The Pharmacology and Therapeutic Utility of Sodium Hydroselenide.

Metabolically active gasotransmitters (nitric oxide, carbon monoxide and hydrogen sulfide) are important signalling molecules that show therapeutic utility in oxidative pathologies. The reduced form of selenium, hydrogen selenide (HSe-/H2Se), shares some characteristics with these molecules. The simple selenide salt, sodium hydroselenide (NaHSe) showed significant metabolic activity, dose-dependently decreasing ex vivo O2 consumption (rat soleus muscle, liver) and transiently inhibiting mitochondrial cytochrome C oxidase (liver, heart). Pharmacological manipulation of selenoprotein expression in HepG2 human hepatocytes revealed that the oxidation status of selenium impacts on protein expression; reduced selenide (NaHSe) increased, whereas (oxidized) sodium selenite decreased the abundance of two ubiquitous selenoproteins. An inhibitor of endogenous sulfide production (DL-propargylglycine; PAG) also reduced selenoprotein expression; this was reversed by exogenous NaHSe, but not sodium hydrosulfide (NaHS). NaHSe also conferred cytoprotection against an oxidative challenge (H2O2), and this was associated with an increase in mitochondrial membrane potential. Anesthetized Wistar rats receiving intravenous NaHSe exhibited significant bradycardia, metabolic acidosis and hyperlactataemia. In summary, NaHSe modulates metabolism by inhibition of cytochrome C oxidase. Modification of selenoprotein expression revealed the importance of oxidation status of selenium therapies, with implications for current clinical practice. The utility of NaHSe as a research tool and putative therapeutic is discussed.

Virtual screening and assessment of anticancer potential of selenium-based compounds against HL-60 and MCF7 cells.

Aim: Selenium-based compounds have antitumor potential. We used a ligand-based virtual screening analysis to identify selenoglycolicamides with potential antitumor activity. Results & Conclusion: Compounds 3, 6, 7 and 8 were selected for in vitro cytotoxicity tests against various cell lines, according to spectrophotometry results. Compound 3 presented the best cytotoxicity results against a promyelocytic leukemia line (HL-60) and was able to induce cell death at a frequency similar to that observed for doxorubicin. The docking study showed that compound 3 has good interaction energies with the targets caspase-3, 7 and 8, which are components of the apoptotic pathway. These results suggested that selenium has significant pharmacological potential for the selective targeting of tumor cells, inducing molecular and cellular events that culminate in tumor cell death.

Synthesis of Se-polysaccharide mediated by selenium oxychloride: Structure features and antiproliferative activity.

Selenium oxychloride (SOC) was employed as a highly reactive selenide reagent to synthesize selenized Artemisia sphaerocephala polysaccharides (SeASP). Se content of SeASP was significantly increased (∼22,400 µg/g) as compared to HNO3/H2SeO3 selenylation method (1703 µg/g). Furthermore, selenized ASP was prepared by using microwave-assisted synthesis which obviously enhanced selenylation kinetics. FT-IR, Raman, XPS and NMR results exhibited seleno-group was substituted at C6 position in the form of selenite (Se4+). SEC-MALLS suggested SOC system could effectively avoid the degradation of polysaccharide chain. Meanwhile, MALLS calculation, MB spectrophotometric method and AFM observation showed SeASP appeared spherical and rod-shaped conformation after selenylation. Seleno-groups were more likely to affect the conformational transformation of polysaccharide chains. Moreover, SeASP could significantly enhance antiproliferative activity against three tumor cells, of which the IC50 value of HepG2 was calculated as 24.35 µg/mL. It was found that higher Se content could effectively improve the antitumor activities of Se-polysaccharides in vitro.

The essentialness of glutathione reductase GorA for biosynthesis of Se(0)-nanoparticles and GSH for CdSe quantum dot formation in Pseudomonas stutzeri TS44.

Pseudomonas stutzeri TS44 was able to aerobically reduce Se(IV) into SeNPs and transform Se(IV)/Cd(II) mixture into CdSe-QDs. The SeNPs and CdSe-QDs were systematically characterized by surface feature analyses, and the molecular mechanisms of SeNPs and CdSe-QD formation in P. stutzeri TS44 were characterized in detail. In vivo, under 2.5 mmol/L Se(IV) exposure, GorA was essential for catalyzing of Se(IV) reduction rate decreased by 67% when the glutathione reductase gene gorA was disrupted, but it was not decreased in the glutathione synthesis rate-limiting gene gshA mutated strain compared to the wild type. The complemented strains restored the phenotypes. While under low amount of Se(IV) (0.5 mmol/L), GSH played an important role for Se(IV) reduction. In vitro, GorA catalyzed Se(IV) reduction with NADPH as the electron donor (Vmax of 3.947 ± 0.1061 µmol/min/mg protein under pH 7.0 and 28℃). In addition, CdSe-QDs were successfully synthesized by a one-step method in which Se(IV) and Cd(II) were added to bacterial culture simultaneously. GSH rather than GorA is necessary for CdSe-QD formation in vivo and in vitro. In conclusion, the results provide new findings showing that GorA functions as a selenite reductase under high amount Se(IV) and GSH is essential for bacterial CdSe-QD synthesis.

Co9 Se8 nanoplates as a new theranostic platform for photoacoustic/magnetic resonance dual-modal-imaging-guided chemo-photothermal combination therapy.

A new theranostic platform is developed based on biocompatible poly(acrylic acid) (PAA)-Co9 Se8 nanoplates. These PAA-Co9 Se8 nanoplates are successfully utilized for photoacoustic imaging (PAI)/magnetic resonance imaging (MRI) dual-modal imaging. Moreover, the PAA-Co9 Se8 -DOX shows pH-responsive chemotherapy and enables the combination of photothermal therapy and chemotherapy to receive superior antitumor efficacy. This work promises further exploration of 2D nanoplatforms for theranostic applications.

Design, synthesis, and evaluation of multitarget-directed selenium-containing clioquinol derivatives for the treatment of Alzheimer's disease.

A series of selenium-containing clioquinol derivatives were designed, synthesized, and evaluated as multifunctional anti-Alzheimer's disease (AD) agents. In vitro examination showed that several target compounds exhibited activities such as inhibition of metal-induced Aß aggregation, antioxidative properties, hydrogen peroxide scavenging, and the prevention of copper redox cycling. A parallel artificial membrane permeation assay indicated that selenium-containing clioquinol derivatives possessed significant blood-brain barrier (BBB) permeability. Compound 8a, with a propynylselanyl group linked to the oxine, demonstrated higher hydrogen peroxide scavenging and intracellular antioxidant activity than clioquinol. Furthermore, 8a exhibited significant inhibition of Cu(II)-induced Aß1-42 aggregation and was capable of disassembling the preformed Cu(II)-induced Aß aggregates. Therefore, 8a is an excellent multifunctional promising compound for development of novel drugs for AD.

Synthesis of selenazoles by in situ cycloisomerization of propargyl selenoamides using oxygen-selenium exchange reaction.

Herein, we describe an approach toward selenazole preparation based on the cycloisomerization of propargyl selenoamides. The selenoamides were synthesized in situ using the Ishihara reagent with spontaneous cyclization to form the 2,5-disubstituted selenazoles. Heterocylcles 9a-j were prepared using readily available starting materials, and yields ranged from moderate to good (20-80%). Methylselenazole 9a could be transformed into a bromomethyl derivative 13 using NBS. The intermediate 13 would provide a more versatile building block for further derivatizations, e.g., the cyanide 14.

A selenium-based ionic liquid as a recyclable solvent for the catalyst-free synthesis of 3-selenylindoles.

The ionic liquid 1-butyl-3-methylimidazolium methylselenite, [bmim][SeO2(OCH3)], was successfully used as solvent in the catalyst-free preparation of 3-arylselenylindoles by the reaction of indole with ArSeCl at room temperature. The products were obtained selectively in good yields without the need of any additive and the solvent was easily reused for several cycles with good results.

Synthesis and utility of ß-selenol-phenylalanine for native chemical ligation-deselenization chemistry.

An efficient synthetic route to a suitably protected ß-selenol-phenylalanine derivative from commercially available Garner's aldehyde is described. The incorporation of this building block into peptides and its application in native chemical ligation reactions with peptide thioesters are demonstrated. Ligation products were chemoselectively deselenized (including in the presence of unprotected cysteine residues) to provide native peptides.

Synthesis of CdSe quantum dots using selenium dioxide as selenium source and its interaction with pepsin.

A novel method has been developed for the synthesis of thioglycolic acid (TGA)-capped CdSe quantum dots (QDs) in an aqueous medium when selenium dioxide worked as a selenium source and sodium borohydride acted as a reductant. The interaction between CdSe QDs and pepsin was investigated by fluorescence spectroscopy. It was proved that the fluorescence quenching of pepsin by CdSe QDs was mainly a result of the formation of CdSe-pepsin complex. Based on the fluorescence quenching results, the Stern-Volmer quenching constant (Ksv), binding constant (KA) and binding sites (n) were calculated. According to the Foster's non-radiative energy transfer theory, the binding distance (r) between pepsin and CdSe QDs was obtained. The influence of CdSe QDs on the conformation of pepsin has been analyzed by synchronous fluorescence spectra, which provided that the secondary structure of pepsin has been changed by the interaction of CdSe QDs with pepsin.

Synthesis of a series of novel 2,4,5-trisubstituted selenazole compounds as potential PLTP inhibitors.

Based on a homology-modeled structure of PLTP and characteristic structural features of reported cholesteryl ester transfer protein (CETP) inhibitors, we designed and synthesized a novel series of 2,4,5-trisubstituted selenazole compounds. Biological evaluation reveals that compounds 12 and 17 exhibit favorable PLTP activity, and their IC(50)s are 8 microM and 10 microM, respectively.

Synthesis and pharmacological screening of several aroyl and heteroaroyl selenylacetic acid derivatives as cytotoxic and antiproliferative agents.

The synthesis and cytotoxic activity of a series of twenty six aroyl and heteroaroyl selenylacetic acid derivatives of general formula Ar-CO-Se-CH(2)-COOH or Heterar-CO-Se-CH(2)-COOH are reported. The synthesis was carried out by reaction of acyl chlorides with sodium hydrogen selenide, prepared in situ, and this led to the formation of sodium aroylselenides that subsequently reacted with alpha-bromoacetic acid to produce the corresponding selenylacetic acid derivatives. All of the compounds were tested against a prostate cancer cell line (PC-3) and some of the more active compounds were assessed against a panel of four human cancer cell lines (CCRF-CEM, HTB-54, HT-29, MCF-7) and one mammary gland-derived non-malignant cell line (184B5). Some of the compounds exhibited remarkable cytotoxic and antiproliferative activities against MCF-7 and PC-3 that were higher than those of the reference compounds doxorubicin and etoposide, respectively. For example, in MCF-7 when Ar = phenyl, 3,5-dimethoxyphenyl or benzyl the TGI values were 3.69, 4.18 and 6.19 microM. On the other hand, in PC-3 these compounds showed values of 6.8, 4.0 and 2.9 microM. Furthermore, benzoylselenylacetic acid did not provoke apoptosis nor did it perturb the cell cycle in MCF-7.

[1-(Phenylseleno)alkyl]stannanes-mixed selenium/tin analogs of acetals: preparation from alpha-hydroxystannanes and use for generating selenium-stabilized carbanions.

Selenium-stabilized carbanions are available by a route that does not involve acid-catalyzed formation of selenoacetals. Aldehydes are converted first into alpha-hydroxystannanes and then into alpha-(phenylseleno)stannanes. Treatment with BuLi affords selenium-stabilized carbanions by preferential Sn/Li exchange.

Selenium modification of nucleic acids: preparation of phosphoroselenoate derivatives for crystallographic phasing of nucleic acid structures.

This protocol describes a simplified means of introducing an anomalously scattering atom into oligonucleotides by conventional solid-phase synthesis. Replacement of a nonbridging phosphate oxygen in the backbone with selenium is practically suitable for any nucleic acid. The resulting oligonucleotide P-diastereomers can be separated using anion exchange HPLC to yield diastereomerically pure phosphoroselenoates (PSes). The total time for the synthesis and ion-exchange HPLC separation of pure PSe is approximately 60 h.

Characterization of nanocrystalline CdSe by size exclusion chromatography.

High-performance size exclusion chromatography (HPSEC) is a powerful tool for probing the size and size distribution of complex materials. Here we report its application to the analysis of cadmium selenide nanocrystals produced in organic solvents. If nanocrystal-column interactions are minimized, this method provides an accurate measure of nanocrystal hydrodynamic diameter directly in solution; such information is complementary to TEM in that it can measure the thickness of various capping agents. While the resolution of single-pass HPSEC is limited to 1 nm, we show here that recycling size exclusion chromatography can be applied to assess the fine details of a sample's distribution. Finally, semiconductor nanocrystals can be made a variety of shapes whose optical characteristics are difficult to distinguish. HPSEC can be applied to the general problem of shape separations which we demonstrate with a tetrapod material.

Characterization of the selenotrisulfide formed by reaction of selenite with end-capped phytochelatin-2.

The phytochelatins are a family of peptides synthesized by plants in response to exposure to heavy metals and metalloids, including selenium in the form of selenite. The amino acid sequence of the phytochelatin (PC) peptides is (gamma-Glu-Cys)n-Gly, where n typically ranges from 2 to 5. In this paper, the products of the reaction of selenite with an end-capped analogue of PC2, Ac-(gamma-Glu-Cys)2-Gly-NH2, are characterized. Selenite reacts with Ac-(gamma-Glu-Cys)2-Gly-NH2 (Ac-PC2-NH2) to form a compound that contains an intramolecular selenotrisulfide (-SSeS-)-linkage (Se[Ac-PC2-NH2]) and oxidized Ac-PC2-NH2. Both Se[Ac-PC2-NH2] and oxidized Ac-PC2-NH2 were isolated by HPLC and were characterized by MALDI-TOF mass spectrometry, by two-dimensional 1H and 13C NMR and, in the case of Se[Ac-PC2-NH2], by 77Se NMR. Using dihedral angles determined from vicinal 1H-1H coupling constants as constraints for the conformations around the Cys(CalphaH)-Cys(CbetaH) bonds, structures were predicted for the most abundant form of both compounds by Monte Carlo molecular mechanics simulations.

Synthesis, properties, and photodynamic properties in vitro of heavy-chalcogen analogues of tetramethylrosamine.

Thio and seleno analogues of tetramethylrosamine were prepared by the directed-metalation/cyclization of the corresponding N,N-diethyl 2-(3-dimethylaminophenylchalcogeno)-4-dimethylaminobenzamide to the 2,7-bis-(N,N-dimethylamino)-9H-chalcogenoxanthen-9-one followed by the addition of phenylmagnesium bromide, dehydration, and ion exchange to the chloride salt. The thio and seleno tetramethylrosamines had longer wavelengths of absorption and higher quantum yields for the generation of singlet oxygen than tetramethylrosamine. Both the thio and selenoanalogues of tetramethylrosamine were efficient photosensitizers against R3230AC rat mammary adenocarcinoma cells in vitro.

9-Fluorenemethyl H-phosphonoselenoate--a versatile reagent for transferring an H-phosphonoselenoate group.

This paper expands the available methods for preparation of H-phosphonoselenoate using a new reagent, 9-fluorenemethyl H-phosphonoselenoate.

Synthesis of structured lipids and etherlipids with antioxidants: combination of a selena fatty acid and a selena fatty alcohol with a carotenoic acid in glyceride molecules.

Selenium and carotenoids show similar and complementary properties and protect against a variety of pathological processes. Mixtures of both compounds are found in nutritional supplements and are used to prevent several diseases. The synthetic connection of carotenoids with selenium in glycerols may increase the chemopreventive activity of the individual compounds. Beta-apo-8'-carotenoic acid and 7-selenacapryloic acid were esterified with glycerol to highly unsaturated stable di- and triglycerides. Intramolecular selenium:carotenoid ratios of 1:1, 2:1 and 1:2 were obtained for 1-(7-selenaoctanoyl)-3-(3beta-apo-8 -carotenoyl)-glycerol, 1,3-di-(beta-apo-8'-carotenoyl)-2-(7-selenaoctanoyl)-glycero l and 1,2-di-(7-selenaoctanoyl)-3-(beta-apo-8'-carotenoyl)-glycero l, respectively. The carotenoic acid was likewise connected to the pharmacologically interesting 11-selenalaurylglycerolether forming an alkyl-acylglyceride: 1-(11-selenadodecyl)-3-(beta-apo-8'-carotenoyl)-glycerol.