphen-yl)-4,5-di-hydro-isoxazole.

The mol-ecule of the title compound, C27H37NO3, was prepared by [3 + 2] 1,3-dipolar cyclo-addition of 4-n-octyl-phenyl-nitrile oxide and 4-tert-but-oxy-styrene, the latter compound being a very useful inter-mediate to the synthesis of liquid-crystalline materials. In the mol-ecule, the benzene rings of the n-octyloxyphenyl and tert-but-oxy-phenyl groups form dihedral angles of 2.83 (7) and 85.49 (3)°, respectively, with the mean plane of the isoxazoline ring. In the crystal, mol-ecules are linked by weak C-H⋯O hydrogen inter-actions into chains running parallel to the b axis.

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.

Reverse Solvatochromism of Imine Dyes Comprised of 5-Nitrofuran-2-yl or 5-Nitrothiophen-2-yl as Electron Acceptor and Phenolate as Electron Donor.

Eight compounds with phenols as electron-donating groups and 5-nitrothiophen-2-yl or 5-nitrofuran-2-yl acceptor moieties in their molecular structures were synthesized. The crystalline structures of six compounds were obtained. Their corresponding phenolate dyes were studied in 29 solvents and the data showed that in all cases a reverse solvatochromism occurred. The results are explained in terms of the ability of the medium to stabilize the electronic ground and excited states of the probes to different extents. The frontier molecular orbitals were analyzed for the protonated and deprotonated forms of the compounds. The calculated geometries are in agreement with the X-ray structures determined for the compounds and it was verified that after their deprotonation an increase in the electron delocalization occurs. Radial distribution functions were calculated for the dyes in water and n-hexane to analyze different solvation patterns resulting from the interaction of the solvents with the dyes. Data obtained by using the Catalán multiparameter equation revealed that the medium acidity is responsible for hypsochromic shifts, whereas the solvent basicity, polarizability, and dipolarity contributed to bathochromic shifts of the solvatochromic band of these dyes. Two model "hybrid cyanine" dyes were used in the design of simple experiments to demonstrate that the solvatochromic behavior of these dyes in solution can be tuned with careful consideration of the properties of the medium.

Synthesis and characterization of novel iminobenzoates with terminal pyrazine moieties.

Apart from its numerous biological activities like antidiabetic, anti-inflammatory, antimicrobial, pyrazine moiety plays an important role in luminescent materials. Its role in luminescent materials is due to its highly electron deficient nature specially when it is in the centre along the mainstay of extended π-conjugated systems. Similarly, new liquid crystalline compounds are being made constantly where the central benzoaromatic moiety is being replaced with the heterocycles including pyrazine due to their more variable nature. Pyrazine derivatives can also be used in supramolecular assemblies due to their efficient hydrogen bonding, protonation and complexation properties. Keeping in view the enormous applications of pyrazine derivatives we planned to synthesize new extended iminobenzoates with pyrazine moieties at the terminal positions. The planned iminobenzoates with terminal pyrazine moieties were prepared following standard procedures. The pyrazine-2-carbohydrazide (1) and 5-methylpyrazine-2-carbohydrazide (2) were prepared by refluxing their methyl esters with hydrazine hydrate in methanol. The esters (3a-3f) were synthesized by reacting 4-hydroxybenzaldehyde with differently substituted acid halides in tetrahydrofuran in the presence of triethyl amine. The target compounds that is, iminobenzoates with the pyrazine moieties at terminal positions (4a-4l), were obtained in good to excellent yields by the reaction of the hydrazides with the esters at reflux. The synthesized compounds were fully characterized using different spectroanalytical techniques including FT-IR, NMR, Mass, elemental analysis and single crystal X-ray diffraction analysis. The paper describes the synthesis of novel iminobenzoates following easy methods while utilizing commercially available starting materials. The synthesized iminobenzoates may possibly be converted to compounds with luminescent and liquid crystalline properties after making suitable changes to the pyrazine moieties. Properly substituted pyrazines on both sides, capable of further suitable extensions, may result in compounds with such properties.

A new polyacetylene glucoside from Vernonia scorpioides and its potential antihyperglycemic effect.

Natural polyacetylene compounds have been found mainly in seven botanical families and remain underexplored and understudied, despite its inherent chemical and biological reactivity, due to the presence of conjugated triple bonds. Some polyacetylene glucosides have been found to stimulate glucose uptake in C5BL/ks-db/db obese diabetic mice, and since polyacetylene glucosides previously found in Vernonia scorpioides showed little to none cytotoxicity, in this study the antihyperglycemic potential of a new V. scorpioides polyacetylene glucoside has been accessed in order to shine a new light on the biological activity of this unique scaffold. For the isolation of this new compound an optimized method of Centrifugal Partition Chromatography (CPC) is for the first time described together with its X-ray data. The results demonstrate that 3,4-dihydrovernoniyne-4-O-ß-glucoside has significant effect on glycaemia at low dose 0.5 mg/kg, and pointing that the anti-hyperglycemic effect may be due in part to the inhibition of intestinal disaccharidases.

Crystal structure of 5-O-benzoyl-2,3-O-iso-propyl-idene-d-ribono-1,4-lactone.

In the title compound, C15H16O6, obtained from the acyl-ation reaction between 2,3-O-iso-propyl-idene-d-ribono-1,4-lactone and benzoyl chloride, the known absolute configuration for the lactone moiety of the ester substituent has been confirmed. The five-membered rings of the bicyclic lactone-dioxolane moiety both show envelope conformations and form a dihedral angle of 19.82 (7)° between the lactone ring and the benzene ring. In the crystal, mol-ecules of the acyl-ated sugar are linked by very weak inter-molecular C-H⋯O inter-actions, forming a three-dimensional network.

Structure-behavior study of a family of "hybrid cyanine" dyes which exhibit inverted solvatochromism.

The inverted solvatochromism of twenty dyes containing an electron-donor phenolate conjugated with an electron-withdrawing nitro-substituted phenyl ring was analyzed in terms of the dye structure and substituents. Structural factors that increased the difference between the electrophilicities of the donor and acceptor moieties, or the donor-acceptor strength of the phenolate dyes, also increased the sensitivity of the dyes to solvent-polarity changes and red-shifted their solvatochromic absorption bands.

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.

Synthesis, characterization and antitumoral activity of new cobalt(II)complexes: Effect of the ligand isomerism on the biological activity of the complexes.

The synthesis, physico-chemical characterization and cytotoxicity against five human tumoral cell lines (THP-1, U937, Molt-4, Colo205 and H460) of three new cobalt(II) coordination compounds are reported (i.e. Co(HL1)Cl (1), Co(HL2)Cl (2) and [Co(HL3)Cl]0.0.5 (CH3)2CHOH (3)). H2L2 (2-{[[2-hydroxy-3-(1-naphthyloxy)propyl](pyridin-2-ylmethyl)amino]methyl}phenol) and H2L3 (2-{[[2-hydroxy-3-(2-naphthyloxy)propyl](pyridin-2-ylmethyl)amino]methyl}phenol) present α and ß-naphthyl groups respectively, which is absent in H2L1 (N-(2-hydroxybenzyl)-N-(2-pyridylmethyl)[(3-chloro)(2-hydroxy)]propylamine. These compounds were characterized by a range of physico-chemical methods. X-ray diffraction studies were performed for complex (3), indicating the formation of a mononuclear complex. Complexes (2) and (3), which contain α and ß-naphthyl groups respectively, have presented lower IC50 values than those exhibited by complex (1). Complex (3) presents IC50 values lower than cisplatin against Colo205 (90 and 196µmolL(-1), respectively) and H460 (147 and 197µmolL(-1), respectively). These human neoplastic cells under investigation were also more susceptible toward complex (3) than peripheral blood mononuclear cells. Transmission electron microscopy investigations are in agreement with the loss of mitochondrial membrane potential (ΔΨm) observed by JC-1 mitochondrial potential sensor and indicate that the activity of complex (3) against leukemic cell line (U937) is mediated by an apoptotic mechanism associated with mitochondrial dysfunction (intrinsic pathway).

Lanostane-type triterpenes from the fungal endophyte Scleroderma UFSMSc1 (Persoon) Fries.

Two lanostane triterpenoids (sclerodols A and B) were isolated from the culture of the Eucalyptus grandis derived from the endophyte Scleroderma UFSM Sc1(Persoon) Fries together with three known compounds: one related triterpenoid lanosta-8,23-dien-3ß,25-diol, the disaccharide α,ß-trehalose, and the sugar alcohol mannitol. Their structures were elucidated on the basis of 2D NMR, HRME, and single-crystal X-ray diffraction data. The methanol crude extract and the isolated lanostane triterpenoids showed promising anticandidal activities.

Azido- and chlorido-cobalt complex as carrier-prototypes for antitumoral prodrugs.

Cobalt(III) complexes are well-suited systems for cytotoxic drug release under hypoxic conditions. Here, we investigate the effect of cytotoxic azide release by cobalt-containing carrier-prototypes for antitumoral prodrugs. In addition, we study the species formed after reduction of Co(3+) → Co(2+) in the proposed models for these prodrugs. Three new complexes, [Co(III)(L)(N3)2]BF4(1), [{Co(II)(L)(N3)}2](ClO4)2(2), and [Co(II)(L)Cl]PF6(3), L=[(bis(1-methylimidazol-2-yl)methyl)(2-(pyridyl-2-yl)ethyl)amine], were synthesized and studied by several spectroscopic, spectrometric, electrochemical, and crystallographic methods. Reactivity and spectroscopic data reveal that complex 1 is able to release N3(-) either after reduction with ascorbic acid, or by ambient light irradiation, in aqueous phosphate buffer (pH6.2, 7.0 and 7.4) and acetonitrile solutions. The antitumoral activities of compounds 1-3 were tested in normoxia on MCF-7 (human breast adenocarcinoma), PC-3 (human prostate) and A-549 (human lung adenocarcinoma epithelial) cell lines, after 24h of exposure. Either complexes or NaN3 presented IC50 values higher than 200 µM, showing lower cytotoxicity than the clinical standard antitumoral complex cisplatin, under the same conditions. Complexes 1-3 were also evaluated in hypoxia on A-549 and results indicate high IC50 data (>200 µM) after 24h of exposure. However, an increase of cancer cell susceptibility to 1 and 2 was observed at 300 µM. Regarding complex 3, no cytotoxic activity was observed in the same conditions. The data presented here indicate that the tridentate ligand L is able to stabilize both oxidation states of cobalt (+3 and +2). In addition, the cobalt(III) complex generates the low cytotoxic cobalt(II) species after reduction, which supports their use as as carrier prototypes for antitumoral prodrugs.