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Notable thermal shifts in diselenides have been documented in 77 Se NMR for more than 50 years, but no satisfactory explanation has been found. Here, five hypotheses are considered as possible explanations for the large temperature dependence of the 77 Se chemical shifts of diaryl and dialkyl diselenides compared to monoselenides and selenols. Density functional theory calculations are provided to bolster hypotheses and better understand the effects of barrier height and dipole energies. It is proposed that the temperature dependence of diselenide 77 Se NMR chemical shifts is due to rotation around the Se-Se bond and sampling of twisted conformers at higher temperatures. The molecular twisting is solvent dependent; here, DMSO- d 6 and toluene- d 8 were evaluated. No correlation was established between para -substituents on diaryl diselenides and the magnitude of the change in the 77 Se NMR shift (Δδ) with temperature.

The SARS-CoV-2 pandemic has prompted global efforts to develop therapeutics. The main protease of SARS-CoV-2 (M pro ) and the papain-like protease (PL pro ) are essential for viral replication and are key targets for therapeutic development. In this work, we investigate the mechanisms of SARS-CoV-2 inhibition by diphenyl diselenide (PhSe) 2 which is an archetypal model of diselenides and a renowned potential therapeutic agent. The in vitro inhibitory concentration of (PhSe) 2 against SARS-CoV-2 in Vero E6 cells falls in the low micromolar range. Molecular dynamics (MD) simulations and density functional theory (DFT) calculations [level of theory: SMD-B3LYP-D3(BJ)/6-311G(d,p), cc-pVTZ] are used to inspect non-covalent inhibition modes of both proteases via π-stacking and the mechanism of covalent (PhSe) 2 + M pro product formation involving the catalytic residue C145, respectively. The in vitro CC 50 (24.61 μM) and EC 50 (2.39 μM) data indicate that (PhSe) 2 is a good inhibitor of the SARS-CoV-2 virus replication in a cell culture model. The in silico findings indicate potential mechanisms of proteases' inhibition by (PhSe) 2 ; in particular, the results of the covalent inhibition here discussed for M pro , whose thermodynamics is approximatively isoergonic, prompt further investigation in the design of antiviral organodiselenides.

While the neurochemistry that underpins the behavioral phenotypes of depression is the subject of many studies, oxidative stress caused by the inflammation comorbid with depression has not adequately been addressed. In this study, we described novel antidepressant-antioxidant agents consisting of selenium-modified fluoxetine derivatives to simultaneously target serotonin reuptake (antidepressant action) and oxidative stress. Excitingly, we show that one of these agents ( 1-F ) carries the ability to inhibit serotonin reuptake in vivo in mice. We therefore present a frontier dual strategy that paves the way for the future of antidepressant therapies., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Experimental studies have indicated that electrophilic mercury forms (e.g., methylmercury, MeHg + ) can accelerate the breakage of selenocysteine in vitro . Particularly, in 2009, Khan et al. ( Environ. Toxicol. Chem . 2009 , 28, 1567-1577) proposed a mechanism for the degradation of a free methylmercury selenocysteinate complex that was theoretically supported by Asaduzzaman et al. ( Inorg. Chem . 2010 , 50, 2366-2372). However, little is known about the fate of methylmercury selenocysteinate complexes embedded in an enzyme, especially in conditions of oxidative stress in which methylmercury target enzymes operate. Here, an accurate computational study on molecular models (level of theory: COSMO-ZORA-BLYP-D3(BJ)/TZ2P) was carried out to investigate the formation of dehydroalanine (Dha) in selenoenzymes, which irreversibly impairs their function. Methylselenocysteine as well as methylcysteine and methyltellurocysteine were included to gain insight on the peculiar behavior of selenium. Dha forms in a two-step process, i.e., the oxidation of the chalcogen nucleus followed by a syn-elimination leading to the alkene and the chalcogenic acid. The effect of an excess of hydrogen peroxide, which may lead to the formation of chalcogenones before the elimination, and of MeHg + , a severe toxicant targeting selenoproteins, which leads to the formation of methylmercury selenocysteinate, are also studied with the aim of assessing whether these pathological conditions facilitate the formation of Dha. Indeed, elimination occurs after chalcogen oxidation and MeHg + facilitates the process. These results indicate a possible mechanism of toxicity of MeHg + in selenoproteins.

Methylmercury (CH 3 Hg + ) binding to catalytically fundamental cysteine and selenocysteine of peroxide-reducing enzymes has long been postulated as the origin of its toxicological activity. Only very recently, CH 3 Hg + binding to the selenocysteine of thioredoxin reductase has been directly observed [Pickering, I. J. Inorg. Chem. , 2020, 59, 2711-2718], but the precise influence of the toxicant on the peroxide-reducing potential of such a residue has never been investigated. In this work, we employ state-of-the-art density functional theory calculations to study the reactivity of molecular models of the free and toxified enzymes. Trends in activation energies are discussed with attention to the biological consequences and are rationalized within the chemically intuitive framework provided by the activation strain model. With respect to the free, protonated amino acids, CH 3 Hg + binding promotes oxidation of the S or Se nucleus, suggesting that chalcogenoxide formation might occur in the toxified enzyme, even if the actual rate of peroxide reduction is almost certainly lowered as suggested by comparison with fully deprotonated amino acids models.

We have quantum chemically explored the mechanism of the substitution reaction between CH3X(-) and the homo- and heterodichalcogenides CH3X'X″CH3 (X, X', X″ = S, Se, Te) using relativistic density functional theory at ZORA-OLYP/TZ2P and COSMO for simulating the effect of aqueous solvation. In the gas phase, all substitution reactions proceed via a triple-well addition-elimination mechanism that involves a stable three-center intermediate. Aqueous solvation, in some cases, switches the character of the mechanism to double-well SN2 in which the stable three-center intermediate has become a labile transition state. We rationalize reactivity trends and some puzzling aspects of these elementary reactions, in particular, vanishing activation energies and ghost three-center intermediates, using the activation strain model (ASM).

In principle, targeted therapies have optimal activity against a specific subset of tumors that depend upon the targeted molecule or pathway for growth, survival, or metastasis. Consequently, it is important in drug development and clinical practice to have predictive biomarkers that can reliably identify patients who will benefit from a given therapy. We analyzed tumor cell-line secretomes (conditioned cell media) to look for predictive biomarkers; secretomes represent a potential source for potential biomarkers that are expressed in intracellular signaling and therefore may reflect changes induced by targeted therapy. Using Gene Ontology, we classified by function the secretome proteins of 12 tumor cell lines of different histotypes. Representations and hierarchical relationships among the functional groups differed among the cell lines. Using bioinformatics tools, we identified proteins involved in intracellular signaling pathways. For example, we found that secretome proteins related to TGF-beta signaling in thyroid cancer cells, such as vasorin, CD109, and βIG-H3 (TGFBI), were sensitive to RPI-1 and dasatinib treatments, which have been previously demonstrated to be effective in blocking cell proliferation. The secretome may be a valuable source of potential biomarkers for detecting cancer and measuring the effectiveness of cancer therapies.

Ostreopsis cf. ovata, a benthic dinoflagellate often blooming along the Mediterranean coasts, has been associated with toxic events ranging from dyspnea to mild dermatitis. In late September 2009, an Ostreopsis cf. ovata bloom occurred in the Gulf of Trieste (Northern Adriatic Sea; Italy), causing pruritus and mild dermatitis in beachgoers. An integrated study was initiated to characterize Ostreopsis cells by light and confocal microscopy, PCR techniques, immunocytochemistry, and high resolution liquid chromatography-mass spectrometry (HR LC-MS). The presence of Ostreopsis cf. ovata of the Atlantic/Mediterranean clade was unambiguously established by morphological and genetic analyses in field samples. Several palytoxin-like compounds (ovatoxin-a,-b,-c,-d,-e) were identified by HR LC-MS, ovatoxin-a being the most abundant (45-64 pg/cell). Surprisingly, no palytoxin was detected. For the first time, monoclonal and polyclonal antipalytoxin antibodies revealed the intracellular cytoplasmic localization of ovatoxins, suggesting their cross-reactivity with these antibodies. Since harmful dinoflagellates do not always produce toxins, the immunocytochemical localization of ovatoxins, although qualitative, can provide an early warning for toxic Ostreopsis cells before their massive diffusion and/or concentration in seafood.

This paper reports on the analysis of the toxin content from Palythoa tuberculosa and Palythoa toxica samples collected off of the Hawaiian coast. Our work, based on in-depth high-resolution liquid chromatography-mass spectrometry analysis along with extensive NMR study, led us to structurally characterize 42-hydroxy-palytoxin, a new palytoxin congener. This toxin and palytoxin itself appeared to be the major components of toxic extract from a P. tuberculosa sample, while 42-hydroxy-palytoxin was proven by far to be the main palytoxin derivative in P. toxica. Functional studies on this new palytoxin-like compound suggest that the new palytoxin analogue and palytoxin itself present similar biological activities.