The stability of <scp>oxygen‐centered</scp> radicals and its response to hydrogen bonding interactions

Korotenko, Vasilii; Zipse, Hendrik

doi:10.1002/jcc.27221

Cited by 5 publications

(3 citation statements)

References 89 publications

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“…From theoretical predictions calculated at the RO-B2PLYP-D3/G3MP2-large//B3LYP/6-31G(d) level of theory, , the N-centered radical 7 rearranges in HAT steps with Δ H 298 ‡ = +35.4 and +31.2 kJ/mol for 1,5-HAT and 1,6-HAT steps to C 5 -centered radical 8 and C 6 -centered radical 9 with reaction enthalpies Δ H rx,298 of −11.4 and −10.8 kJ/mol, respectively (see Supporting Information). Radical 10 can be produced through different HAT reactions: (a) intermolecular HAT from any N-centered or C-centered radical, (b) intramolecular from an N-centered radical ( 7 → 10 ) via 1,2-HAT NC , (c) intramolecular from C 5 radical ( 8 → 10 ) via 1,4-HAT CC , and (d) intramolecular from C 6 radical ( 9 → 10 ) via 1,5-HAT CC .…”

Section: Resultsmentioning

confidence: 99%

“…As mentioned before, different radical fragments present in systems 7 – 14 can be used to gauge the thermodynamic driving force for rearrangement reactions (see Figure 4 ). 44 − 47 , 51 In our system, going from a tosylated methylamine radical ( 7 ) to a secondary C-centered radical ( 8 and 9 ) corresponds to an exothermic reaction (Δ H predict,298 = −19.8 kJ/mol, see Supporting Information ). Additionally, rearrangement from a secondary C-centered radical to a tosylamide-substituted C-centered radical fragment such as 10 is also predicted to be exothermic (see Supporting Information ), which is in line with our experimental observation.…”

Section: Resultsmentioning

confidence: 99%

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Regioselective Rearrangement of Nitrogen- and Carbon-Centered Radical Intermediates in the Hofmann–Löffler–Freytag Reaction

Zubčić,

You,

Zott

et al. 2024

J. Phys. Chem. A

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The Hofmann−Loffler−Freytag (HLF) reaction serves as a late-stage functionalization technique for generating pyrrolidine heterocyclic ring systems. Contemporary HLF protocols utilize in situ halogenated sulfonamides as precursors in the radical-mediated rearrangement cycle. Despite its well-established reaction mechanism, experiments toward the detection of radical intermediates using EPR techniques have only recently been attempted. However, the obtained spectra lack the distinct features of the Ncentered radicals expected for the employed reactants. This paper presents phenylbutylnitrone spin-trapped C-centered and N-centered radicals, generated via light irradiation from N-halogen-tosyl-sulfonamide derivatives and detected using EPR spectroscopy. NMR spectroscopy and DFT calculations are used to explain the observed regioselectivity of the HLF reaction.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Regioselective Rearrangement of Nitrogen- and Carbon-Centered Radical Intermediates in the Hofmann–Löffler–Freytag Reaction

Zubčić,

You,

Zott

et al. 2024

J. Phys. Chem. A

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“…As part of our assessment of different aryl structures, we have found that substituting the benzodioxol with a methoxyphenol group (MM-12-1) led to an active ferroptosis inhibitor at concentrations >32.5 µM. Derivatives of phenol, which has a BDE of 365 kJ/mol, 43 such as α-tocopherol and 2,2,5,7,8-pentamethyl-6-chromanol (PMC, Fig. 1A) were described in the literature as RTAs.…”

Section: Discussionmentioning

confidence: 99%

Assessing the activity of benzodioxol, phenol and aniline derivatives as radical trapping antioxidants that inhibit ferroptosis

Schricker,

Mouzayek,

Wanninger

et al. 2024

Preprint

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A small molecule screen has identified a benzodioxol anilide as a ferroptosis inhibitor. To determine the structure-activity relationship (SAR) of this compound class, we have synthesized a library of 35 derivatives followed by testing their ability to inhibit cell death that was induced via RSL3, an inhibitor of the main ferroptosis regulator glutathione peroxidase 4 (GPX4), in the mouse embryonic fibroblast cell line Pfa-1. Choosing 12 representative structures, rescue experiments were performed following the tamoxifen-induced deletion of GPX4 in Pfa-1 cells to complement the pharmacological induction of ferroptosis with a genetic induction and the experiments were extended to the human epithelial lung adenocarcinoma cell line HCC827. To assess if the compounds act as radical trapping antioxidants (RTAs) that scavenge peroxy radicals which drive lipid peroxidation, a hallmark of ferroptotic cell death, we have used a fluorescence-enabled inhibited autoxidation (Fenix) assay. Mitochondria were identified as the site-of-action using an alkynylated benzodioxol probe together with a copper-catalyzed alkyne-azide cycloaddition (CuAAC)-based Alexa Fluor 488 imaging kit. Our SAR study has yielded insights into the substitution-dependent activity of benzodioxol, aniline and phenol groups as RTAs that inhibit ferroptosis which led to the design of MM-12-Urea as a new broadly applicable chemical probe. Since the investigated functional groups are common motifs in small molecule ligands or natural products, we highlight that it is worth testing their ability to act as RTAs to avoid a potentially compounding factor in their bioactivities.

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Redox‐Mediated Amination of Pyrogallol‐Based Polyphenols

Ashirbaev,

Brás,

Frei

et al. 2024

Chemistry A European J

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Flavonoids are known to covalently modify amyloidogenic peptides by amination reactions. The underlying coupling process between polyphenols and N‐nucleophiles is assessed by several in vitro and in silico approaches. The coupling reaction involves a sequence of oxidative dearomatization, amination, and reductive amination (ODARA) reaction steps. The C6‐regioselectivity of the product is confirmed by crystallographic analysis. Under aqueous conditions, the reaction of baicalein with lysine derivatives yields C‐N coupling as well as hydrolysis products of transient imine intermediates. The observed C‐N coupling reactions work best for flavonoids combining a pyrogallol substructure with an electron‐withdrawing group attached to the C4a‐position. Thermodynamic properties such as bond dissociation energies also highlight the key role of pyrogallol units for the antioxidant ability. Combining the computed electronic properties and in vitro antioxidant assays suggests that the studied pyrogallol‐containing flavonoids act by various radical‐scavenging mechanisms working in synergy. Multivariate analysis indicates that a small number of descriptors for transient intermediates of the ODARA process generates a model with excellent performance (r=0.93) for the prediction of cross‐coupling yields. The same model has been employed to predict novel antioxidant flavonoid‐based molecules are considered as potential covalent inhibitors, opening a new avenue to the design of therapeutically relevant anti‐amyloid compounds.

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The stability of oxygen‐centered radicals and its response to hydrogen bonding interactions

Cited by 5 publications

References 89 publications

Regioselective Rearrangement of Nitrogen- and Carbon-Centered Radical Intermediates in the Hofmann–Löffler–Freytag Reaction

Regioselective Rearrangement of Nitrogen- and Carbon-Centered Radical Intermediates in the Hofmann–Löffler–Freytag Reaction

Assessing the activity of benzodioxol, phenol and aniline derivatives as radical trapping antioxidants that inhibit ferroptosis

Redox‐Mediated Amination of Pyrogallol‐Based Polyphenols

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