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Dithiocarbazate Schiff bases have been reported as a class of compounds that exhibit a wide range of pharmacological activities against neglected diseases such as malaria, trypanosomiasis, and tuberculosis. This work reports the encapsulation of the 1-(S-benzyldithiocarbazate)-3-methyl-5-phenyl-pyrazole (DTC) into biodegradable polymeric nanoparticles (NPs) of poly(lactic acid) (PLA) aiming potential drug delivery application. The DTC-loaded PLA-NPs were prepared by the single-nanoemulsification method using the poly(vinyl alcohol) (PVA) as a surfactant. The nanostructured system was characterized mainly by dynamic light scattering (DLS), electrophoretic light scattering (ELS), and transmission electron microscopy (TEM). The NPs show good colloidal stability exhibiting mean hydrodynamic diameter 157 ± 5 nm and zeta potential − 36 ± 3 mV. The encapsulation efficiency and drug loading were 52 ± 14% and 4.8 ± 1.5%, respectively. The quantifications of DTC and residual PVA in the NPs were performed by UV-Vis absorption spectroscopy. The analytical methods were validated according to regulatory agencies. Both quantification analytical curves showed good precision, in repeatability (intra-day) and intermediate (inter-day), and also good accuracy with low values of detection and quantification. The new nanostructured system, DTC-loaded PLA-NPs, shows advantages to improve stability and to overcome water solubility problems of the dithiocarbazate Schiff bases aiming potential drug delivery applications.

The design of new Ru(II) organometallics is a subject of interest to the field of anticancer metallodrugs. This work reports the interaction of the Ru(II)-η6-p-cymene framework with naproxen-pyridineamide (Npxpya, L1), a structurally modified form of the naproxen (HNpx, HL2) drug, to give the new organometallic [Ru(η6-p-cymene)(L1)Cl2] (1) bearing the Npxpya ligand. The reported naproxenate-derived, [Ru(η6-p-cymene)(L2)Cl] (2), is re-prepared, also from the precursor [Ru(η6-p-cymene)Cl2]2 (3), and additional investigation is performed. The two Ru(II)-arenes and the L1 ligand are fully characterized by ESI-MS, NMR, ATR/FT-IR and UV/VIS, and their structures corroborated by DFT computational calculations. Time-dependent 1H MNR studies show that both Ru(II)-arenes, despite being stable in non-coordinating solvents, undergo distinct step dissociation in dimethylsulfoxide solvent to give the corresponding drug ligands and [Ru(η6-p-cymene)(dmso)Cl2] (4) species. Electronic absorption spectroscopy experimental data show good correlation with DFT calculations. Organometallics 1 and 2, as well as their corresponding parent drug ligands, exhibit luminescence properties mainly associated to the naproxen moiety. Screening in NCI-H460 and A549 lung cancer cells reveals lack of activity for 2 and L2, while the new organometallic 1 is found to inhibit cell proliferation of both types of cell lines in similar way to the L1 drug. The structural modification, by inserting the pyridineamide moiety into the original structure of naproxen to form the Npxpya conjugated drug, is shown to be crucial for the anticancer activity. Compound 1, despite having IC50 close to the IC50 of L1, does not show significant effect on the mitochondrial membrane potential (MMP), in contrast to the behavior of the free L1 parent drug which significantly decreases the MMP in NCI-H460 cells. Interestingly, since 1H MNR studies indicate that organometallic 1 is completely dissociated in dmso (the solvent used to prepare the drug solutions for cell treatment in the biological assays) to give the L1 free drug and species 4, it is plausible to infer that the presence of Npxpya-free Ru species, probably in the form of species 4, might play a role in inhibiting the mechanism related to the mitochondrial function when the cells are treated with 1, in comparison with the cell treatment with the L1 free drug.

The aim of the study was to synthesize and characterize a new ruthenium(II)-pyrazole/dithiocarbazate complex derived from cis-[RuCl2(dmso)4] (Ru-dmso) and coordinated with 3-methyl-5-phenyl-pyrazoline-1-(S-benzyl)dithiocarbazate (dtc). The reaction of Ru-dmso with the dtc ligand was performed with equimolar amount, resulting in a neutral monosubstituted complex [RuCl2(dmso)3(dtc)] (Ru-dtc).To characterize this complex, conductivity measurements and spectroscopic techniques (1H-NMR, FTIR, UV–Vis, ESI–MS) were applied. Thermogravimetric analysis (TG) and differential thermal analysis were used to identify the changes in the thermal decompositions. The molar conductivity in methanol indicates that this complex is nonelectrolyte. Mass spectra showed m/z peak at 697, with a typical isotope pattern of ruthenium, which can be assigned to fragments of [RuCl(dmso)3(dtc)]+. The chemical shifts of dmso resonances in both ruthenium complexes have been compared and indicated that O-dmso from the precursor was substituted by the dithiocarbazate derivative in the Ru-dtc. The FTIR spectrum shows that this coordination was achieved through the N-pyrazole ring. Moreover, spectrophotometric titrations by the addition of increasing concentrations of triethanolamine or acetic acid to the dtc ligand and Ru-dtc complex enabled the determination of constant equilibrium from the absorbance changes in the visible band region. Moreover, density functional theory (DFT) calculations were applied to evaluate the electronic properties, while time-dependent DFT was applied to clarify UV–Vis results. Finally, the thermal data reveal various steps of decomposition of the ruthenium complexes, producing RuO2 as final residue.

Diruthenium(II,III) metal-metal multiply bonded paddlewheel complexes bearing non-steroidal anti-inflammatory drugs are promising anticancer metallodrugs. The [Ru2(Ibp)4Cl] (Ibp, ibuprofenate anion from HIbp ibuprofen drug), free or encapsulated, shows anticancer activity against glioblastoma (in vitro, in vivo), and against human breast and prostate cancer cells. Herein we report the interaction of [Ru2(Ibp)4Cl] and of [Ru2(Ac)4(H2O)2]PF6 (Ac, acetate) with the 4-aminopyridine (4Apy) drug. The N-ligand was capable of cleaving the paddlewheel unit with oxidation of Ru2(II,III) to Ru2(III,III)O μ-oxo core in the ibuprofen complex while the acetate complex underwent axial substitution of water by 4Apy. Carefully designed synthetic and chromatographic methods succeeded in giving the novel [Ru2O(Ibp)2(4Apy)6]Cl2 metallodrug, the first diruthenium(III,III) μ-oxo having chloride as counterion. Characterization was performed by elemental analysis, mass spectrometry, thermogravimetric analysis, electronic absorption and vibrational spectroscopies, molar conductivity and cyclic voltammetry. Kinetic studies for the μ-oxo complex (in 50:50 v/v ethanol:water) suggested an aquation/complexation equilibrium in consecutive step reactions with the exchange of the two 4Apy trans to the μ-oxo bridge by water (aquation) and the back coordination of 4Apy in excess of the N-ligand (complexation). Trypan blue assays for the novel compound showed time- and dose- dependent antiproliferative effects (at 5–50 μmol L−1) and cytotoxicity (> 20 μmol L−1), and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assays gave IC50 value of 7.6 ± 1.5 μmol L−1 (at 48 h, 1–20 μmol L−1) against U87MG human glioblastoma cells (aggressive brain glioma cancer) pointing the metallodrug as potential candidate for novel therapies in gliomas.

Tetraphenylphosphonium salts of Co and Fe complexes with alkyl-substituted, tert-butyl (tb), and isopropyl (dp) 2,3-thiophenedithiolate (α-tpdt) ligands, namely, TPP[Co(α-tb-tpdt)2] (3), TPP2[Fe(α-tb-tpdt)2]2 (4a-b), TPP[Co(α-dp-tpdt)2] (5), and TPP[Fe(α-dp-tpdt)2] (6) were prepared and characterized by cyclic voltammetry, single crystal X-ray diffraction, magnetic susceptibility measurements, and 57Fe Mossbauer spectroscopy. Compound 3 and 5 are isostructural with their Au and Ni analogues with a square-planar coordination geometry. Compound 4 presents two polymorphs (4a-b) both showing a Fe(III) bisdithiolene dimerization. The magnetic susceptibility of 3 and 5 exhibits behavior dominated by antiferromagnetic interactions, with room-temperature magnetic moments of 3.40 and 3.36 μB, respectively, indicating that these square-planar Co(III) complexes assume an intermediate spin electronic configuration (S = 1) as supported by multiconfigurational and DFT calculations.

The neotropical genus Mabuya are obligate placentotrophic viviparous lizards, which have a short vitellogenesis that produces microlecithal oocytes and a prolonged time of gestation (9 to 10 months). The hormonal control of female reproductive activity during follicular growth and pregnancy has not been studied, although it is known that the corpus luteum can produce progesterone, but regresses early in pregnancy, being replaced in this function by the placenta. Through enzyme immunoassay (EIA) we measured the plasma concentrations of estradiol (E2) and progesterone (P4) in females of a population of Mabuya sp at different stages of their reproductive cycle. Previously, we confirmed the presence of P4 in plasma by high-performance liquid chromatography methods with diode-array detector ultraviolet (HPLC-DAD-UV). The average concentration values of E2 and P4 were compared among reproductive stages and their dynamics were related to what is known in other oviparous and viviparous amniotes. The plasma E2 concentrations of Mabuya sp. are below the levels found in other viviparous reptiles, probably related to the substantial reduction of its follicular growth phase. Its highest concentration was detected during vitellogenesis, related to its function in the growth and maturation of the ovarian follicles and oviduct preparation for pregnancy; lower levels were observed during pregnancy, but they increase at the end when a new vitellogenesis event begins and massive placental maternal-fetal nutrient transfer occurs. High concentrations of P4 were found during pregnancy, related to its function in the maintenance of the developing embryos within the oviduct. The highest levels of P4 were found at early gestation, then they descend from mid-gestation to the end of gestation. Although some characteristics of hormonal control related to the high level of placentotrophy were observed in this species, the changes in plasma sex steroid concentrations during the reproductive cycle in females of Mabuya sp. follow patterns seen in other viviparous amniotes.

Nitrogen and sulfur-containing heterocyclic compounds as pyrazole and dithiocarbazate have historically been reported as sources of therapeutic agents. This work reports by fluorescence measurements the colloid phenomena between the 3-methyl-5-phenyl-pyrazoline-1-(S-benzyldithiocarbazate) (DTC) and Pluronic F127, a copolymer that has a tendency to self-assemble into micelles in aqueous medium. The cytotoxicity of the DTC-based micellar system was evaluated in Swiss mice peritoneal macrophages, and the production of nitric oxide (NO) by these cells was also analyzed in vitro and molecular docking analysis. The DTC-based micellar system prevents the DTC decomposition and increases solubility. The Hofmeister ions modulate DTC-micelle interactions. The DTC-based micellar system is not cytotoxic to Swiss mice peritoneal macrophages and induces the production of NO by these cells. These findings make the DTC-based micellar system of great interest in health/disease processes, since its immunomodulatory action on the macrophages may be tools on further studies for the development of novel microbicide or anti-inflammatory drugs.

The endocrinological study by immunological methods allows elucidating mechanisms of response to environmental challenges and reproductive regulatory mechanisms in animals. However, it is often overlooked that immunological assays for the detection and quantification of steroid hormones require prior validation tests. In this study, the efficacy of a commercial enzyme immunoassays (EIA) was evaluated for the quantification of plasma testosterone (T) in males from a population of green iguanas (Iguana iguana) in semi-captivity. The enzyme immunoassay was validated for specificity, accuracy and precision. Testosterone concentrations obtained by EIA were compared to estimates obtained on the same samples by high-performance liquid chromatography (HPLC). The proposed protocol has shown linearity and parallelism, T recovery was found to be within 80–110% accuracy, and precision variation was 0.05) indicating that the commercial EIA kit analyzed can be employed in the laboratory routine to quantify plasma T concentration and consequently differentiate the reproductive status of green iguana males.

Diruthenium paddlewheel-structured complexes bearing a Ru2(II,III) multiply bonded core show promising potential in medicinal chemistry. This work reports studies on the interactions of the tetrakis(acetato)chloridodiruthenium(II,III) complex (RuAc), [Ru2(μ-O2CCH3)4Cl], and the corresponding Ru2(II,III)-non-steroidal anti-inflammatory drug (NSAID) metallodrugs of the NSAIDs ibuprofen (RuIbp) and ketoprofen (RuKet) with the human serum albumin (HSA). Circular dichroism (CD) studies showed that the three Ru2 complexes interact with the HSA and induce conformational changes on the secondary structure of the protein. The reaction of the RuAc complex with the protein was monitored and the RuAc/HSA binding constant was estimated on the basis of electronic absorption spectroscopy data. Fluorescence emission spectroscopy studies were performed for all the Ru2 complex/HSA systems and the Stern–Volmer constants and the thermodynamic parameters were determined for the RuAc/HSA binding. Mass spectrometry data confirm...

The known paddlewheel, tetrakis(acetato)chloridodiruthenium(II,III), offers a versatile synthetic route to a novel class of antitumor diruthenium(II,III) metallo drugs, where the equatorial ligands are nonsteroidal anti-inflammatory carboxylates. This complex was studied here as a soluble starting prototype model for antitumor analogues to elucidate the reactivity of the [Ru(2)(CH(3)COO)(4)](+) framework. Thermodynamic studies on equilibration reactions for axial substitution of water by chloride and kinetic studies on reactions of the diaqua complexes with the amino acids glycine, cysteine, histidine, and tryptophan were performed. The standard thermodynamic reaction parameters ΔH°, ΔS°, and ΔV° were determined and showed that both of the sequential axial substitution reactions are enthalpy driven. Kinetic rate laws and rate constants were determined for the axial substitution reactions of coordinated water by the amino acids that gave the corresponding aqua(amino acid)-Ru(2) substituted species. The results revealed that the [Ru(2)(CH(3)COO)(4)](+) paddlewheel framework remained stable during the axial ligand substitution reactions and was also mostly preserved in the presence of the amino acids.

Análogos da timidina têm sido marcados com diferentes radioisótopos devido ao seu potencial em monitorar a proliferação incontrolável de células. Considerando que o radioisótopo tecnécio-99m ainda mantém uma posição privilegiada devido às suas propriedades químicas e nucleares, este trabalho constituiu-se no desenvolvimento da marcação da timidina com o 99mTc, mediante o emprego de compostos organometálicos. Os objetivos principais foram a síntese do precursor carbonil-tecnécio-99m, marcação da timidina com este precursor, estudo da estabilidade, e avaliações radioquímicas e biológicas com animais sadios e portadores de tumor. A síntese do precursor organometálico e a marcação da timidina com este precursor foi realizada com > 97% e > 94% de pureza radioquímica, respectivamente, obtendo-se também uma boa estabilidade em até 6 h em temperatura ambiente. A transquelação frente aos aminoácidos cisteína e histidina apresentou perdas entre 8 e 11% para concentrações de até 300 mM. Os ensaios de biodistribuição em camundongos sadios indicaram que o complexo radiomarcado apresentou um rápido depuramento sangüíneo e baixa captação nos demais órgãos, com predominância de excreção da droga pelo sistema urinário e hepatobiliar. A captação tumoral foi de 0,28 e 0,18 %DI/g para tumor de pulmão e mama, respectivamente. Os resultados obtidos sugerem maiores investigações em outros análogos da timidina.Thymidine analogs have been labeled with different radioisotopes due to their potential in monitoring the uncontrollable cell proliferation. Considering that the radioisotope technetium-99m still keeps a privileged position as a marker due to its chemical and nuclear properties, this work was designed to develop a new technique of labeling of thymidine analog with 99mTc, by means of the organometallic compounds. The aims of this research were: synthesis of the organometallic precursor technetium-99m-carbonyl, thymidine labeling with this precursor, study of stability, and radiochemical e biological evaluation with healthy and tumor-bearing animals. The organometallic precursor and the labeling of thymidine with this precursor were resulted with a radiochemical pureness of > 97% and > 94%, respectively, with good radiochemical stability up to 6 h in room temperature. The cysteine and histidine challenge indicated losses between 8 and 11% for concentrations until 300 mM. The biodistribution assay in healthy mice revealed rapid blood clearance and low uptake by general organs with renal and hepatobiliary excretion. The tumor concentration was of 0.28 and 0.18 %ID/g for lung and breast cancer, respectively. The results imply more studies in other thymidine analogs.

The Diruthenium-Ibuprofen compound [Ru2Cl(Ibp)4] (or RuIbp) is known to cause significant inhibition of C6 rat glioma cell proliferation in vitro. RuIbp increased the expression of cell cycle-related proteins such as p21 and p27 and the pro-apoptotic protein Bax, as well as causing a reduction in mitochondrial membrane potential and a modest increase in apoptosis in vitro. The present study extended these findings by (i) investigating the effects of RuIbp on human glioma cell line proliferation in vitro and (ii) investigating the acute and chronic toxicology of the compound in normal Wistar rats. The compound was then tested for its anti-tumour properties by either chronic 14 days intra-peritoneal (IP) administration or chronic Alzet osmotic pump infusion, in the rat C6 orthotopic glioma model in vivo. The IP injection of RuIbp caused a 41 % inhibition of tumour area without significant toxic effects but with an increase in blood neutrophils and monocytes and a decrease in blood lymphocytes. In an attempt to reduce this effect RuIbp was administered by Alzet osmotic pump infusion directly into the tumour at a dose of 15 mg/kg with an infusion rate of 0.5 µL/h for 14 days. The direct infusion of RuIbp caused a 45 % inhibition of tumour area without alterations in differential blood leukocyte counts. These results prove the efficacy of RuIbp in human glioma cell lines in vitro and in an in vivo glioma model and point to its potential as an inhibitor of tumour growth in vivo.

Diruthenium(ii,iii)-tetracarboxylates have shown promising anticancer properties as metallotherapeutics. On the basis of the role that bio-reducing agents may play on the mode of action of ruthenium-based anticancer drugs, we performed detailed kinetic studies on the reaction of ascorbic acid and glutathione with the [Ru2(RCOO)4](+) paddlewheel framework by using the non-drug, diaqua complex ion [Ru2(CH3COO)4(H2O)2](+). In the presence of the reducing agents, the diaqua-Ru2 species first undergo a ligand substitution reaction by which the axially-coordinated water is displaced by the reducing agent. In both cases, this reaction is followed by an intra-molecular electron transfer process during which the metal-metal center is reduced from Ru2(5+) to Ru2(4+) and the reducing agent is oxidized. Product analyses were performed with the application of ESI-MS and (1)H-NMR techniques. Rate and activation parameters are reported for the different reaction steps.

A new diruthenium(II,III) complex, of formula [Ru 2 Cl(ket) 4 ], Ruket, containing the non-steroidal anti-inflammatory drug ketoprofen was synthesized and mainly characterized by electrospray ionization mass spectrometry (ESI-MS), UV–Vis–IR electronic spectroscopy and FTIR and Raman vibrational spectroscopies. The four drug-carboxylato bridging ligands stabilize a Ru 2 (II,III) mixed valent core in a paddlewheel type structure as confirmed by ESI mass spectra, electronic and vibrational spectroscopies and magnetic measurements. Ruket and the analogous compounds containing ibuprofen, Ruibp, and naproxen, Runpx, were tested for the biological effects in the human colon carcinoma cells HT-29 and Caco-2 expressing high and low levels of COX-2 respectively. All compounds only weakly affected the proliferation of the colorectal cancer cells HT-29 and Caco-2, and similarly only partially inhibited the production/activity of MMP-2 and MMP-9 by HT-29 cells, suggesting that COX-2 inhibition by these drugs can only partially be involved in the pharmacological effects of these derivatives.