Dipyridyl Diselenide Research Articles

Aromatic diselenide catalytic reactions for the efficient formation of multiple disulfide bonds in peptides

Multiple disulfide bonds (MBDs) play a critical role in maintaining the three-dimensional structure of peptides and proteins affording their pharmaceutical and biological activities. The efficient synthesis of correct MBDs in peptides and proteins remains a challenging task in chemical synthesis these compounds. In this work, aromatic diselenides including diphenyl diselenide (DPDS), bis(2-carboxyphenyl)diselenide (BCPDS), and 2,2′-dipyridyl diselenide (DPDDS) played as catalysts and were successfully used for the synthesis of correct MBDs in peptides. Good yields were achieved by use of the catalytic reactions under mild conditions, and the reaction time decreased with the trend of DPDDS < BCPDS < DPDS. A reaction mechanism was proposed, in which the formation of a selenenylsulfide intermediate played a critical role in the formation of correct MBDs in peptides. On the other hand, phenylselenenyl chloride (PSC) can oxidize fully reduced peptides to their correct MDBs forms.

Towards Anion Recognition and Precipitation with Water-Soluble 1,2,4-Selenodiazolium Salts: Combined Structural and Theoretical Study

The synthesis and structural characterization of a series of supramolecular complexes of bicyclic cationic pyridine-fused 1,2,4-selenodiazoles with various anions is reported. The binding of trifluoroacetate, tetrachloroaurate, tetraphenylborate, perrhenate, and pertechnetate anions in the solid state is regarded. All the anions interact with selenodiazolium cations exclusively via a pair of “chelating” Se⋯O and H⋯O non-covalent interactions, which make them an attractive, novel, non-classical supramolecular recognition unit or a synthon. Trifluoroacetate salts were conveniently generated via novel oxidation reaction of 2,2′-dipyridyl diselenide with bis(trifluoroacetoxy)iodo)benzene in the presence of corresponding nitriles. Isolation and structural characterization of transient 2-pyridylselenyl trifluoroacetate was achieved. X-ray analysis has demonstrated that the latter forms dimers in the solid state featuring very short and strong Se⋯O and Se⋯N ChB contacts. 1,2,4-Selenodiazolium trifluoroacetates or halides show good solubility in water. In contrast, (AuCl4)−, (ReO4)−, or (TcO4)− derivatives immediately precipitate from aqueous solutions. Structural features of these supramolecular complexes in the solid state are discussed. The nature and energies of the non-covalent interactions in novel assembles were studied by the theoretical methods. To the best of our knowledge, this is the first study that regards perrhenate and pertechnetate as acceptors in ChB interactions. The results presented here will be useful for further developments in anion recognition and precipitation involving cationic 1,2,4-selenodiazoles.

Synthesis, characterization, X-ray crystal structure and antibacterial activity of bis[3-(4-chloro-N,N-diethylpyridine-2-carboxamide)] diselenide

An efficient methodology for the synthesis of bis[3-(4-chloro-N,N-diethylpyridine-2-carboxamide)] diselenide has been successfully achieved through ring lithiation using 2.2equivalents oflithium diisopropylamide (LDA) in THF. The hitherto unknown compound has been fully characterized by spectroscopic techniques NMR (1H and 13C), Mass spectrometry and elemental analysis. The crystal structure ofbis[3-(4-chloro-N,N-diethylpyridine-2-carboxamide)] diselenide has been determined by single crystal X-ray diffraction. The diselenide crystallizes in the monoclinic system (C2/c) with torsional angle of the selenium atoms attached to pyridyl rings (-C1–Se–Se–C1-) is −77.5(1). Bis[3-(4-chloro-N,N-diethylpyridine-2-carboxamide)] diselenide was found antibacterial active and results were compared with the most studied pyridylselenium compound (2,2′-dipyridyl diselenide) and standard drug Ampicillin.

2,2'-Dipyridyl diselenide (Py2Se2) induces G1 arrest and apoptosis in human lung carcinoma (A549) cells through ROS scavenging and reductive stress.

Organo-diselenides are well documented for pro-oxidant effects in tumor cells. However, the present study demonstrated that 2,2'-dipyridyl diselenide (Py2Se2) induced cytotoxicity in human non-small cell lung carcinoma (A549) cells through reductive stress marked by a significant decrease in the basal level of reactive oxygen species and a concurrent decrease in the ratio of oxidised (GSSG) and reduced (GSH) glutathione. The IC50 (concentration inducing 50% cytotoxicity) of Py2Se2 in A549 and human normal lung fibroblast (WI38) cells was ∼8.5 μM and ∼5.5 μM, respectively, indicating that Py2Se2 did not exhibit selective toxicity towards cancer cells. Cell free studies indicated that Py2Se2 acted as a substrate of thioredoxin reductase (TrxR) and accordingly it was proposed that TrxR mediated reduction of Py2Se2 within cells might be generating intermediates leading to a reductive environment. Despite generating a reducing environment, Py2Se2 caused significant DNA damage, G1 phase arrest and apoptosis. The mechanistic investigation revealed that Py2Se2 induced G1 arrest was mediated through up-regulation of p21 transcript in a p53 independent manner. Further, the apoptotic effect of Py2Se2 was associated with the increase in the levels of unfolded protein response markers like BiP and CHOP, mitochondrial permeability (JC1) and apoptotic markers such as cleaved caspase-3 and poly (ADP-ribose) polymerase. Finally, pre-treatment with N-acetylcysteine (a stimulator of GSH biosynthesis) or l-buthionine sulfoximine (an inhibitor of GSH biosynthesis) increased and decreased the Py2Se2 mediated apoptosis, respectively. This confirmed that the cytotoxicity of Py2Se2 in A549 cells was triggered through reductive stress.

2,2'-Dipyridyl diselenide: A chemoselective tool for cysteine deprotection and disulfide bond formation.

There are many examples of bioactive, disulfide-rich peptides and proteins whose biological activity relies on proper disulfide connectivity. Regioselective disulfide bond formation is a strategy for the synthesis of these bioactive peptides, but many of these methods suffer from a lack of orthogonality between pairs of protected cysteine (Cys) residues, efficiency, and high yields. Here, we show the utilization of 2,2'-dipyridyl diselenide (PySeSePy) as a chemical tool for the removal of Cys-protecting groups and regioselective formation of disulfide bonds in peptides. We found that peptides containing either Cys(Mob) or Cys(Acm) groups treated with PySeSePy in trifluoroacetic acid (TFA) (with or without triisopropylsilane (TIS) were converted to Cys-S-SePy adducts at 37 °C and various incubation times. This novel Cys-S-SePy adduct is able to be chemoselectively reduced by five-fold excess ascorbate at pH 4.5, a condition that should spare already installed peptide disulfide bonds from reduction. This chemoselective reduction by ascorbate will undoubtedly find utility in numerous biotechnological applications. We applied our new chemistry to the iodine-free synthesis of the human intestinal hormone guanylin, which contains two disulfide bonds. While we originally envisioned using ascorbate to chemoselectively reduce one of the formed Cys-S-SePy adducts to catalyze disulfide bond formation, we found that when pairs of Cys(Acm) residues were treated with PySeSePy in TFA, the second disulfide bond formed spontaneously. Spontaneous formation of the second disulfide is most likely driven by the formation of the thermodynamically favored diselenide (PySeSePy) from the two Cys-S-SePy adducts. Thus, we have developed a one-pot method for concomitant deprotection and disulfide bond formation of Cys(Acm) pairs in the presence of an existing disulfide bond.

Anti-inflammatory and antinociceptive effects of 2,2`-dipyridyl diselenide through reduction of inducible nitric oxide synthase, nuclear factor-kappa B and c-Jun N-terminal kinase phosphorylation levels in the mouse spinal cord

Appropriate treatment of pain requires analgesics and anti-inflammatory drugs generally associated with undesirable side effects and not fully effective in a significant proportion of patients. Organoselenium compounds elicit a plenty of pharmacological effects in different animal models. Among these compounds, the 2,2`-dipyridyl diselenide (DPD) has a potent antioxidant effect and low toxicity. In this way, the aim of this study was to investigate the possible DPD antinociceptive effect and its mechanism of action, as well as the safety of the compound. Female Swiss mice were treated with vehicle or DPD (0.01–50 mg/kg) intragastrically. Dose–response curve and time-course of the antinociceptive effect of DPD were performed on formalin and tail immersion tests. Morphine (2.5 mg/kg, subcutaneous, 15 min earlier) was used as a positive control in behavioral tests. The results showed that DPD presents a rapid antinociceptive effect in low doses, without changing the spontaneous locomotor activity and parameters of toxicity in mice. The DPD antinociceptive effect was also confirmed in male Swiss mice in both formalin and tail immersion tests. In addition, DPD reduced the paw edema induced by 2.5% formalin and ear edema induced by 2.5% croton oil. l-arginine (600 mg/kg, intraperitoneally) reduced the DPD antinociceptive effect in the first phase of the formalin test. Moreover, DPD attenuated the increase in iNOS, NF-κB and JNK phosphorylation in the spinal cord of mice injected with formalin. These results showed that DPD exerts peripheral and central nociceptive actions associated with anti-inflammatory effect and this organoselenium compound could be an interesting alternative therapy for pain treatment.

Effect of a Bromo Substituent on the Glutathione Peroxidase Activity of a Pyridoxine-like Diselenide.

In search for better mimics of the glutathione peroxidase enzymes, pyridoxine-like diselenides 6 and 11, carrying a 6-bromo substituent, were prepared. Reaction of 2,6-dibromo-3-pyridinol 5 with sodium diselenide provided 6 via aromatic nucleophilic substitution of the 2-bromo substituent. LiAlH4 caused reduction of all four ester groups and returned 11 after acidic workup. The X-ray structure of 6 showed that the dipyridyl diselenide moiety was kept in an almost planar, transoid conformation. According to NBO-analysis, this was due to weak intramolecular Se···O (1.1 kcal/mol) and Se···N-interactions (2.5 kcal/mol). That the 6-bromo substituent increased the positive charge on selenium was confirmed by NPA-analysis and seen in calculated and observed (77)Se NMR-shifts. Diselenide 6 showed a more than 3-fold higher reactivity than the corresponding des-bromo compound 3a and ebselen when evaluated in the coupled reductase assay. Experiments followed for longer time (2 h) confirmed that diselenide 6 is a better GPx-catalyst than 11. On the basis of (77)Se-NMR experiments, a catalytic mechanism for diselenide 6 was proposed involving selenol, selenosulfide and seleninic acid intermediates. At low concentration (10 μM) where it showed only minimal toxicity, it could scavenge ROS produced by MNC- and PMNC-cells more efficiently than Trolox.

Dichloridobis(pyridine-2-selenolato-κ2N,Se)tin(IV)

The title compound, [SnCl2(C5H4NSe)2], is the product of a reaction of 2,2′-dipyridyl diselenide with tin tetra­chloride. The mol­ecule is located about a twofold rotation axis. The coordination environment of the SnIV atom is a distorted octa­hedron, with two bidentate 2-pyridine­seleno­late ligands inclined to each other at an angle of 83.96 (7)°. The two Sn—Cl and two Sn—N bonds are in cis configurations, while the two Sn—Se bonds of 2.5917 (3) Å are in a trans configuration, with an Se—Sn—Se angle of 157.988 (15)°. In the crystal, π–π inter­actions between the pyridine rings [centroid-to-centroid distance of 3.758 (3) Å] and weak inter­molecular C—H⋯Cl hydrogen bonds link the mol­ecules into chains along the c axis.

Bis(pyridin-2-yl) selenide-κ2N,N′]tetrachloridotin(IV)

The title compound, [SnCl4(C10H8N2Se)], was obtained by the reaction of 2,2′-dipyridyl diselenide with tin tetra­chloride. The SnIV ion is coordinated by two N atoms [Sn—N = 2.266 (2) and 2.274 (2) Å] from the bis­(2-pyrid­yl)selenide ligand and four chloride anions [Sn—Cl = 2.3717 (6)–2.3939 (6) Å] in a distorted octa­hedral geometry. The central six-membered chelate ring has a boat conformation with the Se and Sn atoms deviating by 0.692 (3) and 0.855 (3) Å, respectively, from the mean plane through the remaining four ring atoms. The pyridine rings are inclined to each other by a dihedral angle of 49.62 (8)°. The crystal packing exhibits short inter­molecular Se⋯Cl contacts [3.5417 (7) and 3.5648 (7) Å], weak C—H⋯Cl hydrogen bonds and π–π stacking inter­actions between the pyridine rings with a centroid–centroid distance of 3.683 (3) Å.

2,2′-Dipyridyl diselenide is a better antioxidant than other disubstituted diaryl diselenides

The aim of this study was to investigate the in vitro antioxidant activity of 2,2'-dipyridyl diselenide (e) by comparing this effect with m-trifluoromethyl-diphenyl diselenide (a), p-fluor-diphenyl diselenide (b), p-chloro-diphenyl diselenide (c), and p-methoxyl-diphenyl diselenide (d) in rat liver homogenate. We also investigated if the mechanisms involved in the antioxidant property of 2,2'-dipyridyl diselenide are the same that of other diselenides. Thiobarbituric acid reactive substances (TBARS) and protein carbonyl (PC) levels were determined in rat liver homogenate, as indicators of antioxidant activity. Dehydroascorbate (DHA) reductase- and glutathione S-transferase (GST)-like activities, 2,2'-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical-scavenging activities and the protection against the oxidation of Fe(2+) were determined to better understand the antioxidant property of compounds. δ-Aminolevulinic dehydratase (δ-ALA-D) activity was also carried out in rat liver homogenates, as a toxicological parameter. Compound e showed the highest potency in reducing TBARS (order of IC(50) values: e < b ≤ a < d ≤ c) and PC (order of IC(50) values: e < c ≤ b ≤ a < d) levels and lower potency in inhibiting δ-ALA-D activity than other diselenides. Compound e at all concentrations tested had no enzyme-mimetic property, but had radical-scavenging activity (≥5 μM) and protected against the oxidation of Fe(2+) (50 μM); while compounds a-d showed GST and DHA-mimetic activities and protected against the oxidation of Fe(2+), but had not radical-scavenging activities. This study indicates that (i) 2,2'-dipyridyl diselenide (e) had better in vitro antioxidant effect than other diselenides and lower inhibitory effect on δ-ALA-D activity, (ii) the presence of pyridine ring is responsible for the best antioxidant effect of this compound, and (iii) 2,2'-dipyridyl diselenide acts by different mechanisms of other diselenides.

Bis-(3-hydroxyphenyl) diselenide inhibits LPS-stimulated iNOS and COX-2 expression in RAW 264.7 macrophage cells through the NF-kB inactivation

Abstract Objectives Previously, we reported that diaryl diselenide compounds have strong inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophages. In this study, we investigated the molecular mechanisms underlying NO suppression and prostaglandin E2 (PGE2) production by diaryl diselenide compounds, bis-(2-hydroxyphenyl) diselenide (DSE-A), bis-(3-hydroxyphenyl) diselenide (DSE-B), bis-(4-hydroxyphenyl) diselenide (DSE-C), dipyridyl diselenide (DSE-D) and diphenyl diselenide (DSE-E). Methods The effect of these compounds on NO suppression and PGE2 production was investigated in RAW 264.7 macrophages. Key findings Our data indicate that of the above, DSE-B most potently inhibits NO and PGE2 production, and that it also significantly reduces the releases of tumour necrosis factor (TNF)-α, interleukin(IL)-1β and IL-6. Consistent with these observations, DSE-B also reduced the protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and the mRNA levels of iNOS, COX-2, TNF-α, IL-1β and IL-6. Furthermore, DSE-B inhibited LPS-induced nuclear factor-κB (NF-κB) activation, which was associated with the prevention of the inhibitor κB-α (IκB-α) degradation and a subsequent reduction in nuclear p65 protein levels. Conclusions Taken together, our data suggest that the anti-inflammatory properties of DSE-B are due to reduction in the expression of iNOS, COX-2, TNF-α, IL-1β and IL-6 through the down-regulation of NF-κB binding activity.

Bis-(3-hydroxyphenyl) diselenide inhibits LPS-stimulated iNOS and COX-2 expression in RAW 264.7 macrophage cells through the NF-κB inactivation

Previously, we reported that diaryl diselenide compounds have strong inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophages. In this study, we investigated the molecular mechanisms underlying NO suppression and prostaglandin E(2) (PGE(2)) production by diaryl diselenide compounds, bis-(2-hydroxyphenyl) diselenide (DSE-A), bis-(3-hydroxyphenyl) diselenide (DSE-B), bis-(4-hydroxyphenyl) diselenide (DSE-C), dipyridyl diselenide (DSE-D) and diphenyl diselenide (DSE-E). The effect of these compounds on NO suppression and PGE(2) production was investigated in RAW 264.7 macrophages. Our data indicate that of the above, DSE-B most potently inhibits NO and PGE(2) production, and that it also significantly reduces the releases of tumour necrosis factor (TNF)-alpha, interleukin(IL)-1beta and IL-6. Consistent with these observations, DSE-B also reduced the protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and the mRNA levels of iNOS, COX-2, TNF-alpha, IL-1beta and IL-6. Furthermore, DSE-B inhibited LPS-induced nuclear factor-kappaB (NF-kappaB) activation, which was associated with the prevention of the inhibitor kappaB-alpha (IkappaB-alpha) degradation and a subsequent reduction in nuclear p65 protein levels. Taken together, our data suggest that the anti-inflammatory properties of DSE-B are due to reduction in the expression of iNOS, COX-2, TNF-alpha, IL-1beta and IL-6 through the down-regulation of NF-kappaB binding activity.

Catalytic Staudinger—Vilarrasa Reaction for the Direct Ligation of Carboxylic Acids and Azides

2,2'-Dipyridyl diselenide (PySeSePy) is the catalyst or activator of choice for the direct reaction of carboxylic acids with azides and trimethylphosphine at room temperature. The mechanism of the process, which is not an aza-Wittig reaction, has been elucidated.

Selenium-Containing Heterocycles: Synthetic Investigation of 3-Amino-2-Ethylselenopyridine Carboxylate Using Sodium Borohydride

3-amino-4,6-dimethyl-2-ethylseleno[2,3-b]pyridine carboxylate (5) was prepared by a reaction of dipyridyl diselenide derivative (3) with sodium borohydride as a reducing agent followed by α-haloester. The reaction of 5 with hydrazine hydrate afforded the corresponding carbohydrazide 8. The benzylidene derivative 9 provided novel heterocycles of pyrimidoseleno pyridine and thiazinoseleno pyridine derivatives (10–12), upon treatment with triethylorthoformate, acetic anhydride, and carbon disulfide, respectively.

On the Temperature Percolation in a w/o Microemulsion in the Presence of Organic Derivatives of Chalcogens

The course of temperature percolation in a w/o microemulsion system comprising water/bis(2-ethylhexyl) sulfosuccinate sodium, AOT/isooctane affected by the presence of additives has been investigated. Additives, viz., organic derivatives of chalcogens including dipyridyl diselenide (Py2Se2), diphenyl diselenide (Ph2Se2), and dipyridyl ditelluride (Py2Te2), have been assimilated in the reverse micellar system. Formulations have been studied in terms of (i) the concentration variation of additives, (ii) the change in omega (= [H2O]/[AOT]), and (iii) the change in the nonpolar continuum, S (= [oil]/[AOT]). Phenyl derivatives hinder the percolation, whereas the pyridyl derivative in moderate amounts favors the phenomenon. The estimated values of the critical exponents are lower than those predicted by the dynamic percolation theory. The association model has been implemented to access the thermodynamic parameters of droplet clustering. Pyridyl compounds are expected to alter the rigidity of the surfactant monolayer, which could help to promote the attractive interdroplet interaction. FT-IR spectroscopy has been used to elucidate the changes occurring in the core water in the presence of organic derivatives of chalcogens as the droplet size is increased. Results have been rationalized in terms of the alteration in the physicochemical behavior of the water/AOT/isooctane microemulsion in the presence of additives.

Conversion of Ketoximes to Ketones with Trimethylphosphine and 2,2′‐Dipyridyl Diselenide.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Conversion of ketoximes to ketones with trimethylphosphine and 2,2′-dipyridyl diselenide

Use of trimethylphosphine (Me3P) and 2,2′-dipyridyl diselenide (PySeSePy) is an excellent method for the conversion of ketoximes to the corresponding ketones, since yields higher than 90% are obtained at rt within a fewminutes (or hours for the more reluctant substrates, which do not react with Bu3P/PhSSPh). In the simplest cases, the reaction can be completed with 30mol% of PySeSePy, provided that an excess of phosphine is present in the reaction medium.

Preparation and Characterization of Methyl Substituted 2,2′-Dipyridyl Diselenides and -Ditellurides: X-ray Structure of 6,6′-Dimethyl-2,2′-dipyridyl Diselenide

A convenient method for the preparation of various methyl substituted 2,2'-dipyridyl diselenides and -ditellurides by the aerial oxidation of lithium 2-pyridylselenolate/tellurolate, prepared from the lithium-halogen exchange between n-butyllithium and 2-bromo methyl substituted pyridines is reported. All the compounds prepared are new and have been characterized by elemental analysis, IR, 1 H, 13 C, 11 Se NMR, and mass spectral studies. Crystal structure of 6,6'-dimethyl-2,2'-dipyridyl diselenide has been determined.

A novel and convenient synthesis towards 2-pyridylselenium compounds: X-ray crystal structure of 4,4′-dimethyl-2,2′-dipyridyl diselenide and tris(2-pyridylseleno)methane

Various 2,2′-dipyridyl diselenides were prepared by a simple and convenient method employing non-cryogenic conditions. The diselenide anion, Se 2 2− formed by reducing elemental selenium with 100% hydrazine hydrate in sodium hydroxide reacts in situ with 2-bromopyridines to afford the title compounds in good to excellent yields. Hydrazine hydrate readily cleaves the selenium-selenium bond in these diselenides to generate 2-pyridylselenolate anion, which reacts with halomethanes to afford 2-pyridylseleno methanes. X-ray crystal structure of 4,4′-dimethyl-2,2′-dipyridyl diselenide ( 4) and tris(2-pyridylseleno)methane ( 10) is described.

Preparation and Characterization of 2,2′-Dipicolyl Diselenide and Their Derivatives

Lithium 2-picolylselenolate/tellurolate is obtained by reacting lithiated 2-picoline with elemental selenium/tellurium which upon aerial oxidation gives 2,2'-dipicolyl diselenide in case of selenium while 1,2-bis(2-pyridyl)ethane in case of tellurium. Condensation of 2-picolylselenolate anion with a variety of electrophiles provides a facile synthesis of 2-picolylalkyl selenides in good to excellent yields. Quenching of lithiated 2-picoline with 2,2'-dipyridyl diselenide gives mixed 2-picolylseleno pyridine in low yield. All the compounds prepared are new and have been characterized by elemental analysis, 1 H NMR, 13 C NMR and mass spectral studies.