Exploring the potential anti-thyroid activity of Acetyl-L-carnitine: Lactoperoxidase inhibition profile, iodine complexation and scavenging power against H2O2. Experimental and theoretical studies.

L-Acetylcarnitine (ALC), a versatile compound, has demonstrated beneficial effects in depression, Alzheimer's disease, cognitive impairment, and other conditions. This study focuses on its antithyroid activity. The precursor molecule, L-carnitine, inhibited the uptake of triiodothyronine (T3) and thyroxine (T4), and it is possible that ALC may reduce the iodination process of T3 and T4. Currently, antithyroid drugs are used to control the excessive production of thyroid hormones (TH) through various mechanisms: (i) forming electron donor-acceptor complexes with molecular iodine, (ii) eliminating hydrogen peroxide, and (iii) inhibiting the enzyme thyroid peroxidase. To understand the pharmacological properties of ALC, we investigated its plausible mechanisms of action. ALC demonstrated the ability to capture iodine (Kc = 8.07 ± 0.32 x 105 M-1), inhibit the enzyme lactoperoxidase (LPO) (IC50 = 17.60 ± 0.76 µM), and scavenge H2O2 (39.82 ± 0.67 mM). A comprehensive physicochemical characterization of ALC was performed using FTIR, Raman, and UV-Vis spectroscopy, along with theoretical DFT calculations. The inhibition process was assessed through fluorescence spectroscopy and vibrational analysis. Docking and molecular dynamics simulations were carried out to predict the binding mode of ALC to LPO and to gain a better understanding into the inhibition process. Furthermore, albumin binding experiments were also conducted. These findings highlight the potential of ALC as a therapeutic agent, providing valuable insights for further investigating its role in the treatment of thyroid disorders.

Complexation of the Antihypertensive Drug Olmesartan with Zn: In Vivo Antihypertensive and Cardiac Effects.

This study is based on the premise that the application of chemical synthesis strategies to structurally modify commercial drugs by complexation with biometals is a valid procedure to improve their biological effects. Our purpose is to synthesize a compound with greater efficacy than the original drug, able to enhance its antihypertensive and cardiac pharmacological activity. Herein, the structure of the coordination compound of Zn(II) and the antihypertensive drug olmesartan, [Zn(Olme)(H2O)2] (ZnOlme), is presented. After 8 weeks of treatment in SHR male rats, ZnOlme displayed a better blood pressure-lowering activity compared with olmesartan, with a noticeable effect even in the first weeks of treatment, while ZnCl2 showed similar results than the control. ZnOlme also reduced left ventricle (LV) weight and left ventricle/tibia length ratio (LV/TL), posterior wall thickness (PWT), and intraventricular septum in diastole (IVSd) suggesting its potential to prevent LV hypertrophy. Besides, ZnOlme reduced interstitial fibrosis (contents of collagen types I and III, responsible for giving rigidity and promoting vascular elasticity, respectively). The recovery of heart function was also evidenced by fractional shortening (diastolic left ventricular/systolic left ventricular) diameter determinations. Furthermore, ZnOlme increased the antioxidant capacity and prevented cardiac oxidative stress: it enhanced the reduction of reactive oxygen species generation, exerted a significant decrease in lipid peroxidation and enhanced glutathione contents in heart tissues compared to the control, Zn, and olmesartan treatments. Our results demonstrate that continuous oral administration of ZnOlme causes a better antihypertensive effect and grants enhancement of cardioprotection through antioxidant activity, in combination with hemodynamic improvement.

Improvement of the cardiovascular effect of methyldopa by complexation with Zn(II): Synthesis, characterization and mechanism of action.

BACKGROUND: the antihypertensive drug α-methyldopa (MD) stands as one of the extensively used medications for managing hypertension during pregnancy. Zinc deprivation has been associated with many diseases. In this context, the synthesis of a Zn coordination complex [Zn(MD)(OH)(H2O)2]·H2O (ZnMD) provide a promising alternative pathway to improve the biological properties of MD. METHODS: ZnMD was synthesized and physicochemically characterized. Fluorescence spectral studies were conducted to examine the binding of both, the ligand and the metal with bovine serum albumin (BSA). MD, ZnMD, and ZnCl2 were administered to spontaneous hypertensive rats (SHR) rats during 8 weeks and blood pressure and echocardiographic parameters were determined. Ex vivo assays were conducted to evaluate levels of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), and nitric oxide (NO). Cross-sectional area (CSA) and collagen levels of left ventricular cardiomyocytes were also assessed. Furthermore, the expression of NAD(P)H oxidase subunits (gp91phox and p47phox) and Superoxide Dismutase 1 (SOD1) was quantified through western blot analysis. RESULTS: The complex exhibited a moderate affinity for binding with BSA showing a spontaneous interaction (indicated by negative ΔG values) and moderate affinity (determined by affinity constant values). The binding process involved the formation of Van der Waals forces and hydrogen bonds. Upon treatment with MD and ZnMD, a reduction in the systolic blood pressure in SHR was observed, being ZnMD more effective than MD (122 ± 8.1 mmHg and 145 ± 5.6 mmHg, at 8th week of treatment, respectively). The ZnMD treatment prevented myocardial hypertrophy, improved the heart function and reduced the cardiac fibrosis, as evidenced by parameters such as left ventricular mass, fractional shortening, and histological studies. In contrast, MD did not show noticeable differences in these parameters. ZnMD regulates negatively the oxidative damage by reducing levels of ROS and lipid peroxidation, as well as the cardiac NAD(P)H oxidase, and increasing SOD1 expression, while MD did not show significant effect. Moreover, cardiac nitric oxide levels were greater in the ZnMD therapy compared to MD treatment. CONCLUSION: Both MD and ZnMD have the potential to be transported by albumin. Our findings provide important evidence suggesting that this complex could be a potential therapeutic drug for the treatment of hypertension and cardiac hypertrophy and dysfunction.

Copper-flavonoid family of complexes involved in alkaline phosphatase activation.

The flavonoid naringenin and a family of naringenin derivative Cu(II) complexes having phenanthroline-based second ligands were selected to study alkaline phosphatase activation. This enzyme plays a critical role in tissue formation, increasing the inorganic phosphate formation, favoring mineralization, and being essential to producing bone mineralization. The effects of those compounds on the function and structure of the enzyme were evaluated by kinetic measurements, fluorescence, FTIR, and UV-Vis spectroscopies. The results showed that naringenin did not affect alkaline phosphatase activity, having a value of the Michaelis-Menten-constant close to the enzyme (Km = 3.07 × 10-6). The binary complex, Cu(II)-naringenin, and the ternary complex Cu(II)-naringenin-phenanthroline behaved as an enzyme activator in all the concentrations range used in this study. Those complexes increased in c.a. 1.9% the catalytic efficiency concerning enzyme and naringenin. The ternary complex Cu(II)-naringenin-bathophenanthroline, provokes an activator mixed effect, dependent on the substrate concentrations. The different kinetic behavior can be correlated with different conformational changes observed under the interaction with ALP. Fluorescence experiments showed a raising of the binding constant with temperature. FTIR determinations showed that the complex with bathophenanthroline modifies the ALP structure but maintains the helical structure. The other copper complexes provoked a structural unfolding, decreasing the α-helix content. None of them affect the dephosphorylation enzyme ability. Even though the interactions and structural modifications on ALP are different, it is evident that the presence of copper favors enzymatic activity. The observed electrostatic interactions probably benefit the dissociation of the bound phosphate. The results suggest potential biological applications for the studied compounds.

Effect of the structural modification of Candesartan with Zinc on hypertension and left ventricular hypertrophy.

Hypertension is the most common cause of left ventricular hypertrophy, contributing to heart failure progression. Candesartan (Cand) is an angiotensin receptor antagonist widely used for hypertension treatment. Structural modifications were previously performed by our group using Zinc (ZnCand) as a strategy for improving its pharmacological properties. The measurements showed that ZnCand exerts a stronger interaction with the angiotensin II receptor, type 1 (AT1 receptor), reducing oxidative stress and intracellular calcium flux, a mechanism implied in cell contraction. These results were accompanied by the reduction of the contractile capacity of mesangial cells. In vivo experiments showed that the complex causes a significant decrease in systolic blood pressure after 8 weeks of treatment in spontaneously hypertensive rats (SHR). The reduction of heart hypertrophy was evidenced by echocardiography, the histologic cross-sectional area of cardiomyocytes, collagen content, the B-type natriuretic peptide (BNP) marker and connective tissue growth factor (CTGF) and the matrix metalloproteinase 2 (MMP-2) expression. Besides, the complex restored the redox status. In this study, we demonstrated that the complexation with Zn(II) improves the antihypertensive and cardiac effects of the parental drug.

Copper(II) cation and bathophenanthroline coordination enhance therapeutic effects of naringenin against lung tumor cells.

The development of new anticancer compounds is one of the challenges of bioinorganic and medicinal chemistry. Naringenin and its metal complexes have been recognized as promising inhibitors of cell proliferation, having enormous potential to act as an antioxidant and antitumorigenic agent. Lung cancer is the second most commonly diagnosed type of cancer. Therefore, this study is devoted to investigate the effects of Cu(II), naringenin (Nar), binary Cu(II)-naringenin complex (CuNar), and the Cu(II)-naringenin containing bathophenanthroline as an auxiliary ligand (CuNarBatho) on adenocarcinoma human alveolar basal epithelial cells (A549 cells) that are used as models for the study of drug therapies against lung cancer. The ternary complex shows selectivity being high cytotoxic against malignant cells. The cell death generated by CuNarBatho involves ROS production, loss of mitochondrial membrane potential, and depletion of GSH level and GSH/GSSG ratio. The structure-relationship activity was assessed by comparison with the reported Cu(II)-naringenin-phenanthroline complex. The CuNarBatho complex was synthesized and characterized by elemental analysis, molar conductivity, mass spectrometry, thermogravimetric measurements and UV-VIS, FT-IR, EPR, Raman and 1H-NMR spectroscopies. In addition, the binding to bovine serum albumin (BSA) was studied at the physiological conditions (pH = 7.4) by fluorescence spectroscopy.

Study on the cytotoxic, antimetastatic and albumin binding properties of the oxidovanadium(IV) chrysin complex. Structural elucidation by computational methodologies.

We have previously synthesized and characterized the chrysin coordination complex with the oxidovanadium(IV) cation (VIVO(chrys)2) and characterized in ethanolic solution and in solid state. Because suitable single crystals for X-ray diffraction determinations could not be obtained, in the present work, we elucidate the geometrical parameters of this complex by computational methodologies. The optimization and vibrational investigation were carried out both in ethanolic solution and in gas phase. The computational results support the experimentally proposed geometries of the VIVO(chrys)2 complex, thus leading to the conclusion that the complex exists as conformers with trans-octahedral geometry in ethanolic solution and as conformers with cis-octahedral geometry in the solid state. The complex also exists as conformers with trans-octahedral geometry in aqueous media. The active species formed after dissolution in DMSO showed anticancer and antimetastatic behavior in human lung cell line A549 with moderate binding (Kaca. 105 M-1) to bovine serum albumin (BSA). The interaction through hydrogen bonding and van der Waals forces resulted in a spontaneous process. Site marker competitive experiments showed binding sites for chrysin mainly located in site II (subdomain IIIA) and in site I (subdomain IIIA) for the complex. FT-IR spectral measurements showed evidences of the alterations of protein secondary structure in the presence of chrysin and VIVO(chrys)2.

Antimetastatic effects of VOflavonoid complexes on A549 cell line.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is the most frequent type of lung cancer and more than 90 % of mortality is due to metastasis-related deaths. Flavonoids are considered nutraceuticals due to the variety of pharmacological properties. In this paper, we studied the effects of baicalin, silibinin, apigenin, luteolin, and its oxidovanadium(IV) cation complexes on the viability, adhesion to fibronectin, invasion, and migration on human lung cancer cell line A549. In addition, in order to complete the study of the interaction of VOflavonoids and bovine serum albumin (BSA), the binding ability of silibinin and VOsil to the protein was evaluated. METHOD: To establish the non-cytotoxic concentration range of the tested compounds, the cancer cell viability was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Cell migration and invasion assays were performed using Boyden chambers and adhesion assay using MTT method. The interaction of compounds with BSA were investigated in physiological buffer (pH = 7.4) by fluorescence spectroscopy. RESULTS: All complexes inhibited the metastatic cascade steps to a greater extent than their respective ligands. Likewise, based on binding constant values (Kb) for BSA-silibinin and BSA-VOsil, we can suggest that both compounds can interact with the protein. CONCLUSION: Although all the complexes suppressed cell adhesion, invasion and migration, VOlut can be considered as a good candidate to continue the trials because it presented encouraging results as a potential antitumor and antimetastatic agent, and can be transported by BSA.

Vanadium Compounds as Biocatalyst Models.

Peroxidovanadium(V) and oxidovanadium(IV) compounds have been tested as peroxidase-similar compounds. Their catalytic performance was tested on phenol red and pyrogallol substrates. Bromination kinetic studies revealed Michaelis-Menten behavior with respect to phenol red for both complexes. Catalytic efficiency is ~ 104 M-1 min-1. Both vanadium complexes showed the capacity to oxidize pyrogallol, but only the oxidovanadium (IV) complex follows Michaelis-Menten kinetics with respect to this substrate (Km = 1.05 × 10-3 M). Peroxidovanadium(V) complex displayed a more complex mechanism, and further studies became necessary to elucidate it. The structure-activity relationship was also assessed.

Ternary copper(II) complex of 5-hydroxytryptophan and 1,10-phenanthroline with several pharmacological properties and an adequate safety profile.

We report the synthesis and biological evaluation of a ternary copper complex, [Cu(5HTP)(phen)(H2O)](NO3).2H2O, with the antioxidant agent 5-hydroxytryptophan (5-HTP) and phenanthroline (phen, added to improve its lipophilicity and membrane transport). The crystal structure of the complex was determined by X-ray diffraction methods. The complex showed antioxidant, antimicrobial, antitumor and antimetastatic properties with an adequate safety profile. The interaction of the metal with phen promotes cellular copper accumulation and cytotoxicity on human lung A549 cell line (IC50 = 3.6 µM). Furthermore, the viability of the normal human fetal lung fibroblast cell line (MRC-5) is not altered by the complex. An oxidative stress mechanism for the anticancer effect has been determined: cellular increase of reactive oxygen species (ROS), decrease of the glutathione (GSH) and oxidized GSH (GSSG) ratio and alteration of the mitochondrial potential. The complex also displays antimetastatic activities with inhibition of cell adhesion, invasion and migration. It has not mutagenic behavior and no toxicity on Artemia salina indicating its potential to act as an effective and safety antimicrobial and antitumor drug.

Improvement of the Anticancer Activities of Telmisartan by Zn(II) Complexation and Mechanisms of Action.

To improve the anticancer activity of telmisartan, its structure has been modified by Zn(II) complexation giving [Zn(Telm)2(H2O)2]·2H2O (ZnTelm). The cytotoxic effect was measured on the human lung cancer cells (A549) and on the lung fibroblast cells (MRC-5). The complex markedly improved anticancer activity (IC50 75 µM) of telmisartan (IC50 125 µM) or ZnSO4 (IC50 225 µM) and did not show toxicity on non-cancer cells, inducing oxidative stress with cellular ROS generation and GSH/GSSG decrease. Apoptosis was the dominant form of cell death for the complex. The Bax/Bcl-XL ratio was significantly increased as well as caspase-3 activation. Both the complex and the ligand bind to bovine serum albumin (BSA) and can be stored and transported by the protein but the interaction with the complex is greater. Telmisartan binds BSA by hydrophobic interactions while the interaction of ZnTelm occurs through van der Waals forces and hydrogen bonding. Therefore, it can be shown that the coordination complex ZnTelm improved the anticancer activity of the antihypertensive drug telmisartan (IC50 75 µM and 125 µM, respectively) and the interaction with BSA. Graphical Abstract Improvement of the anticancer activities of telmisartan by Zn(II) complexation and mechanisms of action. Intrinsic apoptotic pathway: induction ofoxidative stress and regulation of proteins related to apoptosis. The complex interacted with bovine serum albumin (BSA) and can be stored and transported by the protein.

Antidepressant and antinociceptive activities in animal models and in vitro assessment of the anti-thyroid activity of bis(DL-pyroglutamate)magnesium complex.

BACKGROUND: Magnesium is an essential element related with biochemistry of the brain and different types of depression have been associated with its deficiency. METHODS: The structure of a novel magnesium bis(DL-pyroglutamate) (Mg(DL-pGlu)2) was elucidated by X-ray crystallography. Wistar rats were used in the in vivo experiments. The antidepressant-like effect was assessed by the forced swim test (FST) and the antinociceptive activity was evaluated using hot plate test. In both, non-specific effects were evaluated by the open field test. Anti-thyroid activity was examined using Lang's method. Albumin binding behavior was evaluated by 3D fluorescence spectroscopy. RESULTS: For the Mg(DL-pGlu)2 complex (30 mg/kg), the FST test on Wistar rats revealed a decrease of 22% in the immobility time and an increment of 106% in the swimming time. The compound alters neither the locomotor activity nor the body weight after chronic administration. At the same dose, it showed antinociceptive activity, increasing the response latency. It blocks iodination reactions generating a charge transfer complex with iodine hence indicating anti-thyroid activity (Kc = 45366.5 ±â€¯29 M-1). Albumin 3D fluorescence spectroscopy experiments showed intensity increase of peak A and decrease of peak B. CONCLUSIONS: The results showed that the new compound produced a lowering of the immobility time and an increment of the swimming ability of the rats. The compound is able to increase the response latency in 70.0%, to capture iodine (anti-thyroid activity) and to interact with albumin through covalent type of interaction of the free NH groups.

Potential bio-protective effect of copper compounds: mimicking SOD and peroxidases enzymes and inhibiting acid phosphatase as a target for anti-osteoporotic chemotherapeutics.

Copper complexes with transformed methimazole ligand have been synthesized and characterized by elemental analysis, conductivity measurements, thermogravimetric analysis, EPR, FTIR and UV-Vis spectroscopies. Results support their stoichiometries and geometrical structures: [Cu(C4H5N2S)2Cl2]·2H2O(1), [Cu(C8H10N4S)SO4H2O](2) and [Cu(C8H10N4S)SO4](3). ((C4H5N2)2S: bis(l-methylimidazol-2-yl)sulfide; (C4H5N2S)2 = Bis[bis(l-methylimidazol-2-yl)disulfide]) Concurrently, the structurally distinct soluble species corresponding to complexes (1) and (2) were subsequently used in an in vitro investigation of their potential biological properties. In view of their possible pharmaceutical activity, the complexes were in vitro evaluated as phosphatase acid inhibitors. Their radical bio-protective effects were also studied measuring the effect against DPPH• and O2•- radicals. Additional catalytic properties as peroxidase mimics were evaluated using Michaelis-Menten kinetic model by means of phenol red and pyrogallol assays. The complexes exhibited catalytic bromination activity and the ability to oxidize pyrogallol substrate indicating that they can be considered as functional models. The relationships between the structures and the in vitro biological activities have also been considered. Serum protein albumin has attracted the greatest interest as drug carrier and the affinity of biological/pharmaceutical compound is relevant to the development of new medicine. In that sense, interaction studies by fluorescence and EPR spectroscopies were performed showing the binding capacity of the complexes.

Synthesis, characterization, theoretical studies and biological (antioxidant, anticancer, toxicity and neuroprotective) determinations of a copper(II) complex with 5-hydroxytryptophan.

5-Hydroxy-L-tryptophan (5-HTP) is a serotonin pathway metabolite of L-tryptophan in the brain. In the knowledge that the biological properties of some compounds can be modified upon metal complexation, a new solid metal complex, [Cu(5-hydroxytryptophan)2].H2O (Cu5HTP), has been synthesized and characterized to analyze the modification of some biological properties. The conformational investigations (optimized in gas phase at B3LYP/6-311G** theory level) suggest the coexistence of two conformers of Cu5HTP with cis- and trans- arrangements of the amino acids in the equatorial plane. The trans- Cu5HTP1 complex is the most stable conformer. The complexation led to an enhancement of the antioxidant properties of the ligand. The metal complex also improved the anticancer behavior of the ligand (tested in cancer cell lines derived from human lung (A549), cervix (HeLa) and colon (HCT-116)). It did not show toxicity against either the non-malignant human lung fibroblast (MRC-5) cell line or Artemia salina and did not behave as mutagenic agent (Ames test). Cellular reactive oxygen species production may be one of the possible mechanisms of action. Besides, the metal complex exerted neuroprotective action on cortical neurons from embryonic 18 days rats exposed to glutamate.

Interaction of Zn with Losartan. Activation of Intrinsic Apoptotic Signaling Pathway in Lung Cancer Cells and Effects on Alkaline and Acid Phosphatases.

A new losartan [2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol zinc(II) complex [Zn(Los)Cl], was synthesized and characterized. The crystal structure was determined by x-ray diffraction methods. When aqueous solutions of the ligand and the metal were mixed, the known and more soluble powder [Zn(Los)2].3H2O (ZnLos) complex has been obtained. The interactions with phosphatases showed a concerted mechanism displayed by the Zn ions and ZnLos up to 500 µM concentration: a decrease of the acid phosphatase (AcP) associated with an increase in the alkaline phosphatase (ALP) activities. The complex and ZnSO4 showed a cytotoxic behavior on human lung A549 cancer cell line at concentrations higher than 75 µM with reactive oxygen species (ROS) generation and GSH (and GSH/GSSG ratio) depletion. Apoptotic cells were observed using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) method, a mechanism accompanied by upregulation of BAX protein, downregulation of Bcl-XL and release of caspase-3. The BAX/Bcl-XL ratio was found to be significantly higher in cells exposure to ZnLos than cells treated with ZnSO4, in agreement with the higher apoptotic percentage of cells found for the complex. Cell death was found to be produced by apoptosis and no necrosis has been observed. On the contrary, losartan exerted low effects on phosphatases, produced some reduction of cancer cell viability (concentrations > 250 µM, number of apoptotic cells similar to the basal) with low ROS depletion, without alteration of the GSH/GSSG and low BAX/Bcl-XL ratios. In the MRC-5, normal lung fibroblasts cell line only ZnSO4 at concentrations higher than 200 µM displays cytotoxic effects. Graphical abstract Interaction of Zn with losartan. Activation of intrinsic apoptotic signaling pathway in lung cancer cells and effects on alkaline and acid phosphatases.

Comparisons of the spectroscopic and microbiological activities among coumarin-3-carboxylate, o-phenanthroline and zinc(II) complexes.

Coumarins (2H-chromen-2-one) are oxygen-containing heterocyclic compounds that belong to the benzopyranones family. In this work we have synthesized different coordination complexes with coumarin-3-carboxylic acid (HCCA), o-phenanthroline (phen) and zinc(II). In the reported [Zn(CCA)2(H2O)2] complex, coumarin-3-carboxylate (CCA) is acting as a bidentate ligand while in the two prepared complexes, [Zn(phen)3]CCA(NO3) (obtained as a single crystal) and [Zn(CCA)2phen].4H2O, CCA is acting as a counterion of the complex cation [Zn(phen)3]+2 or coordinated to the metal center along with phen, respectively. These compounds were characterized on the basis of elemental analysis and thermogravimetry. NMR, FTIR and Raman spectroscopies of the compounds and the CCA potassium salt (KCCA) allow to determine several similarities and differences among them. Finally, their behavior against alkaline phosphatase enzyme and their antimicrobial activities were also measured.

Azilsartan and its Zn(II) complex. Synthesis, anticancer mechanisms of action and binding to bovine serum albumin.

Azilsartan is the eighth approved member of angiotensin II receptor blockers for hypertension treatment. Considering that some drugs have additional effects when administered, we studied its effects and mechanisms of action on a human lung cancer cell line A549. We have also modified the structure of the drug by complexation with Zn(II) cation and assayed the anticancer effect. The crystal structure of the new binuclear Zn(II) complex, for short [Zn2(azil)2(H2O)4]·2H2O (ZnAzil), was determined by X-ray diffraction methods. The zinc ions are bridged by azilsartan ligands through their carboxylate oxygen and oxadiazol nitrogen atoms. The compounds were examined for their cytotoxic effects against human lung fibroblast (MRC5) and human lung cancer (A549) cell lines. Azilsartan displayed low cytotoxic effects at 150 µM concentrations in A549 human lung cancer cells but the higher effect measured for the Zn complex suggested that this compound may act as an anticancer agent. An apoptotic oxidative stress mechanism of action via the mitochondrial-dependent intrinsic pathway has been determined. Besides, the compounds exerted weak cytotoxic effects in the normal lung related cell line MRC5. Binding constants of the complex formed between each compound and bovine serum albumin (BSA) are in the intermediate range, hence suggesting that azilsartan and ZnAzil could be bonded and transported by BSA.

Synthesis, characterization and biological studies of a cobalt(III) complex of sulfathiazole.

The emergence of old and new antibiotic resistance created in the last decades revealed a substantial medical need for new classes of antimicrobial agents. The antimicrobial activity of sulfa drugs is often enhanced by complexation with metal ions, which is in concordance with the well-known importance of metal ions in biological systems. Besides, sulfonamides and its derivatives constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti-carbonic anhydrase, diuretic, hypoglycemic, antithyroid, antiviral and anticancer activities, among others. The purpose of this work has been the obtainment, characterization and determination of biological properties (antibacterial, antifungal, mutagenicity and phytotoxicity) of a new Co(III)-sulfathiazole complex: Costz, besides of its interaction with bovine serum albumin (BSA). The reaction between sodium sulfathiazole (Nastz) and cobalt(II) chloride in the presence of H2O2 leads to a brown solid, [CoIII(stz)2OH(H2O)3], (Costz). The structure of this compound has been examined by means of elemental analyses, FT-IR, 1H NMR, UV-Visible spectrometric methods and thermal studies. The Co(III) ion, which exhibits a distorted octahedral environment, could coordinate with the N thiazolic atom of sulfathiazolate. The complex quenched partially the native fluorescence of bovine serum albumin (BSA), suggesting a specific interaction with the protein. The Costz complex showed, in vitro, a moderate antifungal activity against Aspergillus fumigatus and A. flavus. As antibacterial, Costz displayed, in vitro, enhanced activity respective to the ligand against Pseudomonas aeruginosa. Costz did not show mutagenic properties with the Ames test. In the Allium cepa test the complex showed cytotoxic properties but not genotoxic ones. These results may be auspicious, however, further biological studies are needed to consider the complex Costz as a possible drug in the future.

Theoretical investigation of the conformational space of baicalin.

Flavonoids are a large group of polyphenolic compounds ubiquitously present in plants. They are important components of human diet. They are recognized as potential drug candidates to be used in the treatment and prevention of a lot of pathological disorders, due to their protective effects. Baicalin (7-glucuronic acid 5, 6-dihydroxyflavone) is one of the main single active constituents isolated from the dried roots of Scutellaria baicalensis Georgi. The great interest on this flavonoid is due to its various pharmacological properties, such as antioxidant, antimicrobial, anti-inflammatory, anticancer and so on, and its high accumulation in the roots of S. baicalensis. The aim of our work was to analyze the geometric and electronic properties of baicalin conformers (BCL), thus performing a complete search on the conformational space of this flavonoid in gas phase and in aqueous solution. The results indicate that the conformational space of baicalin is formed by eight conformers in gas phase and five conformers in aqueous solution optimized at B3LYP/6-311++G** theory level. BCLa2TT and BCLa1TT conformers have low stability in gas phase and very high stability in aqueous solution. This variation is related to a modification in the τ1 angle that represents the relative position of the glucuronide unit respect to the central rings of the flavan nucleus (A and C). This modification was successfully explained by examining the changes in the hydrogen bond (HB) interactions that occur in the region around the hydroxyl group located in position 6 of ring A. Besides, the molecular electrostatic potential (MEP) and frontier molecular orbital (FMO) analyses indicate that BCLa2TT and BCLa1TT conformers are the most favorable conformers for interacting with positively charged species (such as metal ions) in aqueous media (such as biological fluids).

Evidence of promising biological-pharmacological activities of the sertraline-based copper complex: (SerH2)2[CuCl4].

In the current study the ability of copper complex to exert multiple biological activities is combined with the pharmacological action of sertraline (SerH2Cl, antidepressant drug). The hydrated and anhydrous forms of the tetrachlorocuprate(II) salts, namely (SerH2)2[CuCl4]·½H2O and (SerH2)2[CuCl4], were synthesized and characterized by physicochemical methods. The crystal structures were determined by X-ray diffraction methods. The hydrate complex crystallizes in the monoclinic P21 space group with a=8.0807(2) Å, b=36.2781(8) Å, c=12.6576(3) Å, ß=95.665(2)°, and Z=4 molecules per unit cell and the un-hydrate in P21 with a=13.8727(6) Å, b=7.5090(3) Å, c=18.618(1) Å, ß=104.563(6)°, and Z=2. It has been suggested that Cu(II) ions might be critical in the development of mood disorders, showed potent biocidal activity, and also acted as analgesic adjuvant. To improve sertraline efficiency, the antidepressant and analgesic activities of the complex have been assessed in rats denoting a marked synergistic effect. Antithyroid and antimicrobial activities were also evaluated. Because depressive disorders and hyperthyroidism diseases led to an oxidative stress state, antioxidant capability has also been tested. The complex behaved as a good superoxide radical scavenger (IC50=6.3×10-6M). The ability of the complex to act as bromoperoxidase mimic was assessed. A pseudo-first order constant of k=0.157±0.007min-1 has been determined. The complex evidences promising biological-pharmacological activities and the albumin binding studies showed a Kb of 2.90×103M-1 showing an improvement in the uptake of sertraline by albumin at 8h incubation (time required for effective interaction of sertraline with the protein).