Synthesis and mechanistic study of 2-(trifluoromethyl)-10H-phenoselenazine from double cross coupling reaction.

Phenoselenazines are nitrogen and selenium-based heterocyclic compounds that have important biological activities. However, their preparation methods are scarce and difficult to handle. The synthesis of a phenoselenazine from a simple and robust CuO nanoparticle catalyzed methodology, using bis-aniline-diselenide and 1,2-dihalobenzenes under microwave irradiation. Also, the double-cross-coupling reaction mechanism for C-Se and C-N bond formation, including the observation of a reaction intermediate by mass spectrometry have been studied.

Inhibitory effects against SARSCoV-2 main protease (Mpro) of biflavonoids and benzophenones from the fruit of Platonia insignis.

The SARS-CoV-2 mutation and the limitation of the approved drug against COVID-19 are still a challenge in many country healthcare systems and need to be affronted despite the set of vaccines to prevent this viral infection. To contribute to the identification of new antiviral agents, the present study focused on natural products from an edible fruit with potential inhibitory effects against the SARS-CoV-2 main protease (Mpro). First, LC-ESIMS analysis of Platonia insignis fruits was performed and showed the presence of biflavonoids and benzophenones in the seed and pulp, respectively. Then, maceration and chromatographic purification led to the identification of two triglycerides (1 and 2) alongside chamaejasmine (3) and volkensiflavone (4) from the seed and isogarcinol (5) and cycloxanthochymol (6), from the pulp. Compounds 1-6 after evaluating their inhibitory against Mpro, displayed from no to significant activity. Compound 5 was the most potent with an IC50 value of 0.72 µM and was more active than the positive control, Ebselen (IC50 of 3.4 µM). It displayed weak and no cytotoxicity against THP-1 (CC50 of 116.2 µM) and Vero cell lines, respectively. Other active compounds showed no cytotoxicity against THP-1. and Vero cell lines. Molecular docking studies revealed interactions in the catalytic pocket between compound 5 and amino acid residues that composed the catalytic dyads (His 41 and Cyst 145).

Antidepressant Potential of a Functionalized 3-Selanyl Benzo[b]Furan Compound in Mice: Focus on the Serotonergic System.

The present study investigated the antidepressant-like potential of a functionalized 3-selanyl benzo[b]furan (SeBZF) in male Swiss mice. To evaluate possible antidepressant-like actions, the compounds SeBZF1-5 (50 mg/kg, intragastric, i.g., route) were acutely screened in the tail suspension tests (TSTs). The compound 3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran (SeBZF3) was then selected. Dose-response and time-response curves revealed that SeBFZ3 exerts antidepressant-like effects in the TST (5-50 mg/kg) and forced swimming test (FST; 50 mg/kg). Additional tests demonstrated that pretreatment with receptor antagonists WAY100635 (5-HT1A; 0.1 mg/kg, subcutaneous route), ketanserin (5-HT2A/C; 1 mg/kg, intraperitoneal, i.p.), or ondansetron (5-HT3; 1 mg/kg, i.p.) blocked the SeBZF3 antidepressant-like effects (50 mg/kg) in the TST. In addition, the coadministration of subeffective doses of SeBZF3 (1 mg/kg, i.g.) and fluoxetine (a selective serotonin reuptake inhibitor; 5 mg/kg, i.p.) produced synergistic action. A high dose of SeBZF3 (300 mg/kg) did not produce oral acute toxicity. The present results provide evidence for the antidepressant-like action of SeBZF3 and its relative safety, as well as predict the possible interactions with the serotonergic system, aiding in the development of novel options to alleviate psychiatric disabilities.

Selenium-Derivative Compounds: A Review of New Perspectives in the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is one of the most prevalent types of dementia, affecting millions of older people worldwide. AD is stimulating efforts to develop novel molecules targeting its main features associated with a decrease in acetylcholine levels, an increase in oxidative stress and depositions of amyloid-ß (Aß) and tau protein. In this regard, selenium-containing compounds have been demonstrated as potential multi-targeted compounds in the treatment of AD. These compounds are known for their antioxidant and anticholinesterase properties, causing a decrease in Aß aggregation. OBJECTIVE: In this review, we approach structure-activity relationships of each compound, associating the decrease of ROS activity, an increase of tau-like activity and inhibition of AChE with a decrease in the self-aggregation of Aß. METHODS: We also verify that the molecular descriptors apol, nHBAcc and MlogP may be related to optimized pharmacokinetic properties for anti-AD drugs. RESULTS: In our analysis, few selenium-derived compounds presented similar molecular features to FDA-approved drugs. CONCLUSION: We suggest that unknown selenium-derived molecules with apol, nHBAcc and MlogP like FDA-approved drugs may be better successes with optimized pharmacokinetic properties in future studies in AD.

Evaluation of High-Dose Vitamin A Treatment in Postmolar Patients with Low and Plateauing Serum Human Chorionic Gonadotropin Levels.

OBJECTIVE: To compare the effect of high-dose vitamin A (HD Vit-A) use during postmolar follow-up of patients with low and plateauing (L&P) serum human chorionic gonadotropin (hCG) levels, from the moment serum hCG plateaued (P-hCG) to the first normal serum hCG value (< 5 IU/L). METHODS: The present retrospective series case study compared two nonconcurrent cohorts of patients. Control group (CG): 34 patients with L&P serum hCG levels who underwent expectant management for 6 months after uterine evacuation, from 1992 to 2010; study group (SG): 32 patients in similar conditions who received 200,000 IU of Vit-A daily, from the identification of a P-hCG level to the first normal hCG value or the diagnosis of progression to gestational trophoblastic neoplasia (GTN), from 2011 to 2017. The present study was approved by the Ethics Committee of the institution where it was conducted. RESULTS: In both groups, the prevalence of persistent L&P serum hCG levels was < 5%. In the SG, hCG levels at plateau were higher (CG = 85.5 versus SG = 195 IU/L; p = 0.028), the rate of postmolar GTN was lower (CG = 29.4% versus SG = 6.3%, p = 0.034) and follow-up was shorter (CG = 14 versus SG = 10 months, p < 0.001). During GTN follow-up, there were no differences in GTN staging or treatment aggressiveness in both groups. High-dose Vit-A use did not have any relevant toxic effect. There were no GTN relapses or deaths. CONCLUSION: The limited use of HD Vit-A seems to have a safe and significant effect on the treatment of postmolar patients with L&P serum hCG levels and may decrease the development of postmolar GTN in this population.

OBJETIVO: Comparar o efeito de alta dose de vitamina A (VitA) no seguimento pós-molar de pacientes com gonadotrofina coriônica humana (hCG) sérica apresentando valores baixos e em platô (L&P). MéTODOS: Estudo retrospectivo de série de casos comparando duas coortes não simultâneas. Grupo controle (CG): 34 pacientes com títulos de hCG sérico L&P submetidos a manejo expectante por 6 meses após o esvaziamento uterino, de 1992 a 2010; Grupo de Estudo (SG): de 2011 a 2017, 32 pacientes em condições semelhantes de hCG receberam Vit-A na dose de 200.000 IU por dia, do momento da identificação do hCG em platô ate o primeiro hCG normal ou diagnóstico de progressão para neoplasia trofoblástica gestacional (NTG). O presente estudo foi aprovado pelo Comitê de Ética da Instituição na qual foi desenvolvido. RESULTADOS: Em ambos os grupos, a prevalência de hCG L&P foi < 5%. No SG, os níveis de hCG em platô foram maiores (CG = 85.5 versus SG = 195 IU/L; p = 0,028), e foram significantemente menores tanto a prevalência de NTG pós-molar (CG = 29.4% versus SG = 6.3%, p = 0,034) como o tempo de seguimento (CG = 14 versus SG = 10 meses, p < 0.001). Na evolução para NTG não houve diferença no estadiamento da International Federation of Gynecology and Obstetrics (FIGO, na sigla em inglês) ou na agressividade do tratamento. Com altas doses de Vit-A não houve qualquer efeito tóxico relevante. Não houve casos de recidiva de NTG ou de óbito. CONCLUSãO: O uso limitado de altas doses de Vit-A parace ser seguro e apresenta efeitos significativos na evolução de pacientes em controle pós-molar com títulos de hCG sérico L&P, e pode diminuir o desenvolvimento de NTG pós-molar nessa população.

One-pot organocatalytic/multicomponent approach for the preparation of novel enantioenriched non-natural selenium-based peptoids and peptide-peptoid conjugates.

A combined organocatalytic and multicomponent synthetic approach was designed for the preparation of selenium-based peptoids and peptide-peptoid conjugates. This single-step synthetic protocol comprises the organocatalytic asymmetric insertion of phenylselenium in the aldehyde moiety followed by the Ugi four-component reaction which results in obtaining the desired compounds in good-to-moderate yields and with good-to-excellent levels of stereoselectivity.

Toxic, cytogenetic and antitumor evaluations of [6]-gingerol in non-clinical in vitro studies.

Gingerol - [6]-gingerol ((S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone; [6]-G) - is a phenolic compound with several pharmacological properties. Herein, the aim of the study was to evaluate the toxicogenic effects of [6]-G on Artemia salina nauplii, Allium cepa, HL-60 cell line and Sarcoma 180 (S-180) ascitic fluid cells.For toxic and genotoxic analysis, it was used [6]-G concentrations of 5, 10, 20 and 40 µg mL-1. For cytotoxic evaluation using the MTT test (3- [4,5-dimethyl-thiazol-2-yl] -2,5-diphenyl tetrazolium bromide), serial [6]-G dilutions (1.56-100 µg mL-1) were performed, and S-180, HL-60 and peripheral blood mononuclear cells (PBMC) were treated for 72 h. The IC50 of [6]-G were 1.14, 5.73 and 11.18 µg mL-1 for HL-60, S-180 and PBMC, respectively, indicating a possible selectivity against tumor cell lines. At higher concentrations (>10 µg mL-1), toxicity and genotoxicity were observed in the A. cepa test, especially at 40 µg mL-1. Mechanisms indicating apoptosis, such as toxicity, cytotoxicity and nuclear abnormalities (bridges, fragments, delays, loose chromosomes and micronuclei) suggest that [6]-G has potential for antitumor pharmaceutical formulations.

Recurrent pregnancy loss and vitamin D: A review of the literature.

Recurrent pregnancy loss (RPL) affects approximately 1%-2% of reproductive women. Auto- and cellular immune responses seem to be associated with RPL. Vitamin D (VD) has been shown to play a role in the modulation of the immune system. Effects of VD deficiency (VDD) in pregnancy have been associated with preeclampsia, gestational diabetes, fetal growth restriction, preterm labor, and sporadic spontaneous abortion (SA). We systematically reviewed articles that studied women with 2 or more SA and its association with VD. Eleven studies were included. Studies reported a high prevalence of VD insufficiency (VDI) or VDD in women with RPL and suggested that this could be associated with immunological dysregulation and consequently with RPL. Immunological benefits were reported in the peripheral blood of women with RPL after VD exposure. Thus, it is possible to speculate a beneficial role for VD supplementation in RPL. It seems that there are not differences in the vitamin D receptor (VDR) and CYP27B1 expression in endometrium of women with RPL but, in villous and decidual tissues, RPL women seem to have a decreased expression of VDR and, perhaps, a decreased expression of CYP27B1. Further randomized controlled studies are required to investigate the association between VDD or VDI and RPL.

Toxicogenetic study of omeprazole and the modulatory effects of retinol palmitate and ascorbic acid on Allium cepa.

Omeprazole (OME) is a proton pump inhibitor used for the treatment of various gastric and intestinal disease; however, studies on its effects on the genetic materials are still restricted. The present study aimed to evaluate possible toxicogenic effects of OME in Allium cepa meristems with the application of cytogenetic biomarkers for DNA damage, mutagenic, toxic and cytotoxic effects. Additionally, retinol palmitate (RP) and ascorbic acid (AA) were also co-treated with OME to evaluate possible modulatory effects of OME-induced cytogenetic damages. OME was tested at 10, 20 and 40 µg/mL, while RP and AA at 55 µg/mL and 352.2 µg/mL, respectively. Copper sulphate (0.6 µg/mL) and dechlorinated water were used as positive control and negative control, respectively. The results suggest that OME induced genotoxicity and mutagenicity in A. cepa at all tested concentrations. It was noted that cotreatment of OME with the antioxidant vitamins RP and/or AA significantly (p < 0.05) inhibited and/or modulated all toxicogenic damages induced by OME. These observations demonstrate their antigenotoxic, antimutagenic, antitoxic and anticitotoxic effects in A. cepa. This study indicates that application of antioxidants may be useful tools to overcome OME-induced toxic effects.

Is chemotherapy necessary for patients with molar pregnancy and human chorionic gonadotropin serum levels raised but falling at 6months after uterine evacuation?

OBJECTIVE: To compare the outcomes of Brazilian patients with molar pregnancy who continue human chorionic gonadotropin (hCG) surveillance with those treated with chemotherapy when hCG was still positive, but falling at 6months after uterine evacuation. METHODS: Retrospective chart review of 12,526 patients with hydatidiform mole treated at one of nine Brazilian reference centers from January 1990 to May 2016. RESULTS: At 6months from uterine evacuation, 96 (0.8%) patients had hCG levels raised but falling. In 15/96 (15.6%) patients, chemotherapy was initiated immediately per FIGO 2000 criteria, while 81/96 (84.4%) patients were managed expectantly. Among the latter, 65/81 (80.2%) achieved spontaneous remission and 16 (19.8%) developed postmolar gestational trophoblastic neoplasia (GTN). Patients who received chemotherapy following expectant management required more time for remission (11 versus 8months; p=0.001), had a greater interval between uterine evacuation and initiating chemotherapy (8 versus 6months; p<0.001), and presented with a median WHO/FIGO risk score higher than women treated according to FIGO 2000 criteria (4 versus 2, p=0.04), but there were no significant differences in the need for multiagent treatment regimens (1/15 versus 3/16 patients, p=0.60). None of the women relapsed, and no deaths occurred in either group. CONCLUSION: In order to avoid unnecessary exposure of women to chemotherapy, we no longer follow the FIGO 2000 recommendation to treat all patients with molar pregnancy and hCG raised but falling at 6months after evacuation. Instead, we pursue close hormonal and radiological surveillance as the best strategy for these patients.

Synthesis and antitumor activity of selenium-containing quinone-based triazoles possessing two redox centres, and their mechanistic insights.

Selenium-containing quinone-based 1,2,3-triazoles were synthesized using click chemistry, the copper catalyzed azide-alkyne 1,3-dipolar cycloaddition, and evaluated against six types of cancer cell lines: HL-60 (human promyelocytic leukemia cells), HCT-116 (human colon carcinoma cells), PC3 (human prostate cells), SF295 (human glioblastoma cells), MDA-MB-435 (melanoma cells) and OVCAR-8 (human ovarian carcinoma cells). Some compounds showed IC50 values < 0.3 µM. The cytotoxic potential of the quinones evaluated was also assayed using non-tumor cells, exemplified by peripheral blood mononuclear (PBMC), V79 and L929 cells. Mechanistic role for NAD(P)H: Quinone Oxidoreductase 1 (NQO1) was also elucidated. These compounds could provide promising new lead derivatives for more potent anticancer drug development and delivery, and represent one of the most active classes of lapachones reported.

Design, synthesis and evaluation of seleno-dihydropyrimidinones as potential multi-targeted therapeutics for Alzheimer's disease.

In this paper we report the design, synthesis and evaluation of a series of seleno-dihydropyrimidinones as potential multi-targeted therapeutics for Alzheimer's disease. The compounds show excellent results as acetylcholinesterase inhibitors, being as active as the standard drug. All these compounds also show very good antioxidant activity through different mechanisms of action.

Evaluation of the pharmacological properties of salicylic acid-derivative organoselenium: 2-hydroxy-5-selenocyanatobenzoic acid as an anti-inflammatory and antinociceptive compound.

The present study evaluated the antinociceptive and anti-inflammatory effects of per oral (p.o.) administration of salicylic acid-derivative organoselenium compounds in chemical models of nociception in mice. The compounds (50 mg/kg; p.o.) were administered 30 and 60 min before the nociceptive behavior and compared to the positive-control, acetylsalicylic acid (ASA; 200 mg/kg; p.o.). In addition, a dose-response curve (25-100 mg/kg) for compounds was carried out in the formalin test. When assessed in the chemical models, acetic acid-induced writhing behavior, formalin and glutamate tests, the compounds showed the following antinociceptive profile 1B>2B>1A>2A, suggesting a chemical structure-dependent relationship. Then, the anti-inflammatory properties and toxicological potential of compound 1B were investigated. Compound 1B, similar to the positive-control, ASA, diminished the edema formation and decreased the myeloperoxidase activity induced by croton oil (2.5%) in the ear tissue. The results also indicate that a single oral administration of 1B caused neither signs of acute toxicity nor those of gastrointestinal injury. The administration of 1B did not alter the water and food intakes, plasma alanine and aspartate aminotransferase activities or urea levels and cerebral or hepatic δ-aminolevulinate dehydratase activity. Salicylic acid-derivative organoseleniums, mainly compound 1B, have been found to be novel compounds with antinociceptive/anti-inflammatory properties; nevertheless, more studies are required to examine their therapeutic potential for pain treatment.

Hepatoprotective effect of bis(4-methylbenzoyl) diselenide against CCl(4)-induced oxidative damage in mice.

From a pharmacological point of view, organoseleniums are compounds with important and interesting antioxidant and biological activities. The aim of this study was to evaluate the hepatoprotective effect of bis(4-methylbenzoyl) diselenide (BMD) against carbon tetrachloride (CCl4 )-induced oxidative damage in mice. The animals received BMD (25 mg/kg p.o., for 3 days), and after 1 day, CCl4 (1 mg/kg body weight) was administered by intraperitoneal route. One day after the CCl4 exposure, the animals were euthanized for biochemical and histological analysis. Treatment with BMD (25 mg/kg p.o.) protected against aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase and lactate dehydrogenase activity increases induced by CCl4 plasma exposure. Treatment with BMD (25 mg/kg) protected against increases in thiobarbituric reactive species and decreasing non-protein thiols and ascorbic acid levels in liver of mice. Catalase and superoxide dismutase activity inhibition in the liver caused by CCl4 were protected by treatment with BMD (25 mg/kg). Glutathione S-transferase activity was inhibited by CCl4 and remained unaltered even after treatment with BMD. Sections of liver from CCl4 -exposed mice presented an intense infiltration of inflammatory cells and loss of the cellular architecture. BMD (25 mg/kg) attenuated CCl4 -induced hepatic histological alterations. The results demonstrated the hepatoprotective effects of BMD in the mouse liver, possibly by modulating the antioxidant status.

Imidazolium ionic liquids containing selenium: synthesis and antimicrobial activity.

The synthesis and antimicrobial profile of imidazolium ionic liquids containing selenium are described herein. Minimum inhibitory concentration revealed that these compounds are especially active against algae, and their activity is modulated by substituents attached to the selenium moiety as well as by the counterion.

Synthesis of diorganyl selenides mediated by zinc in ionic liquid.

A new approach for the synthesis of diorganyl selenides is described. By using economically attractive zinc dust in BMIM-BF(4), a series of diorganyl selenides were efficiently achieved in excellent yields, under neutral reaction conditions. Compared to the usual organic solvents, BMIM-BF(4) exhibited higher performance with the advantage to be reused up to five successive runs.

3'3-ditrifluoromethyldiphenyl diselenide: a new organoselenium compound with interesting antigenotoxic and antimutagenic activities.

The trace element selenium (Se), once known only for its potential toxicity, is now a well-established essential micronutrient for mammals. The organoselenium compound diphenyl diselenide (DPDS) has shown interesting antioxidant and neuroprotective activities. On the other hand, this compound has also presented pro-oxidant and mutagenic effects. The compound 3'3-ditrifluoromethyldiphenyl diselenide (DFDD), a structural analog of diphenyl diselenide, has proven antipsychotic activity in mice. Nevertheless, as opposed to DPDS, little is known on the biological and toxicological properties of DFDD. In the present study, we report the genotoxic effects of the organoselenium compound DFDD on Salmonella typhimurium, Saccharomyces cerevisiae and Chinese hamster lung fibroblasts (V79 cells). DFDD protective effects against hydrogen peroxide (H(2)O(2))-induced DNA damage in vitro are demonstrated. DFDD did not cause mutagenic effects on S. typhimurium or S. cerevisiae strains; however, it induced DNA damage in V79 cells at doses higher than 25 microM, as detected by comet assay. DFDD protected S. typhimurium and S. cerevisiae against H(2)O(2)-induced mutagenicity, and, at doses lower than 12.5 microM, prevented H(2)O(2)-induced genotoxicity in V79 cells. The in vitro assays demonstrated that DFDD mimics catalase activity better than DPDS, but neither presents superoxide dismutase action. The products of the reactions of DFDD or DPDS with H(2)O(2) were different, as determined by electrospray mass spectrometry analysis (ESI-MS). These results suggest that DFDD is not mutagenic for bacteria or yeast; however, it may induce weak genotoxic effects on mammalian cells. In addition, DFDD has a protective effect against H(2)O(2)-induced damage probably by mimicking catalase activity, and the distinct products of the reaction DFDD with H(2)O(2) probably have a fundamental role in the protective effects of DFDD.

pH-dependent Fe (II) pathophysiology and protective effect of an organoselenium compound.

Influence of pH on the extent of lipid peroxidation and the anti-oxidant potential of an organoselenium compound is explored. Acidosis increased the rate of lipid peroxidation both in the absence and presence of Fe (II) in rat's brain, kidney and liver homogenate and phospholipids extract from egg yolk. The organoselenium compound significantly protected lipids from peroxidation, both in the absence and presence of Fe (II). Changing the pH of the reaction medium did not alter the anti-oxidant activity of the tested compound. This study provides in vitro evidence for acidosis-induced oxidative stress in brain, kidney, liver homogenate and phospholipids extract and the anti-oxidant action of the tested organoselenium compound.

Synthesis of telluroamino acid derivatives with remarkable GPx like activity.

A series of modular telluroamino acid derivatives with remarkable GPx-like behavior was prepared in an efficient and short two-step synthesis.