marcobo

• Rubbi, Alessandro; Lambertini, Francesco; Nogara, Pablo A.; Bortoli, Marco; Rocha, João B.T. & Orian, Laura (2025). Molecular Aspects of Methylcadmium Toxicity: Effects on the H2O2 Reduction by Cysteine and Selenocysteine Disclosed In Silico. Chemical Research in Toxicology. ISSN 0893-228X. 39(1), p. 144–156. doi: 10.1021/acs.chemrestox.5c00409. Full text in Research Archive Show summary

  Cadmium (Cd), like the other group 12 elements (Zn and Hg), has a high affinity for sulfur (S) and selenium (Se), a property that strongly influences its adverse biological effects. Although the symptoms of Cd toxicity are diverse, a common denominator is found in oxidative stress, resulting in the disruption of redox balance in cells and the proliferation of reactive oxygen species (ROS) and harmful radicals. Methylcadmium (CH3Cd+) is a convenient model to study Cd pro-oxidant activity in silico. In this work, the effect of CH3Cd+ on the peroxy-reducing potential of cysteine (Cys) and selenocysteine (Sec) is investigated at the ZORA-BLYP-D3(BJ)/TZ2P level and compared to our current knowledge on the analogous molecular aspects of methylmercury’s toxicity (CH3Hg+). Molecular docking simulations indicate that CH3Cd+ binds favorably to the catalytic sites of the GPx1 and TrxR1 enzymes. The short distances between the metal and Sec suggest that a nucleophilic attack by Se to Cd leading to the inhibition of the enzyme is indeed possible. Methylcadmium pro-oxidant activity is─if not equal─only slightly inferior to that of methylmercury.

• Bortoli, Marco; Bore, Sigbjørn Løland; Eisenstein, Odile & Cascella, Michele (2025). The influence of the organic residue and the solvent in the Schlenk equilibrium for Grignard reagents in THF. A molecular dynamics study with machine learning potentials. Journal of Catalysis. ISSN 0021-9517. 454. doi: 10.1016/j.jcat.2025.116619. Full text in Research Archive Show summary

  The Schlenk equilibrium is an essential characteristic of the Grignard reagents. However, its quantitative aspects remain poorly understood. In this work, we perform molecular dynamics simulations to characterise how the Schlenk reaction is affected by varying the alkyl R groups (Me, Et, i-Pr, t-Bu). For each R group, the reactivity profiles were obtained through enhanced sampling on fully solvated dinuclear species, leveraging a newly developed machine learning potential trained on ab initio data. While the topologies of the Helmholtz energy maps are qualitatively similar, the energy ranges vary significantly with the R groups. Bulkier R groups disfavour higher solvation of the magnesium centre, with direct implications for the activation and mechanism of the Schlenk exchange. With respect to dichloro-bridged species, the concentrations of monochloro-bridged and separated species increase with the size of R and the degree of solvation. The energy barrier for ligand exchange increases with the size of R, and it is particularly noticeable for R = t-Bu, in agreement with experimental data. As excess solvation of one of the magnesium centres is associated with the most important reaction pathways, it can be deduced that early formation of monochloro-bridged species favours the Cl/R exchange, especially for large R groups. The formation of these species is favoured by higher Mg solvation for small R groups, and by the steric volume of R itself for large R, pointing at a constructive effect of the solvent and R promoting Cl/R exchange. Our study shows that a full characterisation of the speciation of Grignard reagents in solution is possible at reasonable computational costs with machine-learning potentials.

• Manasi, Iva; Bortoli, Marco; Bowron, Daniel T.; Campana, Mario; Hammond, Oliver S. & Headen, Thomas F. [Show all 11 contributors for this article] (2025). Are Grignard Reactions in Deep Eutectic Solvents Interface‐Driven? Angewandte Chemie International Edition. ISSN 1433-7851. 64(42). doi: 10.1002/anie.202513649. Full text in Research Archive Show summary

  Due to their high reactivity, organolithium and organomagnesium addition to ketones is usually performed under inert atmosphere at low temperature. Recent work has shown that, by dissolving the substrate in deep eutectic solvents (DES), these processes can be carried out on the benchtop, in air at room temperature. Surprisingly, the organometallic reagent, added to the DES from an organic solution, works in these conditions and gives better yields than in the standard setup. Here, we investigated acetophenone in a (1:2) choline chloride:glycerol (ChCl:Gly) DES solution by experimental liquid diffraction, neutron reflectometry, NMR, interfacial tension measurements, and by computational modelling. Our data show that this DES is a poor solvent for the ketone and promotes its accumulation at the surface of the liquid or its escape into the organic solvent. Molecular dynamics simulations of Grignard reagent i ‐PrMgCl in the (ChCl:Gly)/tetrahydrofuran biphasic system indicate also preference for its localisation at the interface. These results pinpoint why this combination of solvents promote the reaction, require stirring, and accounts for the lack of rapid decomposition of the organometallic reagents.

• Madabeni, Andrea; Bortoli, Marco; Nogara, Pablo A.; Ribaudo, Giovanni; Tiezza, Marco Dalla & Flohé, Leopold [Show all 8 contributors for this article] (2024). 50 Years of Organoselenium Chemistry, Biochemistry and Reactivity: Mechanistic Understanding, Successful and Controversial Stories. Chemistry - A European Journal. ISSN 0947-6539. doi: 10.1002/chem.202403003. Full text in Research Archive Show summary

  In 1973, two major discoveries changed the face of selenium chemistry: the identification of the first mammal selenoenzyme, glutathione peroxidase 1, and the discovery of the synthetic utility of the so-called selenoxide elimination. While the chemical mechanism behind the catalytic activity of glutathione peroxidases appears to be mostly unveiled, little is known about the mechanisms of other selenoproteins and, for some of them, even the function lies in the dark. In chemistry, the capacity of organoselenides of catalyzing hydrogen peroxide activation for the practical manipulation of organic functional groups has been largely explored, and some mechanistic details have been clearly elucidated. As a paradox, despite the long-standing experience in the field, the nature of the active oxidant in various reactions still remains matter of debate. While many successes characterize these fields, the pharmacological use of organoselenides still lacks any true application, and while some organoselenides were found to be non-toxic and safe to use, to date no therapeutically approved use was granted. In this review, some fundamental and chronologically aligned topics spanning organoselenium biochemistry, chemistry and pharmacology are discussed, focusing on the current mechanistic picture describing their activity as either bioactive compounds or catalysts.

• Solorzano, Eliana Rita; Roverso, Marco; Bogialli, Sara; Bortoli, Marco; Orian, Laura & Badocco, Denis [Show all 9 contributors for this article] (2024). Antioxidant activity of Zuccagnia-type propolis: A combined approach based on LC-HRMS analysis of bioanalytical-guided fractions and computational investigation. Food Chemistry. ISSN 0308-8146. 461. doi: 10.1016/j.foodchem.2024.140827. Full text in Research Archive Show summary

  This study reports a combined approach to assess the antioxidant activity of Zuccagnia-type propolis. Fractions exhibiting the highest antioxidant activities evidenced by DPPH, a β-carotene bleaching and superoxide radical scavenging activity-non-enzymatic assays, were processed by LC-HRMS/MS to characterize the relevant chemical compounds. A computational protocol based on the DFT calculations was used to rationalize the main outcomes. Among the 28 identified flavonoids, caffeic acids derivatives were in the fraction exhibiting the highest antioxidant activity, with 1-methyl-3-(4′-hydroxyphenyl)-propyl caffeic acid ester and 1-methyl-3-(3′,4′-dihydroxyphenyl)-propyl caffeic acid ester as major components. Results clearly showed roles of specific chemical motifs, which can be supported by the computational analysis. This is the first report ascribing the antioxidant ability of Zuccagnia-type propolis to its content in specific caffeic acid derivatives, a potential source of radical scavenging phytochemicals. The proposed protocol can be extended to the study of other plant-products to address the most interesting bioactive compounds.

• Sancineto, Luca; Mangiavacchi, Francesca; Dabrowska, Agnieszka; Pacuła-Miszewska, Agata J.; Obieziurska-Fabisiak, Magdalena & Scimmi, Cecilia [Show all 20 contributors for this article] (2024). New insights in the mechanism of the SARS-CoV-2 M^pro inhibition by benzisoselenazolones and diselenides. Scientific Reports. 14(1). doi: 10.1038/s41598-024-75519-6. Full text in Research Archive Show summary

  Although global vaccination campaigns alleviated the SARS-CoV-2 pandemic in terms of morbidity and mortality, the ability of the virus to originate mutants may reduce the efficacy of vaccines, posing a serious risk of a renewed pandemic. There is therefore a need to develop small molecules capable of targeting conserved viral targets, such as the main protease (Mpro). Here, a series of benzisoselenazolones and diselenides were tested for their ability to inhibit Mpro; then the most potent compounds were measured for antiviral activity in vitro, and the mechanism of action was investigated. Density functional theory calculations, molecular docking and molecular dynamics simulations were also used to elucidate the protein/drug interaction. Finally, a bio-organic model was established to study the reaction between selenorganic compounds and biologically relevant thiols to unveil possible metabolic pathways of such compounds. The overall results contribute to the identification of a series of novel Se-containing molecules active against SARS-CoV-2 and to the clarification of some important aspects in the mechanisms of action of such inhibitors targeting SARS-CoV-2 Mpro.

• Zeppilli, Davide; Aldinio-Colbachini, Anna; Ribaudo, Giovanni; Tubaro, Cristina; Tiezza, Marco Dalla & Bortoli, Marco [Show all 8 contributors for this article] (2023). Antioxidant Chimeric Molecules: Are Chemical Motifs Additive? The Case of a Selenium-Based Ligand. International Journal of Molecular Sciences. ISSN 1661-6596. 24(14). doi: 10.3390/ijms241411797. Full text in Research Archive Show summary

  We set up an in silico experiment and designed a chimeric compound integrating molecular features from different efficient ROS (Reactive Oxygen Species) scavengers, with the purpose of investigating potential relationships between molecular structure and antioxidant activity. Furthermore, a selenium centre was inserted due to its known capacity to reduce hydroperoxides, acting as a molecular mimic of glutathione peroxidase; finally, since this organoselenide is a precursor of a N-heterocyclic carbene ligand, its Au(I) carbene complex was designed and examined. A validated protocol based on DFT (Density Functional Theory) was employed to investigate the radical scavenging activity of available sites on the organoselenide precursor ((SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)), as well as on the organometallic complex ((SMD)-M06-2X/SDD (Au), 6-311+G(d,p)//ZORA-BLYP-D3(BJ)/TZ2P), considering HAT (Hydrogen Atom Transfer) and RAF (Radical Adduct Formation) regarding five different radicals. The results of this case study suggest that the antioxidant potential of chemical motifs should not be considered as an additive property when designing a chimeric compound, but rather that the relevance of a molecular topology is derived from a chemical motif combined with an opportune chemical space of the molecule. Thus, the direct contributions of single functional groups which are generally thought of as antioxidants per se do not guarantee the efficient radical scavenging potential of a molecular species.

• Bortoli, Marco; Balasso, Antonella; Carta, Giovanni; Cestaro, Maristella; Colla, Viviana & Togni, Alessandra De [Show all 31 contributors for this article] (2023). Chemical Quest: general knowledge and popular culture quizzes about the elements in a board game for the class. Chemistry Teacher International (CTI). doi: 10.1515/cti-2023-0045. Full text in Research Archive Show summary

  Chemical Quest is an innovative trivia game based on the 102 elements of the periodic table from H to No, developed collaboratively by upper secondary school and university teachers with the aim of increasing the interest of young students (age 14–18) in chemistry. As part of the project, a software version of the game was successfully played in 24 classes. ‘Challenging, sometimes difficult, highly instructive, relaxing, captivating, ….’ are some of the positive comments by students and teachers. In addition, Chemical Quest was conceived to be adaptable since the rules can be modified and the cards can be selected to match the educational objective.

• Zeppilli, Davide; Ribaudo, Giovanni; Pompermaier, Nicola; Madabeni, Andrea; Bortoli, Marco & Orian, Laura (2023). Radical Scavenging Potential of Ginkgolides and Bilobalide: Insight from Molecular Modeling. Antioxidants. 12(2), p. 525–525. doi: 10.3390/antiox12020525. Full text in Research Archive Show summary

  The reactive oxygen species (ROS) scavenging capacities of ginkgolides and bilobalide, which are the peculiar constituents of the extract of Ginkgo biloba, are investigated in silico (level of theory: (SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)). Unlike other popular antioxidant natural substances, the carbon backbones of these compounds are entirely aliphatic and exclusively single C–C bonds are present. The selectivity for alkoxyl radicals via hydrogen-atom transfer (HAT) is assessed; importantly, the scavenging of peroxyl radicals is also possible from a peculiar site, here labeled C10 both for ginkgolides and bilobalide. The energetics are described in detail, and the analysis discloses that the studied compounds are powerful scavengers, with thermodynamic and kinetic properties similar to those of Trolox and melatonin, and that, in addition, they display selectivity for peroxyl radicals. These are all chemical-reactivity features contributing to the therapeutic action of the extract of G. biloba.

• Ribaudo, Giovanni; Zeppilli, Davide; Ongaro, Alberto; Bortoli, Marco; Zagotto, Giuseppe & Orian, Laura (2023). Synthesis of Selenium-Based Small Molecules Inspired by CNS-Targeting Psychotropic Drugs and Mediators. Chemistry. 5(3), p. 1488–1496. doi: 10.3390/chemistry5030101. Full text in Research Archive Show summary

  Due to its endogenously high oxygen consumption, the central nervous system (CNS) is vulnerable to oxidative stress conditions. Notably, the activity of several CNS-targeting compounds, such as antidepressant and hypnotic drugs, or endogenous mediators, such as melatonin, is indeed linked to their ability of mitigating oxidative stress. In this work, we report the synthesis of two organoselenium compounds of which the structure was inspired by CNS-targeting psychotropic drugs (zolpidem and fluoxetine) and an endogenous mediator (melatonin). The molecules were designed with the aim of combining the ROS-scavenging properties, which were already assessed for the parent compounds, with a secondary antioxidant action, a glutathione peroxidase (GPx) mimic role empowered by the presence of selenium. The compounds were obtained through a facile three-step synthesis and were predicted by computational tools to passively permeate through the blood–brain barrier and to efficiently bind to the GABA A receptor, the macromolecular target of zolpidem. Of note, the designed synthetic pathway enables the production of several other derivatives through minor modifications of the scheme, paving the way for structure–activity relationship studies.

• Bortoli, Marco & Orian, Laura (2023). Antioxidant Potential of Anthocyanidins: A Healthy Computational Activity for High School and Undergraduate Students. Journal of Chemical Education. ISSN 0021-9584. 100(7), p. 2591–2600. doi: 10.1021/acs.jchemed.2c01070. Full text in Research Archive Show summary

  Molecules and Computer: Chemistry Calculations in Class (MC4) is a computational laboratory intended for final-year high school or undergraduate students. The topic is the antioxidant potential of anthocyanidins, which is chemically related to their radical scavenging action via the mechanism of hydrogen atom transfer (HAT). This laboratory combines (bio)chemical and nutraceutical concepts with organic chemical reactions involving radical species. It allows students to apply important physicochemical (thermodynamic) concepts, such as Gibbs free energy of reaction and solvation. Finally, the procedure can easily be tailored to the resources at hand as well as the knowledge of the students. In fact, when computing facilities are not available, the whole set of molecular structures and energy data are provided as well as a simple datasheet required for their analysis. Alternatively, the whole protocol and useful scripts are provided so that students can generate their own results by experiencing the approach to computational chemistry.

• Nogara, Pablo A.; Oliveira, Cláudia S.; Madabeni, Andrea; Bortoli, Marco; Rocha, João Batista T. & Orian, Laura (2023). Thiol modifier effects of diphenyl diselenides: insight from experiment and DFT calculations. New Journal of Chemistry. ISSN 1144-0546. doi: 10.1039/d2nj05976b. Full text in Research Archive Show summary

  A combination of spectroscopic, chromatographic and computational approaches was employed to investigate the reaction of several diselenides with a thiolate nucleophile, leading to the breaking of the selenium–selenium (Se–Se) bond.

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• Eliasson, Sondre Hilmar Hopen; Giovanetti, Marinella de; Bore, Sigbjørn Løland; Bortoli, Marco; Cascella, Michele & Eisenstein, Odile (2023). Machine Learned Potential for Organolithium in THF. Full text in Research Archive
• Eliasson, Sondre Hilmar Hopen; Giovanetti, Marinella de; Bore, Sigbjørn Løland; Bortoli, Marco & Cascella, Michele (2023). Machine Learned Potential for Organolithium Compounds in THF. Full text in Research Archive

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