Anna M. Deobald

An efficient one-pot synthesis of symmetrical diselenides or ditellurides from halides with CuO nanopowder/Se0 or Te0/base.

A CuO nanopowder-catalyzed coupling reaction of aryl, alkyl, and heteroaryl iodides with elemental selenium and tellurium takes place in the presence of KOH at 90 degrees C in DMSO. A wide range of substituted symmetrical diselenides and ditellurides were afforded with good to excellent yields.

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 rats 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.

Influence of pH on the reactivity of diphenyl ditelluride with thiols and anti-oxidant potential in rat brain.

Thiol oxidation by diphenyl ditelluride is a favorable reaction and may be responsible for alteration in regulatory or signaling pathways. We have measured rate constants for reactions of diphenyl ditelluride with cysteine, dimercaptosuccinic acid, glutathione and dithiothreitol in phosphate buffer. The relative reactivities of the different thiols with diphenyl ditelluride were independent of the pK(a) of the thiol group, such that at pH 7.4, cysteine and dithiothreitol were the most reactive and low reactivity was observed with glutathione and dimercaptosuccinic acid. The reactivity of diphenyl ditelluride was not modified by change in pH. Rate of oxidation increased with increasing pH for all thiols except dimercaptosuccinic acid, where the rate of oxidation was faster at low pH. The lipid peroxidation product malonaldehyde (MDA) was measured in rat brain homogenate and phospholipids extract from egg yolk after incubation in phosphate buffer at various pHs ranging from 7.4 to 5.4. TBARS production increased when homogenates were incubated in the pH (5.4-6.8) medium both in the absence and presence of Fe(II). These data indicate that lipid peroxidation processes, mediated by iron, are enhanced with decreasing pH. The iron mobilization may come from reserves where it is weakly bound. Diphenyl ditelluride significantly protected TBARS production at all studied pH values in a concentration dependent manner in brain homogenate. This study provides in vitro evidence for acidosis induced oxidative stress and anti-oxidant action of diphenyl ditelluride.

Antioxidant properties of diorganoyl diselenides and ditellurides: modulation by organic aryl or naphthyl moiety

Diorganoyl dichalcogenide compouds can have antioxidant activity in different in vitro and in vivo models. Here, we have compared the potential antioxidant activity of 1-dinaphthyl diselenide (1-NapSe)2, 2-dinaphthyl diselenide (2-NapSe)2, 1-dinaphthyl distelluride (1-NapTe)2, 2-dinaphthyl ditelluride (2-NapTe)2 with their well-studied analogs diphenyl diselenide ((PhSe)2) and diphenyl telluride ((PhTe)2). (PhSe)2, (PhTe)2, and naphthalene analogs-inhibited Fe(II)-induced lipid peroxidation, catalytically decomposed hydrogen peroxide and oxidized thiols, such as dithiothreitol (DTT), Cysteine (CYS), dimercaptopropionic acid (DMPS), and thiophenol (PhSH). (PhSe)2 was the less potent of the tested compounds against Fe(II)-induced lipid peroxidation in brain homogenates and the change in the organic moiety from an aryl to naphthyl group increased considerably the antioxidant potency of diselenide compounds. However, the change from aryl to naphthyl had little effect on the thio-peroxidase-like activity of diorganoyl dichalcogenides. These results suggest that minor changes in the organic moiety of aromatic diselenide compounds can modify profoundly their capacity to inhibit iron-induced lipid peroxidation. The pharmacological properties of organochalcogens are thought to be linked to their capacity of modulating oxidative stress. Consequently, it becomes important to explore the toxicological properties of dinaphthyl diselenides and ditellurides.

Hydroxyl containing seleno-imine compound exhibits improved anti-oxidant potential and does not inhibit thiol-containing enzymes

Design and synthesis of organoselenium compounds with high thiol peroxidase (TPx) and low thiol oxidase (TOx) activities have been a difficult task and remains a synthetic-activity relationship dilemma. In this regard we are reporting for the first time a detail experimental data (both in vitro and in vivo) about the anti-oxidant and toxicological profile of an Imine (-N) containing organoselenium compound (Compound A). The TPx activity of Compound A was significantly higher than diphenyl diselenide (DPDS). Both Compound A and DPDS protected sodium nitropruside (SNP) induced thiobarbituric acid reactive species (TBARS) production in rats tissue homogenate with significantly higher activity observed for Compound A than DPDS (p<0.05). The Compound A also exhibited strong antioxidant activity in the DPPH and ABTS radical scavenging assays. This study reveals that an imine group close to selenium atom drastically enhances the catalytic activities in the aromatic thiol (PhSH) assay systems. The oxidation of biologically significant thiols reflects the toxicity of the compounds. However, the present data showed that treatment with Compound A at 0, 10, 25 or 50mg/kg was not associated with mortality or body weight loss. Similarly it did not inhibit α-ALA-D and Na(+1)/K(+1) ATPase (sulfhydryl group containing enzymes) activities after acute oral treatment; rather it enhanced non-protein thiols (NPSH) concentration. The Compound A did not cause any oxidative stress as measured by TBARS production in rats tissue preparation. Our data also indicate that exposure to Compound A did not affect plasma transaminase activities or levels of urea and creatinine in rats. Ascorbic acid is always considered a marker of oxidative stress and the reduction of its content may indicate an increase in oxidative stress. Treatment with Compound A did not alter Ascorbic acid levels in rats. The conducted in vitro and in vivo tests show the versatile therapeutic potential of this compound in the area of free radical induced damages, will undoubtedly enhance our understanding of the mechanism of model compounds and may ultimately yield insights that result in improved GPx mimics.

Disubstituted diaryl diselenides as potential atheroprotective compounds: Involvement of TrxR and GPx-like systems.

Oxidative modifications of low-density lipoproteins (LDLs) have a determinant role in atherogenesis and the study of agents that can modulate LDL oxidation is of pharmacological and therapeutic significance. Therefore, the aim of this study was to evaluate the antioxidant effect of the disubstituted diaryl diselenides, p-methoxyl-diphenyl diselenide (p-CH(3)O-C(6)H(4)Se)(2) (DM) and p-chloro-diphenyl diselenide (p-Cl-C(6)H(4)Se)(2) (DC), on Cu(2+)-induced LDL oxidation. Both compounds caused a dose-dependent inhibition of human serum and isolated LDL oxidation evidenced by the increasing of the lag phase of lipid peroxidation and decreased the lipid oxidation rate (V(max)). The protein moieties from isolated LDL were also protected from Cu(2+)-induced oxidation. Moreover, the disubstituted diaryl diselenides efficiently decreased the oxidized LDL (ox-LDL) induced foam cell formation in J774A.1 macrophage cells. Mechanistically, we have demonstrated that the antioxidant and antiatherogenic effects of DM and DC are related to formation of their selenol intermediates (RSeH) either by a direct reaction with endogenous thiols (GPx-like activity) or via their reduction by TrxR (using NADPH as electron donor). Considering the powerful effect of DM and DC against LDL-induced toxicity, they could be considered for developing of new therapeutic approaches to preventing and treating atherosclerosis and cardiovascular diseases.

An Organoselenium Drug with Antioxidant Activity and Free Radical Scavenging Capacity In Vitro

Organoselenum compounds have been reported to have a wide range of pharmacological properties. Amine-based diselenide, (Z)-N-(4-methylbenzylidene)-1-(2-((2-(1-((E)-4-methyl benzylideneamino)ethyl)phenyl)diselanyl)phenyl)ethanamine ethyl)phenyl) diselanyl) phenyl) ethylimino) methyl)phenol (compound A), and diphenyl diselenide (PhSe)2 were screened for in vitro antioxidant activity. Compound A and (PhSe)2 were tested against sodium nitroprusside (SNP)- and Fe(II)-induced thiobarbituric acid-reactive species (TBARS) in rat brain homogenates. The radical scavenging activity was measured by 1,1-diphenyl-2-picrylhydrazyl assay. Both compounds A and (PhSe)2 decreased Fe(II)- and SNP-stimulated TBARS production in rat brain homogenates. Compound A exhibited the strongest antioxidant activity in the radical scavenging assay, although (PhSe)2, the simplest of the diaryl diselenide, presented no activity. In conclusion, the results of the present investigation indicated that compound A and (PhSe)2 had preventive effects against SNP- and Fe(II)-induced oxidative stress in rat brain homogenates. The amine group in the organic moiety dramatically changed the potency of amine-based diselenide.

Asymmetric synthesis and evaluation of epoxy-α-acyloxycarboxamides as selective inhibitors of cathepsin L

Cathepsin L plays important roles in physiological processes as well as in the development of many pathologies. Recently the attentions were turned to its association with tumor progress what makes essential the development of more potent and selective inhibitors. In this work, epoxipeptidomimetics were investigated as new cathepsin inhibitors. This class of compounds is straightforward obtained by using a green one-pot asymmetric epoxidation/Passerini 3-MCR. A small library of 17 compounds was evaluated against cathepsin L, and among them LSPN423 showed to be the most potent. Investigations of the mechanism suggested a tight binding uncompetitive inhibition.

Crystal structure of 1-{1-[2-(phenyl­selan­yl)phen­yl]-1H-1,2,3-triazol-4-yl}cyclo­hexan-1-ol

Two independent molecules, A and B, comprise the asymmetric unit of the title compound, C20H21N3OSe. While the benzene ring directly bound to the central triazole ring is inclined to the same extent in both molecules [dihedral angles = 40.41 (12) (molecule A) and 44.14 (12)° (B)], greater differences are apparent in the dihedral angles between the Se-bound rings, i.e. 74.28 (12) (molecule A) and 89.91 (11)° (B). Close intramolecular Se⋯N interactions of 2.9311 (18) (molecule A) and 2.9482 (18) Å (B) are noted. In the crystal, supramolecular chains along the a axis are formed via O—H⋯N hydrogen bonding. These are connected into layers via C—H⋯O and C—H⋯N interactions; these stack along (01-1) without directional intermolecular interactions between them.

Crystal structure of 4-phenyl-1-{2-[(2,4,6-tri-methyl-phen-yl)selan-yl]phen-yl}-1H-1,2,3-triazole.

In the title compound, C23H21N3Se, the C-bound phenyl ring is almost coplanar with the central five-membered ring [dihedral angle = 2.84 (10)°], but the N-bound benzene ring is inclined [dihedral angle = 47.52 (10)°]. The dihedral angle between the Se-bound rings is 69.24 (9)°. An intramolecular Se⋯N interaction of 3.0248 (15) Å is noted. In the crystal, C—H⋯π interactions connect molecules into double layers that stack along the a axis with no directional interactions between them.