Selenium-containing Analogues Research Articles

Tellurium-containing Thiol-peroxidase-like Antioxidants and their Catalytic Mechanism

Abstract: The development of novel small molecules with effective catalytic antioxidant properties is highly sought after. A wide array of structurally diverse selenium- and tellurium-containing glutathione peroxidase mimics have been studied over the past two decades. Within this arena, organotellurium compounds generally exhibit higher catalytic properties with respect to selenium-containing analogues. Different mechanisms accounting for the thiol-peroxidase-like activity of various classes of organotellurium derivatives have been proposed. This review documents developments in this area and provides an overview of the catalytic mechanisms proposed for the various classes of telluriumcontaining thiol-peroxidase-like-catalysts.

Novel bioactive hybrid Celecoxib-HDAC Inhibitor, induces apoptosis in human acute lymphoblastic leukemia cells

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Here, we exploited the synergy between histone deacetylase inhibitors (HDACi) and cyclooxygenase 2 (COX-2) inhibitors by generating and testing a series of hybrid Celecoxib-HDAC inhibitors (selenium-containing analogues of Celecoxib) on ALL cells, of which compound 11 exhibited significant inducement to kill NALM6 cells with an average IC50 of 9.95 ± 0.44 μM compared with control Celecoxib at 28.58 ± 1.44 μM and inhibited NALM6 cells growth via the inhibition of the cell cycle in G2 phase. Furthermore, compound 11 induced apoptosis by activating PARP cleavage. Taken together, compound 11 possessed the potential to be developed further as a chemotherapeutic agent for ALL.

Antioxidant Activity of New Sulphur- and Selenium-Containing Analogues of Potassium Phenosan against H2O2-Induced Cytotoxicity in Tumour Cells.

Among known phenolic antioxidants, the overwhelming majority of compounds have lipophilic properties and the number of known water-soluble compounds is very small. The list of hydrophilic phenolic antioxidants can be expanded via the synthesis of a structurally related series of polyfunctional compounds for further research on their biological activity in vitro. New sulphur- and selenium-containing analogues of antioxidant potassium phenosan were synthesised. In vitro cytotoxicity and cytostaticity as well as antioxidant activity against H2O2-induced cytotoxicity to human cell lines (HepG2, Hep-2 and MCF-7) were investigated by high-content analysis. A selenium-containing analogue showed higher biological activity than did a sulphur-containing one. As compared to the activity of potassium phenosan, the selenium-containing analogue had a cell line-dependent antioxidant effect against H2O2-induced cytotoxicity: comparable in HepG2 cells and greater in Hep-2 cells. The selenium-containing analogue significantly increased the death of MCF-7 cells at concentrations above 50 µM. The sulphur-containing analogue has lower biological activity as compared to potassium phenosan and the selenium-containing analogue.

Reprint of: Comparison of the Chemical Properties of Selenocysteine and Selenocystine with Their Sulfur Analogs

Some chemical properties of cystine and cysteine have been compared with those of their selenium-containing analogs. Major differences were noted between their titration curves, pK values of 2.01, 5.24, and 9.96 were observed for the ionizations of the carboxyl, selenohydryl, and amino groups, respectively, of selenocysteine. These values are compared with a pK of 2.3 for the carboxyl group of cysteine and values in the range of 8-10 for the ionization of the sulfhydryl and amino groups. Selenocysteine is much more reactive with halo acid derivatives than is cysteine, and reacts readily with iodoacetate even at pH values much below the pK of the selenohydryl group. Selenocysteine has an apparent half-wave potential of —0.212 V compared with 0.021 V for cysteine. It is unstable to acid hydrolysis, being completely decomposed by heating at 110° in 6 n HCl. It is also more soluble in water than is cysteine.

Synthesis of functionalised organochalcogenides and in vitro evaluation of their antioxidant activity

Differently substituted β-hydroxy- and β-amino dialkyl and alkyl-aryl tellurides and selenides have been prepared through ring-opening reactions of epoxides and aziridines with selenium- or tellurium-centered nucleophiles. The antioxidant properties and the cytotoxicity of such compounds have been investigated on normal human dermal fibroblasts. Most of the studied compounds exhibited a low cytotoxicity and a number of them proved to be non-toxic, not showing any effect on cell viability even at the highest concentration used (100 μM). The obtained results showed a significant antioxidant potential of the selected organotellurium compounds, particularly evident under conditions of exogenously induced oxidative stress. The antioxidant activity of selenium-containing analogues of active tellurides has also been evaluated on cells, highlighting that the replacement of Se with Te brought about a significant increase in the peroxidase activity.

Density Functional Theory Investigation of As(III) S-Adenosylmethionine Methyltransferase.

Arsenic is one of the most pervasive environmental toxins. It enters our water and food supply through many different routes, including the burning of fossil fuels, the application of arsenic-based herbicides, and natural sources. Using a density functional theory (DFT) cluster approach, the mechanism of arsenic (III) S-adenosylmethionine methyltransferases and various selenium-containing analogues was investigated. Notably, the methylation of arsenic by arsenic (III) S-adenosylmethionine is proposed to be a way to remove arsenic from contaminated water or soil. From the DFT cluster results, it was found that the selective substitution of the active-site Cys44, Cys72, and Cys174 residues with selenocysteines had a marginal effect on the barrier for CH3 transfer. Specifically, the average Gibbs activation energy was calculated to be only 4.2 kJ mol–1 lower than the Gibbs activation energy of 107.4 kJ mol–1 for the WT enzyme. However, importantly, it was found that with selective mutation, the methylation process becomes considerably more exergonic, where the methylation reaction can be made to be 26.4 kJ mol–1 more exergonic than the reaction catalyzed by the WT enzyme. Therefore, we propose that the selective substitution of the active-site Cys44, Cys72 and Cys174 residues with selenocysteines could make the process of methylation and volatilization more advantageous for bioremediation.

Synthesis of new selenium-containing analogs of phenozan acid

Selenium-containing analogs of phenozan acid, [3-(3,5-di-tert-butyl-4-hydroxyphenyl)-propylseleno]ethanoic and 3-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propylseleno]propanoic acids, were synthesized from bis-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]diselenide. The possibility of functionalization of the obtained compounds via the esterification and preparation of potassium salts was demonstrated. According to the in silico evaluation of acute toxicity towards rats, the synthesized compounds are low toxic and non-toxic substances.

Further insights of selenium-containing analogues of WC-9 against Trypanosoma cruzi.

As a continuation of our project aimed at searching for new chemotherapeutic agents against American trypanosomiasis (Chagas disease), new selenocyanate derivatives were designed, synthesized and biologically evaluated against the clinically more relevant dividing form of Trypanosoma cruzi, the etiologic agent of this illness. In addition, in order to establish the role of each part of the selenocyanate moiety, different derivatives, in which the selenium atom or the cyano group were absent, were conceived, synthesized and biologically evaluated. In addition, in order to study the optimal position of the terminal phenoxy group, new regioisomers of WC-9 were synthesized and evaluated against T. cruzi. Finally, the resolution of a racemic mixture of a very potent conformationally rigid analogue of WC-9 was accomplished and further tested as growth inhibitors of T. cruzi proliferation. The results provide further insight into the role of the selenocyanate group in its antiparasitic activity.

5-Hydroxy-2,3-dihydrobenzofuran-derived polyfunctional antioxidants 3. Synthesis and antioxidant activity of 2-dodecylthiomethyland 2-dodecylselenomethyl-5-hydroxy-4,6,7-trimethyl-2,3-dihydrobenzofurans

New sulfur- and selenium-containing analogs of α-tocopherol, namely, 2-dodecylthiomethyl- and 2-dodecylselenomethyl-5-hydroxy-4,6,7-trimethyl-2,3-dihydrobenzofurans were synthesized from 4-ethoxy-3,5-dimethylphenol through intermediate 2-allyl-4-ethoxy-3,5,6- trimethylphenol, 2-iodomethyl-, 2-dodecylthiomethyl-, and 2-dodecylselenomethyl-5-ethoxy- 4,6,7-trimethyl-2,3-dihydrobenzofurans. The compounds terminated oxidation chains of AIBN-initiated oxidation of styrene at 50 °C with rate constant of 5.0•106 mol L–1 s–1 and stoichiometric coefficients of 1.9±0.1. The O—H bond dissociation energies for obtained compounds (326.5 kJ mol–1) are calculated based on the measured rate constants.

Hydroxamic acid derivatives as histone deacetylase inhibitors: a DFT study of their tautomerism and metal affinities/selectivities

Hydroxamic acids are regarded as potent inhibitors of histone deacetylases (HDAC), and can therefore be used to reduce malignancy growth and size in affected organisms. Although there is a substantial body of information on the structures, syntheses, and biological activities of HDAC inhibitors, several important questions regarding their physicochemical properties and metal affinities/selectivities remain answered. First, how do the conformation and ionization of the hydroxamic group depend on its chemical composition and the dielectric properties of the medium? Second, how do these factors affect the affinities and selectivities of HDAC inhibitors for essential biogenic metal cations? Third, what is the preferred deprotonation site of the hydroxamic moiety and its mode of binding to the metal cation? The present work addressed these questions by performing density functional calculations combined with polarizable continuum model computations. The geometry, deprotonation pattern, metal-binding mode, and metal affinity/selectivity of SAHA, a typical HDAC inhibitor, were examined, and key factors affecting its ligation properties were elucidated. Sulfur- and selenium-containing analogs of SAHA were also modeled for the first time, and their potential as efficient metal-binding entities (to Mg2+, Fe2+, and Zn2+ cations) was assessed. The present calculations shed light on the thermodynamics of the binding of HDAC inhibitors to metal ions, and suggest techniques for enhancing their metal-ligating properties.

Selenium and Selenocysteine in Protein Chemistry.

Selenocysteine, the selenium-containing analogue of cysteine, is the twenty-first proteinogenic amino acid. Since its discovery almost fifty years ago, it has been exploited in unnatural systems even more often than in natural systems. Selenocysteine chemistry has attracted the attention of many chemists in the field of chemical biology owing to its high reactivity and resulting potential for various applications such as chemical modification, chemical protein (semi)synthesis, and protein folding, to name a few. In this Minireview, we will focus on the chemistry of selenium and selenocysteine and their utility in protein chemistry.

Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation

The obligate intracellular parasite, Trypanosoma cruzi is the etiologic agent of Chagas disease or American trypanosomiasis, which is the most prevalent parasitic disease in the Americas. The present chemotherapy to control this illness is still deficient particularly in the chronic stage of the disease. The ergosterol biosynthesis pathway has received much attention as a molecular target for the development of new drugs for Chagas disease. Especially, inhibitors of the enzymatic activity of squalene synthase were shown to be effective compounds on T. cruzi proliferation in in vitro assays. In the present study we designed, synthesized and evaluated the effect of a number of isosteric analogues of WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, on T. cruzi growth in tissue culture cells. The selenium-containing derivatives turned out to be extremely potent inhibitors of T. cruzi growth. Certainly, 3-phenoxyphenoxyethyl, 4-phenoxyphenoxyethyl, 4-(3-fluorophenoxy)phenoxyethyl, 3-(3-fluorophenoxy)phenoxyethyl selenocyanates and (±)-5-phenoxy-2-(selenocyanatomethyl)-2,3-dihydrobenzofuran arose as relevant members of this family of compounds, which exhibited effective ED50 values of 0.084 µM, 0.11 µM, 0.083, µM, 0.085, and 0.075 µM, respectively. The results indicate that compounds bearing the selenocyanate moiety are at least two orders of magnitude more potent than the corresponding skeleton counterpart bearing the thiocyanate group. Surprisingly, these compounds exhibited excellent selectively index values ranging from 900 to 1800 making these molecules promising candidates as antiparasitic agents.

Comparison of the redox chemistry of sulfur- and selenium-containing analogs of uracil

Selenium is present in proteins in the form of selenocysteine, where this amino acid serves catalytic oxidoreductase functions. The use of selenocysteine in nature is strongly associated with redox catalysis. However, selenium is also found in a 2-selenouridine moiety at the wobble position of tRNAGlu, tRNAGln and tRNALys. It is thought that the modifications of the wobble position of the tRNA improves the selectivity of the codon-anticodon pair as a result of the physico-chemical changes that result from substitution of sulfur and selenium for oxygen. Both selenocysteine and 2-selenouridine have widespread analogs, cysteine and thiouridine, where sulfur is used instead. To examine the role of selenium in 2-selenouridine, we comparatively analyzed the oxidation reactions of sulfur-containing 2-thiouracil-5-carboxylic acid (s2c5Ura) and its selenium analog 2-selenouracil-5-carboxylic acid (se2c5Ura) using 1H-NMR spectroscopy, 77Se-NMR spectroscopy, and liquid chromatography-mass spectrometry. Treatment of s2c5Ura with hydrogen peroxide led to oxidized intermediates, followed by irreversible desulfurization to form uracil-5-carboxylic acid (c5Ura). In contrast, se2c5Ura oxidation resulted in a diselenide intermediate, followed by conversion to the seleninic acid, both of which could be readily reduced by ascorbate and glutathione. Glutathione and ascorbate only minimally prevented desulfurization of s2c5Ura, whereas very little deselenization of se2c5Ura occurred in the presence of the same antioxidants. In addition, se2c5Ura but not s2c5Ura showed glutathione peroxidase activity, further suggesting that oxidation of se2c5Ura is readily reversible, while oxidation of s2c5Ura is not. The results of the study of these model nucleobases suggest that the use of 2-selenouridine is related to resistance to oxidative inactivation that otherwise characterizes 2-thiouridine. As the use of selenocysteine in proteins also confers resistance to oxidation, our findings suggest a common mechanism for the use of selenium in biology.

Selenium analogs of raloxifene: antioxidant activity endowed to an old drug

The antioxidant activity of selenium-containing analogs of raloxifene was studied by the ability to scavenge 2,2-diphenyl-1-picrylhydrazyl, superoxide, nitric oxide, and peroxyl radicals. These compounds exhibited similar scavenging properties as resveratrol with respect to superoxide radical and had an impressive activity in peroxyl radical scavenging, making them promising candidates for the development of antioxidant agents.

Extended rhodamine photosensitizers for photodynamic therapy of cancer cells

Extended thio- and selenorhodamines with a linear or angular fused benzo group were prepared. The absorption maxima for these compounds fell between 640 and 700nm. The extended rhodamines were evaluated for their potential as photosensitizers for photodynamic therapy in Colo-26 cells. These compounds were examined for their photophysical properties (absorption, fluorescence, and ability to generate singlet oxygen), for their dark and phototoxicity toward Colo-26 cells, and for their co-localization with mitochondrial-specific agents in Colo-26 and HUT-78 cells. The angular extended rhodamines were effective photosensitizers toward Colo-26 cells with 1.0Jcm−2 laser light delivered at λmax±2nm with values of EC50 of (2.8±0.4)×10−7M for sulfur-containing analogue 6-S and (6.4±0.4)×10−8M for selenium-containing analogue 6-Se. The linear extended rhodamines were effective photosensitizers toward Colo-26 cells with 5 and 10Jcm−2 of broad-band light (EC50’s⩽2.4×10−7M).

Abstract 5539: Therapeutic efficacy of novel selenium-containing HDACi in acute leukemia

Abstract Despite tremendous advances in treatment of leukemia that have resulted in increased survival of patients with this disease, therapy for high-risk and relapsed leukemia remains a clinical challenge. This necessitates the development of novel, more potent therapeutic modalities. Epigenetic therapy with various types of inhibitors of histone deacetylases (HDACi), have demonstrated therapeutic efficacy in a range of malignancies, often with minimal side effects. Dr. Shantu Amin's group recently reported the development of a potent, novel, selenium-containing HDAC inhibitor (SelSA-1), which showed efficacy against Hodgkin's lymphoma and chronic myelogenous leukemia cells, as well as against lung cancer and melanoma cell lines. Here we expand efficacy studies of selenium-containing HDAC inhibitors to include a broad range of hematopoietic malignancies and begin to address the drug effects on cellular functions. We tested the therapeutic efficacy of two novel HDAC inhibitors - SelSa-1 and SelSa-2 on acute lymphoblastic leukemia, acute myelogenous leukemia and non-Hodgkin's B cell lymphoma. Cell proliferation assays demonstrated sharp dose-dependent cytotoxic effects in all the above cell lines at 96-hours post-treatment. Quantitative analysis showed that SelSa-1 and SelSa-2 have distinct effects in different types of hematopoietic malignancies. In T-cell acute lymphoblastic leukemia (T-ALL) and in non-Hodgkin's lymphoma, both SelSa-1 and Selsa-2 have similar therapeutic activity with IC50 = 1uM and 1-2uM, respectively. In B-cell acute lymphoblastic leukemia, SelSa-1 has superior therapeutic activity compared to SelSa-2 with IC50 = 0.2 uM vs. 1.25, respectively. In acute promyelocytic leukemia (APML) without the t:15:17 translocation, SelSa-1 was superior to SelSa-2 (IC50= 0.25uM and 1uM respectively), while APML with the t:15:17 translocation showed similar sensitivity to both compounds with an IC50 of 1-2uM. Cell cycle analysis performed by flow cytometry revealed that these agents induce G1-cell cycle arrest in leukemia cells. Preliminary data suggest that both SelSa-1 and SelSa-2 have a synergistic effect with standard chemotherapeutic agents that induce DNA-damage. In summary, these results demonstrate the effectiveness of two selenium-containing analogs of SAHA, SelSA-1 and 2, on leukemia cells from multiple hematopoietic lineages. Additional studies to identify detailed mechanisms of the effects of these drugs on cellular function are underway. Citation Format: Mansi Sachdev, Dhimant Desai, Sunil Muthusami, Chandrika Gowda, Chunhua Song, Shantu G. Amin, Sinisa Dovat. Therapeutic efficacy of novel selenium-containing HDACi in acute leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5539. doi:10.1158/1538-7445.AM2014-5539

Susceptibility of Escherichia coli to the toxic L-proline analogue L-selenaproline is dependent on two L-cystine transport systems.

L-Selenaproline (L-selenazolidine-4-carboxylic acid) is a toxic analogue of L-proline that inhibits the growth of the urinary tract pathogen Escherichia coli in both laboratory culture media and normal human urine. The aim of this study was to identify the transport systems involved in its uptake. Deletion mutants from the Keio collection were tested for their susceptibility to L-selenaproline (SCA) and L-selenocystine (SeCys) on minimal salts agar medium. All single-gene mutants were sensitive to both compounds, but double mutants with deletions in fliY and ydjN or in yecS and ydjN were resistant to SCA and SeCys. The YdjN transporter active in strain JW1905 (ΔfliY::kan yecC(+) yecS(+) ydjN(+)) was inhibited by both SCA and SeCys, but the FliY YecS YecC ABC transporter system active in strain JW1718 (fliY(+) yecC(+) yecS(+) ΔydjN::kan) was best inhibited by these compounds in the presence of dithiothreitol. L-selenaproline and L-selenocystine are accumulated by both the FliY YecC YecS and the YdjN L-cystine transporter systems in E. coli. Because susceptibility to selenium-containing analogues of L-proline and L-cystine is dependent on multiple transport systems, these compounds may be effective in the treatment of urinary tract infections.

Spontaneous H2Loss through the Interaction of Squaric Acid Derivatives and BeH2

The most stable complexes between squaric acid and its sulfur- and selenium-containing analogues (C4X4H2 ; X = O, S, Se) with BeY2 (Y = H, F) were studied by means of the Gaussian 04 (G4) composite ab initio theory. Squaric acid derivatives are predicted to be very strong acids in the gas phase; their acidity increases with the size of the chalcogen, with C4Se4H2 being the strongest acid of the series and stronger than sulfuric acid. The relative stability of the C4X4H2⋅BeY2 (X = O, S, Se; Y = H, F) complexes changes with the nature of the chalcogen atom; but more importantly, the formation of the C4X4H2⋅BeF2 complexes results in a substantial acidity enhancement of the squaric moiety owing to the dramatic electron-density redistribution undergone by the system when the beryllium bond is formed. The most significant consequence of this acidity enhancement is that when BeF2 is replaced by BeH2, a spontaneous exergonic loss of H2 is observed regardless of the nature of the chalcogen atom. This is another clear piece of evidence of the important role that closed-shell interactions play in the modulation of physicochemical properties of the Lewis acid and/or the Lewis base.

Tandem free-radical addition/substitution chemistry and its application to the preparation of novel AT1receptor antagonists

Benzothiophene and benzoselenophene analogues of the thiophene-containing antihypertensives milfasartan and eprosartan were prepared and tested for AT(1) receptor antagonist properties. While the sulfur-containing systems were prepared following existing methodology, the selenium-containing analogues required the development of novel, tandem free-radical chemistry involving addition of aryl radicals to alkynes, followed by intramolecular homolytic substitution at the higher heteroatom. All four compounds prepared proved to be excellent AT(1) receptor antagonists, with pK(B) estimates of 7.2-9.5.

Selenium-containing analogs of SAHA induce cytotoxicity in lung cancer cells

Cancer therapy has moved beyond conventional chemotherapeutics to more mechanism-based targeted approaches. Studies demonstrate that histone deacetylase (HDAC) is a promising target for anticancer agents. Numerous, structurally diverse, hydroxamic acid derivative, HDAC inhibitors have been reported and have been shown to induce growth arrest, differentiation, autophagy, and/or apoptotic cell death by inhibiting multiple signaling pathways in cancer cells. Suberoylanilide hydroxamic acid (SAHA) has emerged as an effective anticancer therapeutic agent and was recently approved by the FDA for the treatment of advanced cutaneous T-cell lymphoma. In our previous study, we reported the development of the novel, potent, selenium-containing HDAC inhibitors (SelSA-1 and SelSA-2). In this study, the effects of SelSA-1 and SelSA-2 on signaling pathways and cytotoxicity were compared with the known HDAC inhibitor, SAHA, in lung cancer cell lines. After 24h of treatment, SelSA-1 and SelSA-2 inhibited lung cancer cell growth to a greater extent than SAHA in a dose-dependent manner with IC50 values at low micromolar concentrations. SelSA-1 and SelSA-2 inhibited ERK and PI3K-AKT signaling pathways while simultaneously increasing in autophagy in A549 cells in a time dependent manner. This preliminary study demonstrates the effectiveness of the selenium-containing analogs of SAHA, SelSA-1, and SelSA-2, as HDAC inhibitors and provides insight into the improvement and/or development of these analogs as a therapeutic approach for the treatment of lung cancer.