Experimental and DFT characterization, antioxidant and anticancer activities of a Cu(II)-irbesartan complex: structure-antihypertensive activity relationships in Cu(II)-sartan complexes.

The coordination compound of the antihypertensive ligand irbesartan (irb) with copper(II) (CuIrb) was synthesized and characterized by FTIR, FT-Raman, UV-visible, reflectance and EPR spectroscopies. Experimental evidence allowed the implementation of structural and vibrational studies by theoretical calculations made in the light of the density functional theory (DFT). This compound was designed to induce structural modifications on the ligand. No antioxidant effects were displayed by both compounds, though CuIrb behaved as a weak 1,1-diphenyl-2-picrylhydrazyl radical (DPPH(·)) scavenger (IC50 = 425 µM). The measurements of the contractile capacity on human mesangial cell lines showed that CuIrb improved the antihypertensive effects of the parent medication. In vitro cell growth inhibition against prostate cancer cell lines (LNCaP and DU 145) was measured for CuIrb, irbesartan and copper(II). These cell lines have been selected since the angiotensin II type 1 (AT1) receptor (that was blocked by the angiotensin receptor blockers, ARB) has been identified in them. The complex exerted anticancer behavior (at 100 µM) improving the activity of the ligand. Flow cytometry determinations were used to determine late apoptotic mechanisms of cell death. Experimental and DFT characterization of an irbesartan copper(II) complex has been performed. The complex exhibits low scavenging activity against DPPH(·) and significant growth inhibition of LNCaP and DU 145 prostate cancer cell lines. Flow cytometry determinations were used to determine late apoptotic mechanisms of cell death. This compound improved the antihypertensive effect of irbesartan. This effect was observed earlier for the mononuclear Cu-candesartan complex, but not in structurally modified sartans forming dinuclear or octanuclear Cu-sartan compounds.

Determining the molecular basis for the pH-dependent interaction between 2'-deoxynucleotides and 9H-pyrido[3,4-b]indole in its ground and electronic excited states.

Interaction between norharmane and three different 2'-deoxynucleotides (dNMP) (2'-deoxyguanosine 5'-monophosphate (dGMP), 2'-deoxyadenosine 5'-monophosphate (dAMP) and 2'-deoxycytidine 5'-monophosphate (dCMP)), in aqueous solution, was studied in the ground state by means of UV-vis and (1)H-NMR spectroscopy and in the first electronic excited state using steady-state and time-resolved fluorescence spectroscopy. In all cases, the norharmane-dNMP interaction dependence on the pH was examined. Possible mechanisms for the interaction of both ground and electronic excited states of norharmane with nucleotides are discussed. Spectroscopic, molecular modeling and chemometric analysis were performed to further characterize the chemical structure of the complexes formed and to get additional information concerning the interaction between dNMPs and norharmane.

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.

Photosensitized electron transfer within a self-assembled norharmane-2'-deoxyadenosine 5'-monophosphate (dAMP) complex.

Norharmane is a compound that belongs to a family of alkaloids called ß-carbolines (ßCs). These alkaloids are present in a wide range of biological systems, playing a variety of significant photo-dependent roles. Upon UV-A irradiation, ßCs are able to act as efficient photosensitizers. In this work, we have investigated the photosensitized oxidation of 2'-deoxyadenosine 5'-monophosphate (dAMP) by norharmane in an aqueous phase, upon UV-A (350 nm) irradiation. The effect of the pH was evaluated on both the interactions between norharmane and dAMP in the ground and electronic excited states, and on the dAMP photosensitized oxidation. A quite strong static interaction between norharmane and dAMP was observed, especially under those pH conditions where the protonated form of the alkaloid is present (pH < 7). Theoretical studies were performed to further characterize the static complex structure. The participation of reactive oxygen species (ROS) in the photosensitized reaction was also investigated and the photoproducts were characterized by means of UV-LDI-MS and ESI-MS. All the data provided herein indicate that electron transfer (Type I) within a self-assembled norharmane-dAMP complex is the operative mechanism in the dAMP photosensitization.

Radioactive seed migration after prostate brachytherapy with iodine-125 using loose seeds versus stranded seeds.

OBJECTIVES: To assess the incidence and clinical parameters that could influence migration of seeds in localized prostate cancer patients treated by stranded versus loose sources by Iodine-125 brachytherapy. MATERIALS AND METHODS: 100 patients were treated from January/1998 until December/2006. Age, PSA, clinical stage, Gleason, prostate volume, number of seeds, activity of radioactive seeds, and dosimetric parameters, such as V100, V150 and D90 were evaluated. RESULTS: Mean follow-up was 79 months (18 - 120. CI 95%: 72 - 85). Overall, 6 of 100 patients experienced seed migration. Seed migration was found in 4/50 (8%) patients using loose seeds and in 2/50 (4%) treated by stranded seeds. Mean value dosimetric parameters for stranded seeds were greater than those for loose seeds (V100(%): 88.7/82, D90(Gy): 149.2/140.3, D90(%): 104.2/93.8, V150 (%): 53.8/47, respectively). No significant difference in migration of seeds was detected between loose and stranded seeds considering age (p = 0.33), PSA (p = 0.391), prostate volume (p = 0.397), activity of radioactive seeds (p = 0.109), number of seeds (p = 0.338), V100 (p = 0.332), although significant differences were measured in the values of D90(% and Gy) (p = 0.022 and 0.011) and V150 (p = 0.023). CONCLUSIONS: Seed migration after brachytherapy might occur and it does affect post-implant dosimetry.

Metvan, bis(4,7-Dimethyl-1,10-phenanthroline)sulfatooxidovanadium(IV): DFT and Spectroscopic Study-Antitumor Action on Human Bone and Colorectal Cancer Cell Lines.

The complex bis(4,7-dimethyl-1,10-phenantroline)sulfatooxidovanadium(IV), commonly known as Metvan, was prepared using a known synthetic procedure. Its optimized molecular structure was obtained by DFT calculations, as it was impossible to grow single crystals adequate for a crystallographic study. The complex was also characterized by a detailed analysis of its infrared spectrum, supported by the theoretical calculations, and also by some data derived from its Raman spectrum. In addition, cytotoxicity studies were performed using human osteosarcoma (MG-63) and human colorectal adenocarcinoma (HT-29) cell lines. The results show that Metvan impaired cell viability of both cancer cell lines in a low concentration range (0.25-5.0 µM).

Photo release of nitrous oxide from the hyponitrite ion studied by infrared spectroscopy. Evidence for the generation of a cobalt-N2O complex. Experimental and DFT calculations.

The solid state photolysis of sodium, silver and thallium hyponitrite (M2N2O2, M=Na, Ag, Tl) salts and a binuclear complex of cobalt bridged by hyponitrite ([Co(NH3)5-N(O)-NO-Co(NH3)5]4+) were studied by irradiation with visible and UV light in the electronic absorption region. The UV-visible spectra for free hyponitrite ion and binuclear complex of cobalt were interpreted in terms of Density Functional Theory calculations in order to explain photolysis behavior. The photolysis of each compound depends selectively on the irradiation wavelength. Irradiation with 340-460nm light and with the 488nm laser line generates photolysis only in silver and thallium hyponitrite salts, while 253.7nm light photolyzed all the studied compounds. Infrared spectroscopy was used to follow the photolysis process and to identify the generated products. Remarkably, gaseous N2O was detected after photolysis in the infrared spectra of sodium, silver, and thallium hyponitrite KBr pellets. The spectra for [Co(NH3)5-N(O)-NO-Co(NH3)5]4+ suggest that one cobalt ion remains bonded to N2O from which the generation of a [(NH3)5CoNNO]+3 complex is inferred. Density Functional Theory (DFT) based calculations confirm the stability of this last complex and provide the theoretical data which are used in the interpretation of the electronic spectra of the hyponitrite ion and the cobalt binuclear complex and thus in the elucidation of their photolysis behavior. Carbonate ion is also detected after photolysis in all studied compounds, presumably due to the reaction of atmospheric CO2 with the microcrystal surface reaction products. Kinetic measurements for the photolysis of the binuclear complex suggest a first order law for the intensity decay of the hyponitrite IR bands and for the intensity increase in the N2O generation. Predicted and experimental data are in very good agreement.

A new oxidovanadium(IV) complex of oxodiacetic acid and dppz: spectroscopic and DFT study. Antitumor action on MG-63 human osteosarcoma cell line.

The oxidovanadium(IV) complex of oxodiacetic acid (H2ODA) and dppz (dipyrido[3,2-a:2',3'-c] phenazine) of stoichiometry [VO(ODA)(dppz)]·3H2O could be synthesized for the first time by reaction between [VO(ODA)(H2O)2] and dppz. It was characterized by infrared and electronic spectroscopies. Its optimized molecular structure was obtained by DFT calculations, as it was impossible to grow single crystals adequate for crystallographic studies. The antitumor action of the complex on MG-63 human osteosarcoma cell line was also investigated. It was found that it caused a concentration-related inhibitory effect in the concentration range between 5 and 25 µM and diminished the cell viability ca. 45% in the range from 25 to 100 µM, without dose/response effects in this range. These biological effects are, in general, similar to those previously reported for the related [VO(ODA)(ophen)]·1.5H2O complex.

Synthesis, X-ray crystal structure, thermal behavior and spectroscopic analysis of 1-(1-naphthoyl)-3-(halo-phenyl)-thioureas complemented with quantum chemical calculations.

Two novel 1-(1-naphthoyl)-3-(halo-phenyl) substituted thioureas, namely 1-(1-naphthoyl)-3-(2,4-di-fluoro-phenyl)-thiourea (1) and 1-(1-naphthoyl)-3-(3-chloro-4-fluoro-phenyl)-thiourea (2), were synthesized and fully characterized. The X-ray crystal and molecular structures have been determined resulting in a planar acylthiourea group, with the C=O and C=S adopting a pseudo-antiperiplanar conformation. An intramolecular N-H⋯O=C hydrogen bond occurs between the thioamide and carbonyl groups. The crystal packing of both compounds is characterized by extended intermolecular N-H⋯S=C and N-H⋯O=C hydrogen-bonding interactions involving the acylthiourea moiety. Compound 2 is further stabilized by π-stacking between adjacent naphthalene and phenyl rings. The thermal behavior, as well as the vibrational properties, studied by infrared and Raman spectroscopy data complemented by quantum chemical calculations at the B3PW91/6-311++G(d,p) support the formation of these intra- and intermolecular hydrogen bonds. Furthermore, the UV-Vis spectrum is interpreted in terms of TD-DFT quantum chemical calculations with the shapes of the simulated absorption spectra in good accordance with the experimental data.

Enantioseparation of α-amino acids by means of Cinchona alkaloids as selectors in chiral ligand-exchange chromatography.

A conventional nonchiral column was used for the enantioseparation of several racemic α-amino acids (native and derivatized) through the use of Cinchona alkaloids as chiral selectors along with Cu(II) ions in chiral ligand-exchange chromatography. The mobile phase composition (i.e., the organic modifier content and pH) was studied in order to modulate retention and enantioselectivity. Good enantioseparation of many amino acids was obtained using equimolar amounts of Cu(II) and either cinchonidine, quinine or quinidine as chiral selectors in the mobile phase. The molecular geometry of the diastereomeric complexes formed was modeled and energetic differences between both compounds were calculated by methods based on semi-empirical force-field. Good correlations were obtained between experimental enantioselectivity factors and calculated energetic differences.

The seven-year preliminary results of brachytherapy with Iodine-125 seeds for localized prostate cancer treated at a Brazilian single-center.

OBJECTIVE: To report the seven-year preliminary results of a single-center on brachytherapy with Iodine-125 seeds, used in combination with external beam radiotherapy in selected patients with localized prostate cancer (T1-T2). MATERIALS AND METHODS: All 105 patients treated by brachytherapy with Iodine-125 seeds, from January/1998 to December/2004, were retrospectively analyzed. The prescribed dose was 144 Gy at the periphery of the prostate for isolated brachytherapy, and 110 Gy for the combination with external beam radiotherapy. The external beam radiotherapy dose was 45 Gy, at the prostatic bed. Neoadjuvant hormone therapy was indicated for selected patients, who received luteinizing hormone-releasing hormone (LH-RH) and/or antiandrogens. For definition of biochemical relapse, it was adopted the American Society for Therapeutic Radiology and Oncology consensus. RESULTS: Of the 105 patients treated, 90 were followed for a mean period of 70 months. Biochemical disease control was achieved in 62 (69%) and biochemical recurrence was manifested in 28 (31%). The analysis of each risk group showed biochemical disease control rates of 79%, 71% and 52% in the low, intermediate and high risk groups, respectively. The mean time for biochemical recurrence was 22 months. Genitourinary acute toxicity was classified as grade 0-2 (RTOG) in 88.5% and in 94.2% for the late toxicity (RTOG/EORTC). Gastrointestinal acute toxicity was graded as 0-2 (RTOG) in 100% and in 97.7% for the late morbidity. No grade 5 was detected. CONCLUSIONS: Brachytherapy with Iodine-125 seeds is an effective alternative treatment for early stage prostatic cancer, with good biochemical disease control rates and low to moderate toxicity. The best results were obtained in low and intermediate risk patients.

Sea-land limits: a case study

The limits between sea and land were estimated at "Pulso" beach located in the Southeastern Brazilian shelf (φ = 23°33/17.4886"S; Λ = 045° 13'13.0504"W - WGS84), between the island of São Sebastião and the city of Ubatuba, SP, Brazil. The relative sea level of the year 1831 at "Pulso" beach, as per Brazilian law Number 9760 dated from 1946, was estimated and materialized. The retro-estimation allowed the demarcation of the Legal Sea-Land Limits at "Pulso" beach as per the terms of the law. The accuracy of the procedure for the transference of the long-term sea level from the research station of Ubatuba to "Pulso" beach was assessed by parallel work of geometrical leveling referred to the IBGE (Brazilian Institute of Geography and Statistics) geodetic network. The motivation, the hypotheses (Brest, Cananeia and IPCC) and the methods here used are described, together with a short history of the Legal Sea-Land Limits. The results indicated that the legal Sea-Land Limits at "Pulso" beach are well within the beach area. They were determined as per law 9760, and there is the need to reactivate the national network of sea level gauge.

Os limites entre mar e terra foram estimados na praia chamada Pulso, localizada na costa sudeste do Brasil (φ = 23°33'17, 4886"S; Λ = 045°13'13, 0504"W) entre a Ilha de São Sebastião e a cidade de Ubatuba, no Estado de São Paulo, SP, Brasil. O nível relativo do mar do ano de 1831 na praia do Pulso, ou "Praia do Pulso" (PP), foi estimado e materializado, de acordo com a Lei brasileira Número 9760 de 1946. A acurácia do procedimento foi acompanhada por trabalho paralelo de nivelamento geométrico referido ao sistema nacional de geodésia do IBGE (Instituto Brasileiro de Geografia e Estatística). A motivação, as hipóteses (Brest, Cananeia e IPCC) e os métodos utilizados são descritos, acompanhados por um breve histórico dos "Terrenos de Marinha". Os resultados indicaram que os limites em (PP) estão bem dentro da área da praia. Eles fora deterinados de acordo co a Lei No. 9760 e há a necessidade de reativar a rede nacional de medidores do nível do mar.

Radioactive seed migration after prostate brachytherapy with Iodine-125 using loose seeds versus stranded seeds

Objectives: To assess the incidence and clinical parameters that could influence migration of seeds in localized prostate cancer patients treated by stranded versus loose sources by Iodine-125 brachytherapy. Material and Methods: 100 patients were treated from January/1998 until December/2006. Age, PSA, clinical stage, Gleason, prostate volume, number of seeds, activity of radioactive seeds, and dosimetric parameters, such as V100, V150 and D90 were evaluated. Results: Mean follow-up was 79 months (18 - 120. CI 95 percent: 72 - 85). Overall, 6 of 100 patients experienced seed migration. Seed migration was found in 4/50 (8 percent) patients using loose seeds and in 2/50 (4 percent) treated by stranded seeds. Mean value dosimetric parameters for stranded seeds were greater than those for loose seeds (V100( percent): 88.7/82, D90(Gy): 149.2/140.3, D90( percent): 104.2/93.8, V150 ( percent): 53.8/47, respectively). No significant difference in migration of seeds was detected between loose and stranded seeds considering age (p = 0.33), PSA (p = 0.391), prostate volume (p = 0.397), activity of radioactive seeds (p = 0.109), number of seeds (p = 0.338), V100 (p = 0.332), although significant differences were measured in the values of D90( percent and Gy) (p = 0.022 and 0.011) and V150 (p = 0.023). Conclusions: Seed migration after brachytherapy might occur and it does affect post-implant dosimetry.

The seven-year preliminary results of brachytherapy with Iodine-125 seeds for localized prostate cancer treated at a Brazilian single-center

OBJECTIVE: To report the seven-year preliminary results of a single-center on brachytherapy with Iodine-125 seeds, used in combination with external beam radiotherapy in selected patients with localized prostate cancer (T1-T2). MATERIALS AND METHODS: All 105 patients treated by brachytherapy with Iodine-125 seeds, from January/1998 to December/2004, were retrospectively analyzed. The prescribed dose was 144 Gy at the periphery of the prostate for isolated brachytherapy, and 110 Gy for the combination with external beam radiotherapy. The external beam radiotherapy dose was 45 Gy, at the prostatic bed. Neoadjuvant hormone therapy was indicated for selected patients, who received luteinizing hormone-releasing hormone (LH-RH) and/or antiandrogens. For definition of biochemical relapse, it was adopted the American Society for Therapeutic Radiology and Oncology consensus. RESULTS: Of the 105 patients treated, 90 were followed for a mean period of 70 months. Biochemical disease control was achieved in 62 (69 percent) and biochemical recurrence was manifested in 28 (31 percent). The analysis of each risk group showed biochemical disease control rates of 79 percent, 71 percent and 52 percent in the low, intermediate and high risk groups, respectively. The mean time for biochemical recurrence was 22 months. Genitourinary acute toxicity was classified as grade 0-2 (RTOG) in 88.5 percent and in 94.2 percent for the late toxicity (RTOG/EORTC). Gastrointestinal acute toxicity was graded as 0-2 (RTOG) in 100 percent and in 97.7 percent for the late morbidity. No grade 5 was detected. CONCLUSIONS: Brachytherapy with Iodine-125 seeds is an effective alternative treatment for early stage prostatic cancer, with good biochemical disease control rates and low to moderate toxicity. The best results were obtained in low and intermediate risk patients.