Selenium Derivatives Research Articles

Effect of Virulence Factors on the Photodynamic Inactivation of Cryptococcus neoformans

Opportunistic fungal pathogens may cause an array of superficial infections or serious invasive infections, especially in immunocompromised patients. Cryptococcus neoformans is a pathogen causing cryptococcosis in HIV/AIDS patients, but treatment is limited due to the relative lack of potent antifungal agents. Photodynamic inactivation (PDI) uses the combination of non-toxic dyes called photosensitizers and harmless visible light, which produces singlet oxygen and other reactive oxygen species that produce cell inactivation and death. We report the use of five structurally unrelated photosensitizers (methylene blue, Rose Bengal, selenium derivative of a Nile blue dye, a cationic fullerene and a conjugate between poly-L-lysine and chlorin(e6)) combined with appropriate wavelengths of light to inactivate C. neoformans. Mutants lacking capsule and laccase, and culture conditions that favoured melanin production were used to probe the mechanisms of PDI and the effect of virulence factors. The presence of cell wall, laccase and melanin tended to protect against PDI, but the choice of the appropriate photosensitizers and dosimetry was able to overcome this resistance.

Preventing Protein Oxidation with Sugars: Scavenging of Hypohalous Acids by 5-Selenopyranose and 4-Selenofuranose Derivatives

Heme peroxidases including myeloperoxidase (MPO) are released at sites of inflammation by activated leukocytes. MPO generates hypohalous acids (HOX, X = Cl, Br, SCN) from H(2)O(2); these oxidants are bactericidal and are key components of the inflammatory response. However, excessive, misplaced or mistimed production can result in host tissue damage, with this implicated in multiple inflammatory diseases. We report here methods for the conversion of simple monosaccharide sugars into selenium- and sulfur-containing species that may act as potent water-soluble scavengers of HOX. Competition kinetic studies show that the seleno species react with HOCl with rate constants in the range 0.8-1.0 × 10(8) M(-1) s(-1), only marginally slower than those for the most susceptible biological targets including the endogenous antioxidant, glutathione. The rate constants for the corresponding sulfur-sugars are considerably slower (1.4-1.9 × 10(6) M(-1) s(-1)). Rate constants for reaction of the seleno-sugars with HOBr are ~8 times lower than those for HOCl (1.0-1.5 × 10(7) M(-1) s(-1)). These values show little variation with differing sugar structures. Reaction with HOSCN is slower (~10(2) M(-1) s(-1)). The seleno-sugars decreased the extent of HOCl-mediated oxidation of Met, His, Trp, Lys, and Tyr residues, and 3-chlorotyrosine formation, on both isolated bovine serum albumin and human plasma proteins, at concentrations as low as 50 μM. These studies demonstrate that novel selenium (and to a lesser extent, sulfur) derivatives of monosaccharides could be potent modulators of peroxidase-mediated damage at sites of acute and chronic inflammation, and in multiple human pathologies.

Selenium- and tellurium-containing redox modulators with distinct activity against macrophages: possible implications for the treatment of inflammatory diseases

Various selenium- and tellurium-containing molecules are able to modulate the intracellular redox state of cells, an effect which may be used for the (selective) targeting of cancer cells, which are naturally under oxidative stress (OS). As macrophages also generate an environment rich in Reactive Oxygen Species (ROS) and nitric oxide (NO), they may represent an additional, prime target for such redox-modulating agents. A range of selenium and tellurium-containing quinones have therefore been synthesized and subsequently tested in macrophage culture. The tellurium agents were generally cytotoxic at very low concentrations, and their mode of action seemed to involve the upregulation of intracellular ROS levels. This redox-modulating effect was confirmed by simple yeast-based chemogenetic analysis in conjunction with in vitro redox assays and electrochemistry. Together, these studies point towards an intracellular build-up of superoxide radicals as the most likely cause of toxicity. In contrast, some of the selenium derivatives were less toxic and exerted a pronounced inhibitory effect on the formation of lipopolysaccharide-induced NO production. Whilst the Te-analogues therefore may enable the resolute, effective and fairly selective targeting of macrophages, the selenium agents could act less severely, but equally effectively by interfering with inflammatory signalling molecules.

Thermal stability of selenium, sulfur and nitrogen analogous phthalazine derivatives

Differential scanning calorimetry (DSC) and thermogravimetry (TG) are analytical and quantitative methods capable of providing reliable, fast and reproducible results. These data allow establishing the thermal stability, purity degree and the polymorphic behavior of organic compounds. Thermal analysis of fusion and degradation processes was carried out on organonitrogen, organosulfur and organoselenium phthalazine derivatives to establish thermal stability criteria. Decomposition and fusion temperatures of 27 biological active compounds, synthesized by our research group were determined using TG and DSC. Analysis of the thermal data indicated that: (a) in general, nitrogen compounds are more stable than sulfur and selenium compounds; (b) thioderivatives possess degradation temperatures higher than selenium compounds; (c) the presence of selenium atoms in molecular structure has associated a minor thermal stability; (d) sulfide derivatives decomposition process have higher Tonset values than disulfide compounds; (e) there are differences in the stability due to groups selenol, methylseleno, and cyanoseleno; (f) the nature of the substituent located on the benzyl ring has no effects on selenophthalazines thermal stability.

Synthesis of benzothieno[2,3-b]thiophenes, [2,3-b:3′,2′-d]-dithienothiophenes and their selenium derivatives via electrophilic cyclization and McMurry cyclization

Benzothieno[2,3-b]thiophenes, [2,3-b:3′,2′-d]-dithienothiophenes, and their selenium derivatives were synthesized in good yields from readily available 3-ethynyllithio-benzo[b]thiophenyllithio compounds, sulfur or selenium, and 2equiv of acid chlorides. Two heteroarene rings were constructed by a twofold cyclization via an acid chloride-induced electrophilic ring closing and the McMurry cyclization using Zn/TiCl4 reagents.

ChemInform Abstract: Procedure‐Controlled Selective Synthesis of 5‐Acyl‐2‐iminothiazolines and Their Selenium and Tellurium Derivatives by Convergent Tandem Annulation.

AbstractA selective synthesis of 5‐acyl‐2‐iminothiazoles (IV) and their analogues (VI) is achieved via reaction of carbodiimides with carboxylic acid chlorides followed by treatment with lithiated chalcogenoalkynes.

Sulfur and selenium derivatives of quinazoline and pyrido[2,3- d]pyrimidine: Synthesis and study of their potential cytotoxic activity in vitro

The synthesis, cytotoxic activities and selectivities of 35 derivatives related to quinazoline and pyrido[2,3- d]pyrimidine are described. The synthesized compounds were screened in vitro against four tumoral cell lines – leukemia (CCRF-CEM), colon (HT-29), lung (HTB-54) and breast (MCF-7) – and two cell lines derived from non-malignant cell lines, one mammary (184B5) and one from bronchial epithelium (BEAS-2B). MCF-7 and HTB-54 were the most sensitive cell lines with GI 50 values below 10 μM for eleven and ten compounds, respectively. Two compounds ( 2o and 3a) were identified that evoked a marked cytotoxic effect in all cell lines tested and one compound, 7h, was potent and selective against MCF-7. A preliminary study into the mechanism of the potent derivatives 2o, 3a and 7h indicated that the cytotoxic activities of these compounds might be mediated by inducing cell death without affecting cell cycle phases.

Procedure‐Controlled Selective Synthesis of 5‐Acyl‐2‐iminothiazolines and their Selenium and Tellurium Derivatives by Convergent Tandem Annulation

Ringschluss im Tandem: Die Synthese der Titelverbindungen gelang erstmals über eine organolithiumvermittelte, konvergente Tandemanellierung unter Beteiligung leicht verfügbarer terminaler Alkine, Chalkogene (S, Se und Te), Carbodiimide und Säurechloride. Eine neuartige 1,5-Acylverschiebung ist wahrscheinlich essenziell für diese nützliche Umsetzung.

Procedure‐Controlled Selective Synthesis of 5‐Acyl‐2‐iminothiazolines and their Selenium and Tellurium Derivatives by Convergent Tandem Annulation

Concise and selective: the procedure-controlled synthesis of the title compounds has been achieved for the first time by an organolithium-promoted convergent tandem annulation involving readily available terminal alkynes, chalcogen elements (S, Se, and Te), carbodiimides, and acid chlorides. A novel 1,5-acyl migration is considered to be essential for this useful transformation.

Organic Selenocyanates: Synthesis, Characterization and Uses in Chemistry and Biology

In the first part, the preparation of these compounds is reported. Organic selenocyanates have been synthesized by reaction of substrates with potassium selenocyanate, selenium diselenocyanate, diselenocyanate or selenium dicyanate. The reactions of selenenyl halides with cyanide ions or selenolates with cyanogen bromide are also efficient. In the second part, the physicochemical properties of organic selenocyanates are described. Infrared, NMR, Photoelectron and Microwave spectra are successively commented for the simplest alkyl, aryl and functionalized derivatives, viz. methyl-, phenyl-, vinyl-, ethynyl-, allyl-, propargyl-, allenyl and cyclopropylselenocyanates. The chemical reactions involving organic selenocyanates are then reported showing the diversity of applications of these compounds in the preparation of other selenium derivatives. In the last part, the recent applications of some derivatives for their antistress, antiradiation, antioxidative, antimutagenic, anticarcinogen and chemopreventive properties are summarized.

Kinase Regulation by Sulfur and Selenium Containing Compounds

Kinases are enzymes that are involved in a wide-range of cellular targets such as cell proliferation, metabolism, survival and apoptosis. Aberrations in the activity of the kinases have been linked to many human diseases such as diabetes, inflammation and cancer. The discovery of more than 518 kinases encoded by the human genome has spurred the development of rapid screening techniques for potential drugs against these enzymes and these have been identified as interesting targets for medicinal chemistry programs, especially in cancer therapy. On the other hand, sulfur and selenium have been increasingly recognized as essential elements in biology and medicine. Converging data from epidemiological and clinical studies have highlighted these elements as effective chemopreventive agents, particularly against various types of cancer (prostate, lung, breast, leukemia, colon, skin, lymphome, thyroid, pancreas, liver). These elements act through a wide range of potential mechanisms where one identified signal pathway event is kinase modulation, which is common for the two elements and emerges as a valid target. The kinases modulated by sulfur and selenium derivatives include MAP, ERK, JNK, Akt, Cdc2, Cyclin B1 and Cdc25c amongst others. Although both of the elements in question are in the same group in the periodic table and have similar biochemistries, there are relevant differences related to redox potentials, stabilities, oxidation states and anticancer activity. Literature data suggest that the replacement of sulfur by selenium in established cancer chemopreventive agents results in more effective chemopreventive analogs. In view of the multi-target kinase mechanisms in preventing cellular transformation, as well as the differences and similarities between them, in this review we focus on the development of new structures that contain selenium and/or sulfur and discuss our understanding of the regulation of antitumoral effects with emphasis on kinase modulation activity and its implications in cancer.

Synthesis of Cyclic Selenenate/Seleninate Esters Stabilized byortho‐Nitro Coordination: Their Glutathione Peroxidase‐Like Activities

The syntheses of selenenate/seleninate esters and related derivatives by aromatic nucleophilic substitution (S(N)Ar) reactions of 2-bromo-3-nitrobenzylalcohol (13) and 2-bromo-3-nitrobenzaldehyde (17) with Na(2)Se(2)/nBuSeNa are described. The reaction of 13 with Na(2)Se(2) at room temperature afforded 7-nitro-1,2-benzisoselenole(3H) (15) instead of the desired diaryl diselenide 14. Oxidation of selenenate ester 15 with hydrogen peroxide afforded the corresponding selenium(IV) derivative, 7-nitro-1,2-benzisoselenole(3H) selenium oxide (18). 2-(Butylselanyl)-3-nitrobenzaldehyde (19) was synthesized by treating compound 17 with in situ generated nBuSeNa. The bromination reaction of selenide 19 did not afford the expected arylselenenyl bromide 20, instead, it resulted in the formation of the unexpected 7-nitro-1,2-benzisoselenol(3H)-3-ol (21) and 3,3'-oxybis(7-nitro-1,2-benzisoselenole(3H)) (22), respectively. The facile formation of heterocycles 21 and 22 is rationalized in terms of the aromatic ring strain in selenenyl bromide 20. The presence of intramolecular secondary Se···O interactions in esters 15, 18, 21, 22, and selenenic anhydride 29 has been confirmed by single-crystal X-ray diffraction studies as well as computational studies. The presence of an intramolecular Se···O interaction in esters 4b, 8, 15, 18, 21, and 22 has been further proved by natural bond orbital (NBO) and atoms in molecules (AIM) calculations. Glutathione peroxidase-like (GPx) antioxidant activities of 15, 18, 21, 22, and related heterocycles such as 7-nitro-1,2-benzisoselenol(2H)-3-one selenium oxide (4b), 7-nitro-1,2-benzisoselenol(2H)-3-one (8), and 29 have been determined by the coupled reductase assay.

Intramolecularly coordinated azobenzene selenium derivatives: Effect of strength of the Se⋯N intramolecular interaction on luminescence

A series of selenium derivatives (6-12) of 2-phenylazophenyl have been synthesized using o-lithiation route. The effect of the strength of the intramolecular Se···N interaction on the absorption spectra as well as emission spectra has been studied. The studies suggest that the secondary bonding Se···N interaction give rise to fluorescence, however, the strength of Se···N interaction cannot be directly correlated with the intensity of the fluorescence. TD-DFT calculations show that the main transition involved in the absorption spectra of the compound is the ligand based π-π* type.

Synthesis, structures and ab initio studies of selenium and tellurium bis(carbodithioates and carbothioates)

A series of selenium and tellurium bis(carbodithioates and carbothioates) were synthesized. X-Ray structure analysis revealed that Se(SSCC(6)H(4)OMe-2)(2), Te(SSCC(6)H(4)OMe-2)(2) and Te(SSCC(6)H(4)Me-4)(2) have trapezoidal-planar configuration of ES(4) (E = Se, Te) and despite the larger atomic radii, the C=S···Te distances in Te(SSCC(6)H(4)OMe-2)(2) are comparable to those in the corresponding selenium derivatives Se(SSCC(6)H(4)OMe-2)(2). Molecular-orbital calculations performed on compounds E(E'SCR)(2) (E = S, Se, Te; E' = O, S; R = Me, Ph, C(6)H(4)OMe-2) showed that the syn-conformers of Se(SSCR)(2) and Te(SSCR)(2) are more stable than the corresponding anti-ones, while, in the case of carbothioic acid derivatives, E(SOCR)(2) showed that their anti-conformers are all more stable than the corresponding syn-ones. Natural bond orbital (NBO) analyses of these dithio-compounds revealed that two types of orbital interactions, n(S(1))→σ*(E-S(2)) and n(O)→σ*(E-S(2)), play a role in the bonding of E[S(2)S(1)CC(6)H(4)OMe-2](2) (E = Se, Te) and the former play a particularly predominant role.

Synthesis, structures and anti-malaria activity of some gold(i) phosphine complexes containing seleno- and thiosemicarbazonato ligands

A series of both mono- and dinuclear gold(I) phosphine complexes containing monoanionic seleno- and thiosemicarbazones as ligands were prepared and fully characterized by spectroscopic methods and, in some cases, by single crystal X-ray diffraction. The in vitro anti-malaria activity of some of these compounds was investigated in chloroquine sensitive strains of Plasmodium falciparum. The IC(50) results show that the sulfur containing compounds exhibit activity similar to that of chloroquine, whilst the selenium derivatives display only moderate anti-malaria activity.

Reactions of nitroxides. Part X: Antifungal activity of selected sulfur and selenium derivatives of 2,2,6,6-tetramethylpiperidine

The antifungal activity of nitroxyl radicals—derivatives of 2,2,6,6-tetramethylpiperidine-1-oxyl with reactive substituents 4-isothiocyanato-, 4-isocyano-, and 4-isoselenocyanato- and of N-formyl-, N-thioformyl-, N-selenoformyl-derivatives of 2,2,6,6-tetramethylpiperidine was investigated. Those of the above compounds, which contain a sulfur or selenium atom are the most active against four fungus plant patogens: Botrytiscinerea, Fusariumculmorum, Phytophthoracactorum, Rhizoctoniasolani. 4-Isoselenocyanato-2,2,6,6-tetramethylpiperidine-1-oxyl proved to be the most active compound.

Aluminosilicate Relatives: Chalcogenoaluminogermanates Rb3(AlQ2)3(GeQ2)7(Q = S, Se)

The new compounds Rb(3)(AlQ(2))(3)(GeQ(2))(7) [Q = S (1), Se (2)] feature the 3D anionic open framework [(AlQ(2))(3)(GeQ(2))(7)](3-) in which aluminum and germanium share tetrahedral coordination sites. Rb ions are located in channels formed by the connection of 8, 10, and 16 (Ge/Al)S(4) tetrahedra. The isostructural sulfur and selenium derivatives crystallize in the space group P2(1)/c. 1: a = 6.7537(3) Å, b = 37.7825(19) Å, c = 6.7515(3) Å, and β = 90.655(4)°. 2: a = 7.0580(5) Å, b = 39.419(2) Å, c = 7.0412(4) Å, β = 90.360(5)°, and Z = 2 at 190(2) K. The band gaps of the congruently melting chalcogenogermanates are 3.1 eV (1) and 2.4 eV (2).

New reaction of 1H-pyrazoles with selenium dioxide: one-pot synthesis of bis(1H-pyrazol-4-yl)selenides

Abstract A novel reaction between 3- and 3,5-substituted pyrazoles with selenium dioxide proceeds with formation of bis(3R,5R′-1H-pyrazol-4-yl)selenides in high yield. On this basis, an efficient one-pot synthetic procedure has been developed. In the case of the unsubstituted pyrazole a selenonium compound has been obtained. The identity and structure of the isolated selenium derivatives have been confirmed by spectral methods and their molecular structures investigated by X-ray analysis.

ChemInform Abstract: Chemistry of Dications as a Novel Unusual Valency of Chalcogen Elements (S, Se, Te)

Dications bonded by two positively charged heteroatoms have received a little attention, and study of their properties is of great interest. This article presents the preparation, structure, and properties of σ-bonded dications from the medium-sized cyclic compounds containing S, Se and Te atoms. Both the oxidation of 1, 5-dithiacyclooctane (1, 5-DTCO), the related selenium and tellurium derivatives (1, 5-DSeCO, 1, 5-DTeCO), and their dibenzocyclooctane derivatives using either concd H2SO4 or oxidizing agent such as NOBF4 and the treatment of their monooxide in concd H2SO4 or with (CF3SO2) 2O revealed the formation of dications containing transannular bond between two heteroatoms. The structures of the dication salts of 1, 5-DTCO and 1, 5-DSeCO were determined by X-ray crystallographic analysis. These dications act as an oxidant or as an electrophile depending on the added reagents. These new species are of particular interest and become attractive if one could prepare the analogous derivatives bearing multiheteroatoms. As typical example, inspection of the spectrum of the dication of the tris-sulfide, 1, 11- (methanothiomethano) -5 H, 7 H-dibenzo [b, g] [1, 5] dithiocin, and its oxides in concd D2SO4 indicated that the central sulfur atom should have a hypervalent bonding structure composed of two sulfur and two carbon ligands i.e., 10- S-4 (C2S2).

Synthesis and antitumor properties of selenocoxib‐1 against rat prostate adenocarcinoma cells

Hormone refractory prostate cancer poses a huge problem and standard of care chemotherapy has not been very successful. We used a novel strategy to combine properties of 2 well-studied class of compounds (selenium and COX-2 inhibitor) and examined the resulting effectiveness against prostate cancer. Bearing in mind that sulfonamide moiety and pyrazole ring is important for the proapoptotic activity of Celecoxib, we synthesized a selenium derivative, Selenocoxib-1, by modifying Celecoxib at position 3 of the pyrazole ring. The PAIII cells derived from a metastatic prostate tumor that arose spontaneously in a Lobund-Wistar (LW) rat were used to examine the efficacy of Selenocoxib-1 in vitro. In addition, human metastatic prostate cancer cells, PC-3M, were tested for antitumor effect of Selenocoxib-1 in vitro. The IC(50) in PAIII and PC-3M cells for Selenocoxib-1 was about 5 microM, while for Celecoxib it was more than 20 microM. Selenocoxib-1 induced apoptosis in a dose-dependent manner in the PAIII cells. COX-2 expression in PAIII cells was downregulated by Celecoxib and Selenocoxib-1 at 20 and 5 microM, respectively; the COX-2 activity was, however, not affected by Selenocoxib-1. Following treatment with Selenocoxib-1, PAIII cells resulted in dose-dependent decrease in HIF-1alpha, p-AKT and Bcl-2 levels. A reduction in weights was observed in subcutaneous tumors produced by PAIII cells pretreated with Selenocoxib-1 as compared to Celecoxib in LW rats. Further, following 1 week Selenocoxib-1 treatment of PAIII tumors resulted in significant reduction of tumor weights. This study demonstrates that Selenocoxib-1 is more effective against prostate cancer than Celecoxib.