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In search of semisynthetic derivatives with increased antitumor activity, we condensed sulforaphane (SFR) with rhodol, a fluorophore platform capable of modifying the intracellular trafficking and pharmacokinetics of the linked molecules. The two tested derivatives, namely MG28 and MG46, showed a far higher, as compared to SFR, cytotoxicity toward cancer cells. Apoptotic cell death was preceded by the extensive generation of DNA lesions, which were repaired relatively slowly and caused formation of micronuclei. Unlike SFR, rhodol-SFR conjugates' DNA lesions resulted from direct interactions with nuclear DNA. Overall, MG28 and MG46 exhibit a remarkable cytotoxic effect, which is the likely consequence of their direct and intense DNA damaging activity, i.e., a novel and peculiar mechanism arising from the conjugation of the parental rhodol and SFR. Considering that a wide number of clinically used drugs kill cancer cells by inducing DNA damage, MG could represent a new and promising chance in antitumor chemotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Ferryl ions (Fe(IV)) are often thought to play an important role in iron-based advanced oxidation processes (AOPs), and their presence is typically inferred through the unique pathway of methyl phenyl sulfoxide (PMSO) conversion to methyl phenyl sulfone (PMSO 2 ). Here, we first employed probe method by degrading the mixed system containing PMSO, benzoic acid (BA), nitrobenzene (NB) to analyze the steady-state concentration of Fe (IV) in the iron-based heterogeneous persulfate reaction system. In addition, studies were conducted on the direct oxidation of PMSO by different oxidants under different pH conditions, and the results showed that peroxymonosulfate (PMS), sodium hypochlorite (NaClO) and sodium periodate (PI) can directly oxidize PMSO and convert it into PMSO 2 . Furthermore, the influence of different types of iron salts and biomass on the prepared iron-biochar (Fe-BC) for the activation of persulfate on degradation of PMSO and the formation of PMSO 2 was also investigated. This study may provide new insights into the use of PMSO as a probe for the analysis of Fe(IV) in heterogeneous reaction systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sulforaphane (SFaN) is a food-derived compound with several bioactive properties, including atherosclerosis, diabetes, and obesity treatment. However, the mechanisms by which SFaN exerts its various effects are still unclear. To elucidate the mechanisms of the various effects of SFaN, we explored novel SFaN-binding proteins using SFaN beads and identified acyl protein thioesterase 2 (APT2). We also found that SFaN binds to the APT2 via C56 residue and attenuates the palmitoylation of APT2, thereby reducing plasma membrane localization of APT2. This study reveals a novel bioactivity of SFaN as a regulator of APT2 protein palmitoylation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study explores the reasons behind the variations in the enantioselectivity of the sulfoxidation of methyl phenyl sulfide by marine-derived vanadium-dependent haloperoxidases (VHPOs). Twelve new VHPOs of marine organisms were overexpressed, purified, and tested for their ability to oxidize sulfide. Most of these marine enzymes exhibited nonenantioselective behavior, underscoring the uniqueness of An VBPO from the brown seaweed Ascophyllum nodosum and Cp VBPO from the red seaweed Corallina pilulifera , which produce ( R )- and ( S )-sulfoxides, respectively. The enantioselective sulfoxidation pathway is likely due to direct oxygen transfer within the VHPO active site. This was demonstrated through molecular docking and molecular dynamics simulations, which revealed differences in the positioning of sulfide within An VBPO and Cp VBPO, thus explaining their distinct enantioselectivities. Nonenantioselective VHPOs probably follow a different oxidation pathway, initiating with sulfide oxidation to form a positively charged radical. Further insights were gained from studying the catalytic effect of VO 4 3- on H 2 O 2 -driven sulfoxidation. This research improves the understanding of VHPO-mediated sulfoxidation and aids in developing biocatalysts for sulfoxide synthesis.

A peptide-catalyzed enantioselective oxidation of sulfides to yield pharmaceutically relevant chiral sulfoxides is reported. Experimental evidence suggesting that a hydrogen bond-donating moiety must be present in the substrate to achieve high levels of enantioinduction is supported by computational modeling of transition states. These models also indicate that dual points of contact between the peptidic catalyst and substrate are likely responsible for the formation of one desired sulfoxide in 94:6 er.

Flavin-containing monooxygenase from Methylophaga sp. ( m FMO) was previously discovered to be a valuable biocatalyst used to convert small amines, such as trimethylamine, and various indoles. As FMOs are also known to act on sulfides, we explored m FMO and some mutants thereof for their ability to convert prochiral aromatic sulfides. We included a newly identified thermostable FMO obtained from the bacterium Nitrincola lacisaponensis ( Ni FMO). The FMOs were found to be active with most tested sulfides, forming chiral sulfoxides with moderate-to-high enantioselectivity. Each enzyme variant exhibited a different enantioselective behavior. This shows that small changes in the substrate binding pocket of m FMO influence selectivity, representing a tunable biocatalyst for enantioselective sulfoxidations.

Monoacylglycerol lipase (MAGL) is the key enzyme for the hydrolysis of endocannabinoid 2-arachidonoylglycerol (2-AG). The central role of MAGL in the metabolism of 2-AG makes it an attractive therapeutic target for a variety of disorders, including inflammation-induced tissue injury, pain, multiple sclerosis, and cancer. Previously, we reported LEI-515 , an aryl sulfoxide, as a peripherally restricted, covalent reversible MAGL inhibitor that reduced neuropathic pain and inflammation in preclinical models. Here, we describe the structure-activity relationship (SAR) of aryl sulfoxides as MAGL inhibitors that led to the identification of LEI-515 . Optimization of the potency of high-throughput screening (HTS) hit 1 yielded compound ±43 . However, ±43 was not metabolically stable due to its ester moiety. Replacing the ester group with α-CF 2 ketone led to the identification of compound ±73 ( LEI-515 ) as a metabolically stable MAGL inhibitor with subnanomolar potency. LEI-515 is a promising compound to harness the therapeutic potential of MAGL inhibition.

An advanced insulin synthesis is presented that utilizes one-pot/stepwise disulfide bond formation enabled by acid-activated S-protected cysteine sulfoxides in the presence of chloride anion. S-chlorocysteine generated from cysteine sulfoxides reacts with an S-protected cysteine to afford S-sulfenylsulfonium cation, which then furnishes the disulfide or reversely returns to the starting materials depending on the S-protection employed and the reaction conditions. Use of S-acetamidomethyl cysteine (Cys(Acm)) and its sulfoxide (Cys(Acm)(O)) selectively give the disulfide under weak acid conditions in the presence of MgCl 2 even if S-p-methoxybenzyl cysteine (Cys(MBzl)) and its sulfoxide (Cys(MBzl)(O)) are also present. In contrast, the S-MBzl pair yields the disulfide under more acidic conditions in the presence of a chloride anion source. These reaction conditions allowed a one-pot insulin synthesis. Additionally, lipidated insulin was prepared by a one-pot disulfide-bonding/lipidation sequence., (© 2024 Wiley-VCH GmbH.)

Myrosinase (Myr) catalyzes the hydrolysis of glucosinolates, yielding biologically active metabolites. In this study, glucoraphanin (GRA) extracted from broccoli seeds was effectively hydrolyzed using a Myr-obtained cabbage aphid ( Brevicoryne brassicae ) ( Bb Myr) to produce (R)-sulforaphane (SFN). The gene encoding Bb Myr was successfully heterologously expressed in Escherichia coli , resulting in the production of 1.6 g/L (R)-SFN, with a remarkable yield of 20.8 mg/g broccoli seeds , achieved using recombination E. coli whole-cell catalysis under optimal conditions (pH 4.5, 45 °C). Subsequently, Bb Myr underwent combinatorial simulation-driven mutagenesis, yielding a mutant, DE9 (N321D/Y426S), showing a remarkable 2.91-fold increase in the catalytic efficiency ( k cat / K M ) compared with the original enzyme. Molecular dynamics simulations demonstrated that the N321D mutation in loopA of mutant DE9 enhanced loopA stability by inducing favorable alterations in hydrogen bonds, while the Y426S mutation in loopB decreased spatial resistance. This research lays a foundation for the environmentally sustainable enzymatic (R)-SFN synthesis.

The absolute configuration and stability of two thianthrene chiral sulfoxides has been determined by means of X-ray single-crystal structure determinations. The analyses and configurations allow verification that the diastereomeric sulfoxides are stable in solution and are not interconverting, which has been suggested in some studies of sulfoxides. The two thianthrene sulfoxides have slightly different R f values, which allowed their separation using flash chromatography on silica. The spots run back-to-back, which posed a challenge for their separation. The pure, separated compounds in solution remain as separate, single spots on a Thin Layer Chromatography (TLC) plate.

Methionine sulfoxide reductase A (MsrA) has emerged as promising biocatalysts in the enantioselective kinetic resolution of racemic (rac) sulfoxides. In this study, we engineered robust MsrA variants through directed evolution, demonstrating substantial improvements of thermostability. Mechanism analysis reveals that the enhanced thermostability results from the strengthening of intracellular interactions and increase in molecular compactness. Moreover, these variants demonstrated concurrent improvements in catalytic activities, and notably, these enhancements in stability and activity collectively contributed to a significant improvement in enzyme substrate tolerance. We achieved kinetic resolution on a series of rac-sulfoxides with high enantioselectivity under initial substrate concentrations reaching up to 93.0 g/L, representing a great improvement in the aspect of the substrate concentration for biocatalytic preparation of chiral sulfoxide. Hence, the simultaneously improved thermostability, activity and substrate tolerance of MsrA represent an excellent biocatalyst for the green synthesis of optically pure sulfoxides., Competing Interests: Declaration of competing interest The authors confirm that they have no conflicts of interest with respect to the work described in this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The influence of mobile phase composition on the efficiency of enantiomer separation by achiral chromatography (ACh) was investigated. The separation was induced by the phenomenon of self-disproportionation of enantiomers (SDE) triggered by their homo and hetero-chiral interactions in an achiral environment. Typically, SDE occurs in apolar mobile phases of weak elution strength, which causes the separation time to extend and the process productivity to deteriorate. To mitigate that effect, we altered the content of a strong solvent (modifier) in the mobile phase by use of a solvent gradient in which the target enantiomer was separated in the presence of the weak solvent, whereas the unresolved mixture of enantiomers was eluted by increasing the modifier content in the mobile phase. This enabled accelerating the solute elution while preserving the separation selectivity. The approach was examined for the separation of nonracemic mixtures of two structurally different compounds that exhibited the SDE effect in ACh, i.e., metalaxyl (MX) and methyl p-tolyl sulfoxide (MTSO). The target compound of the separation was the more abundant enantiomer in the enantiomeric mixture. The process realization was preceded by the determination of the effect of the modifier content on the separation yield for enantiomeric mixtures of MX and MTSO of different enantiomeric excess (ee). In the case of MX, yield of the pure target enantiomer varied from 2 %, for the maximum concentration of the modifier, to 45 % for the minimum modifier concentration and the largest ee used in the experiments. In the case of MTSO, the yield varied from minimum 40 % to maximum 66 %. To predict the process, we employed a dynamic model, in which underlying thermodynamic dependencies were implemented., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

In this paper, the adsorption behavior of group III nitrides (B12N12, Al12N12, and Ga12N12) nanocages to sulforaphane (SF) anticancer medicine were studied by density functional theory (DFT). The adsorption energy, solvation energy, desorption time and related quantum molecular descriptors were calculated in neutral and acidic solutions. When the drugs were adsorbed to nanocages, the structure of nanocages and drugs changed after adsorption, indicating that the process was effective adsorption. The adsorption energy and solvation energy of the complexes created after adsorption were negative values, which indicated that the structure of complexes formed by adsorption were stable. According to charge decomposition analysis (CDA) and natural bonding orbitals (NBO), drugs act as charge donors and nanocages act as charge acceptors, so that the charge flows from drugs to nanocages. Thermodynamic calculations demonstrate that drugs adsorption on nanocages is a spontaneous exothermic process. The calculation of quantum molecular descriptors confirmed that drugs adsorption on nanocages increased the chemical reactivity and solubility of drugs, which facilitated its transfer in biological fluids. Both interaction region index (IRI) and topological analysis of atom in molecule (AIM) revealed Van Der Waals interaction between drugs and nanocages. Protonation studies demonstrated that acidic circumstances could improve the polarity of complexes, increase the solvation effect, and boost drugs release in target cancer cells. The results of this work indicate that X12N12(X = B, Al, Ga) nanocages can be used as the delivery vehicle of SF drug.Communicated by Ramaswamy H. Sarma.

Introduction: Twisted-leaf garlic (Allium obliquum L.) is a wild Allium species, which is traditionally used as aroma plant for culinary purposes due to its unique, garlic-like flavor. It represents an interesting candidate for domestication, breeding and cultivation., Objectives: The objective of this work was to explore and comprehensively characterize polar and semi-polar phytochemicals accumulating in leaves and bulbs of A. obliquum., Method: Plant material obtained from a multiyear field trial was analyzed using a metabolite profiling workflow based on ultra-high performance liquid chromatography-coupled electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC/ESI-QTOFMS) and two chromatographic methods. For annotation of metabolites, tandem mass spectrometry experiments were carried out and the resulting accurate-mass collision-induced dissociation (CID) mass spectra interpreted. Onion and garlic bulb extracts were used as reference samples., Results: Important metabolite classes influencing nutritional, sensory and technological properties were detected and structurally characterized including fructooligosaccharides with a degree of polymerization of 3-5, S-alk(en)ylcysteine sulfoxides and other S-substituted cysteine conjugates, flavonoids including O- and C-glycosylated flavones as well as O-glycosylated flavonols, steroidal saponins, hydroxycinnamic acid conjugates, phenylethanoids and free sphingoid bases. In addition, quantitative data for non-structural carbohydrates, S-alk(en)ylcysteine sulfoxides and flavonoids are provided., Conclusion: The compiled analytical data including CID mass spectra of more than 160 annotated metabolites provide for the first time a phytochemical inventory of A. obliquum and lay the foundation for its further use as aroma plant in food industry., (© 2023. The Author(s).)

A challenge in mimicking tyrosinase activity using model compounds is to reproduce its enantioselectivity. Good enantioselection requires rigidity and a chiral center close to the active site. In this study, the synthesis of a new chiral copper complex, [Cu 2 (mXPhI)] 4+/2+ , based on an m -xylyl-bis(imidazole)-bis(benzimidazole) ligand containing a stereocenter with a benzyl residue directly bound on the copper chelating ring, is reported. Binding experiments show that the cooperation between the two metal centers is weak, probably due to steric hindrance given by the benzyl group. The dicopper(II) complex [Cu 2 (mXPhI)] 4+ has catalytic activity in the oxidations of enantiomeric couples of chiral catechols, with an excellent discrimination capability for Dopa-OMe enantiomers and a different substrate dependence, hyperbolic or with substrate inhibition, for the L- or D- enantiomers, respectively. [Cu 2 (mXPhI)] 4+ is active in a tyrosinase-like sulfoxidation of organic sulfides. The monooxygenase reaction requires a reducing co-substrate (NH 2 OH) and yields sulfoxide with significant enantiomeric excess (e.e.). Experiments with 18 O 2 and thioanisole yielded sulfoxide with 77% incorporation of 18 O, indicating a reaction occurring mostly through direct oxygen transfer from the copper active intermediate to the sulfide. This mechanism and the presence of the chiral center of the ligand in the immediate copper coordination sphere are responsible for the good enantioselectivity observed.

Plants of the genus Allium such as chives, onions or garlic produce S-alk(en)yl cysteine sulfoxides as flavor precursors. Two major representatives are S-propenyl cysteine sulfoxide (isoalliin) and S-propyl cysteine sulfoxide (propiin), which only differ by a double bond in the C 3 side chain. The propenyl group of isoalliin is derived from the amino acid valine, but the source of the propyl group of propiin remains unclear. Here, we present an untargeted metabolomics approach in seedlings of chives (Allium schoenoprasum) to track mass features containing sulfur and/or 13 C from labeling experiments with valine- 13 C 5 guided by their isotope signatures. Our data show that propiin and related propyl-bearing metabolites incorporate carbon derived from valine- 13 C 5 , but to a much lesser extent than isoalliin and related propenyl compounds. Our findings provide new insights into the biosynthetic pathways of flavor precursors in Allium species and open new avenues for future untargeted labeling experiments., (© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Optically pure sulfoxides are noteworthy compounds that find wide applications in various industrial fields. Here, we report a methionine sulfoxide reductase B (MsrB) homologue that exhibits high enantioselectivity and broad substrate scope for the kinetic resolution of racemic ( rac ) sulfoxides. This MsrB homologue, named li MsrB, was identified from Limnohabitans sp. 103DPR2 and showed good activity together with enantioselectivity towards a series of aromatic, heteroaromatic, alkyl and thioalkyl sulfoxides. Chiral sulfoxides in the S configuration were prepared in approximately 50% yield and 92-99% enantiomeric excess through kinetic resolution at an initial substrate concentration of up to 90 mM (11.2 g L -1 ). This study presents an efficient route for the enzymatic preparation of ( S )-sulfoxides through kinetic resolution.

Sulfoxides and selenoxides oxidize thiols to disulfides while being reduced back to sulfides and selenides. While the reduction mechanism of sulfoxides to sulfides has been thoroughly explored experimentally as well as computationally, less attention has been devoted to the heavier selenoxides. In this work, we explore the reductive mechanism of dimethyl selenoxide, as an archetypal selenoxide and, for the sake of comparison, the reductive mechanism of dimethyl sulfoxide to gain insight into the role of the chalcogen on the reaction substrate. Particular attention is devoted to the key role of sulfurane and selenurane intermediates. Moreover, the capacity of these system to oxidize selenols rather than thiols, leading to the formation of selenyl sulfide bridges, is explored in silico. Notably, this analysis provides molecular insight into the role of selenocysteine in methionine sulfoxide reductase selenoenzyme. The activation strain model of chemical reactivity is employed in the studied reactions as an intuitive tool to bridge the computationally predicted effect of the chalcogen on the chalcogenoxide as well as on the chalcogenol.

The development of MS-cleavable cross-linking mass spectrometry (XL-MS) has enabled the effective capture and identification of endogenous protein-protein interactions (PPIs) and their residue contacts at the global scale without cell engineering. So far, only lysine-reactive cross-linkers have been successfully applied for proteome-wide PPI profiling. However, lysine cross-linkers alone cannot uncover the complete PPI map in cells. Previously, we have developed a maleimide-based cysteine-reactive MS-cleavable cross-linker (bismaleimide sulfoxide (BMSO)) that is effective for mapping PPIs of protein complexes to yield interaction contacts complementary to lysine-reactive reagents. While successful, the hydrolysis and limited selectivity of maleimides at physiological pH make their applications in proteome-wide XL-MS challenging. To enable global PPI mapping, we have explored an alternative cysteine-labeling chemistry and thus designed and synthesized a sulfoxide-containing MS-cleavable haloacetamide-based cross-linker, Dibromoacetamide sulfoxide (DBrASO). Our results have demonstrated that DBrASO cross-linked peptides display the same fragmentation characteristics as other sulfoxide-containing MS-cleavable cross-linkers, permitting their unambiguous identification by MS n . In combination with a newly developed two-dimensional peptide fractionation method, we have successfully performed DBrASO-based XL-MS analysis of HEK293 cell lysates and demonstrated its capability to complement lysine-reactive reagents and expand PPI coverage at the systems-level.

A chemoselective procedure for MCPBA oxidation of 26-thiodiosgenin to corresponding sulfoxides and sulfone was elaborated. An unusual equilibration of sulfoxides in solution was observed. Moreover, α-alkylation of sulfoxide and sulfone was investigated. Finally, the biological activity of obtained compounds was examined.

Sulfoxides and sulfinamides represent versatile sulfur functional groups found in ligands, chiral auxiliaries, and bioactive molecules. Canonical two-component syntheses, however, rely on substrates with a preinstalled C-S bond and impede efficient and modular access to these sulfur motifs. Herein is presented the application of an easily prepared, bench-stable sulfoxide reagent for one-pot, three-component syntheses of sulfoxides and sulfinamides. The sulfoxide reagent donates the SO unit upon the reaction with a Grignard reagent (RMgX) as a sulfenate anion (RSO - ). While subsequent trapping reactions of this key intermediate with carbon electrophiles provide sulfoxides, a range of tertiary, secondary, and primary sulfinamides can be prepared by substitution reactions with electrophilic amines. The syntheses of sulfinamide analogs of amide- and sulfonamide-containing drugs illustrate the utility of the method for the rapid preparation of medicinally relevant molecules., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Sulfoximines provide aza-analogues of sulfones, with potentially improved properties for medicinal chemistry. The sulfoximine nitrogen also provides an additional vector for the inclusion of other functionality. Here, we report improved conditions for rhodium catalyzed synthesis of sulfoximine (and sulfilimine) carbamates, especially for previously low-yielding carbamates containing π-functionality. Notably we report the preparation of propargyl sulfoximine carbamates to provide an alkyne as a potential click handle. Using Rh 2 (esp) 2 as catalyst and a DOE optimization approach provided considerably increased yields.

Natural monoterpenes and their derivatives are widely considered as effective ingredients for the design and production of new biologically active compounds with high antioxidant, antimicrobial and anti-protozoa properties. In this study, we synthesized two series of thiotherpenoids "sulfide-sulfoxide-sulfone", with different bicyclic monoterpene skeleton (bornane and pinane) structures. The effect of the obtained compounds on platelet aggregation was investigated by using the molecular docking technique. The obtained data revealed that all the synthesized compounds may act as potential inhibitors of platelet aggregation. Moreover, the studied sulfides have shown high antioxidant activity as revealed by lipid peroxidation (LPO) process inhibition in a non-cellular substrate containing animal lipids. The sulfides were able to inhibit erythrocyte oxidative hemolysis, to reduce the accumulation of secondary LPO products in cells and to prevent the oxidation of native oxyhemoglobin. Additionally, the corresponding sulfones and sulfoxides exhibited insignificant antioxidant activity. However, the sulfides were found to exhibit significant antiaggregant and anticoagulant effects. These findings suggest as well that the sulfides could serve as a leader compound for future research and possible practical applications.

The intermediate oxidation state of sulfoxides is central to the plethora of their applications in chemistry and medicine, yet it presents challenges for an efficient synthetic access, limiting the structural diversity of currently available sulfoxides. Here, we report a data-guided development of direct decarboxylative sulfinylation that enables the previously inaccessible functional group interconversion of carboxylic acids to sulfoxides in a reaction with sulfinates. Given the broad availability of carboxylic acids and the growing synthetic potential of sulfinates, the direct decarboxylative sulfinylation is poised to improve the structural diversity of synthetically accessible sulfoxides. The reaction is facilitated by a kinetically favored sulfoxide formation from the intermediate sulfinyl sulfones, despite the strong thermodynamic preference for the sulfone formation, unveiling the previously unknown and chemoselective radicalophilic sulfinyl sulfone reactivity., (© 2022 Wiley-VCH GmbH.)

Optically pure sulfoxides are noteworthy compounds applied in a wide range of industrial fields; however, the biocatalytic deracemization of racemic sulfoxides is challenging. Herein, a high-enantioselective methionine sulfoxide reductase A (MsrA) was combined with a low-enantioselective styrene monooxygenase (SMO) for the cyclic deracemization of sulfoxides. Enantiopure sulfoxides were obtained in >90 % yield and with >90 % enantiomeric excess (ee) through dynamic "selective reduction and non-selective oxidation" cycles. The cofactors of MsrA and SMO were subsequently regenerated by the cascade catalysis of three auxiliary enzymes through the consumption of low-cost D-glucose. Moreover, this "one-pot, one-step" cyclic deracemization strategy exhibited a wide substrate scope toward various aromatic, heteroaromatic, alkyl and thio-alkyl sulfoxides. This system proposed an efficient strategy for the green synthesis of chiral sulfoxide., (© 2022 Wiley-VCH GmbH.)

Conformational isomerization can be guided by weak interactions such as chalcogen bonding (ChB) interactions. Here we report a catalytic strategy for asymmetric access to chiral sulfoxides by employing conformational isomerization and chalcogen bonding interactions. The reaction involves a sulfoxide bearing two aldehyde moieties as the substrate that, according to structural analysis and DFT calculations, exists as a racemic mixture due to the presence of an intramolecular chalcogen bond. This chalcogen bond formed between aldehyde (oxygen atom) and sulfoxide (sulfur atom), induces a conformational locking effect, thus making the symmetric sulfoxide as a racemate. In the presence of N-heterocyclic carbene (NHC) as catalyst, the aldehyde moiety activated by the chalcogen bond selectively reacts with an alcohol to afford the corresponding chiral sulfoxide products with excellent optical purities. This reaction involves a dynamic kinetic resolution (DKR) process enabled by conformational locking and facile isomerization by chalcogen bonding interactions., (© 2022. The Author(s).)

We report here the use of simple and readily available alkyl sulfoxides as precursors to radicals and their application in the preparation of pyridine derivatives. We show that alkyl sulfoxides, N-methoxy pyridinium salts and fluoride anions form electron donor-acceptor (EDA) complexes in solution, which, upon visible light irradiation, undergo a radical chain process to afford various pyridine derivatives smoothly. This reaction displays broad scope with respect to both sulfoxides and N-methoxy pyridiniums. The synthetic versatility of sulfoxides as a handle in chemistry adds to their power as radical precursors. Glycosyl sulfoxides are converted to the corresponding pyridyl C-glycosides with high stereoselectivities. Computational and experimental studies provide insights into the reaction mechanism., (© 2022 Wiley-VCH GmbH.)

Sulfoxide-containing molecules are an important class of compounds in the pharmaceutical industry and many efforts have been made to develop new and green protocols, targeting the chemoselective transformation of sulfides into sulfoxides. Photochemistry is a rapidly expanding research field employing light as the energy source. Photochemical aerobic processes possess additional advantages to photochemistry and may find applications in the chemical industries. Herein, a 370 nm catalyst-free aerobic protocol was developed, using 2-Me-THF as the green solvent. At the same time, two low-catalyst-loading anthraquinone-based processes (under a CFL lamp or 427 nm irradiation) in 2-Me-THF were developed. Furthermore, a broad range of substrates was tested. We also implemented our protocols towards the synthesis of the pharmaceutical active ingredients (APIs) sulforaphane and modafinil.

The N-terminal region of the huntingtin protein, encoded by exon-1 (htt ex1 ) and containing an expanded polyglutamine tract, forms fibrils that accumulate in neuronal inclusion bodies, resulting in Huntington's disease. We previously showed that reversible formation of a sparsely populated tetramer of the N-terminal amphiphilic domain, comprising a dimer of dimers in a four-helix bundle configuration, occurs on the microsecond timescale and is an essential prerequisite for subsequent nucleation and fibril formation that takes place orders of magnitude slower on a timescale of hours. For pathogenic htt ex1 , such as htt ex1 Q 35 with 35 glutamines, NMR signals decay too rapidly to permit measurement of time-intensive exchange-based experiments. Here, we show that quantitative analysis of both the kinetics and mechanism of prenucleation tetramerization and aggregation can be obtained simultaneously from a series of 1 H- 15 N band-selective optimized flip-angle short-transient heteronuclear multiple quantum coherence (SOFAST-HMQC) correlation spectra. The equilibria and kinetics of tetramerization are derived from the time dependence of the 15 N chemical shifts and 1 H- 15 N cross-peak volume/intensity ratios, while the kinetics of irreversible fibril formation are afforded by the decay curves of 1 H- 15 N cross-peak intensities and volumes. Analysis of data on htt ex1 Q 35 over a series of concentrations ranging from 200 to 750 μM and containing variable (7 to 20%) amounts of the Met 7 O sulfoxide species, which does not tetramerize, shows that aggregation of native htt ex1 Q 35 proceeds via fourth-order primary nucleation, consistent with the critical role of prenucleation tetramerization, coupled with first-order secondary nucleation. The Met 7 O sulfoxide species does not nucleate but is still incorporated into fibrils by elongation.

Sulfoxides are actively engaged as versatile synthetic building blocks, chiral ligands, bioactive molecules, and function materials. However, their oxidative syntheses from thioethers are inevitably impeded by overoxidation, excess oxidants, and the tedious preparation of thioethers. To address these shortcomings, we report herein a highly selective electrochemical sulfoxidation reaction featuring the use of simple starting materials, i.e ., thiols and alkyl halides, in a single operation.

The concurrent operation of chemical and biocatalytic reactions in one pot is still a challenging task, and, in particular for chemical photocatalysts, examples besides simple cofactor recycling systems are rare. However, especially due to the complementary chemistry that the two fields of catalysis promote, their combination in one pot has the potential to unlock intriguing, unprecedented overall reactivities. Herein we demonstrate a concurrent biocatalytic reduction and photocatalytic oxidation process. Specifically, the enantioselective biocatalytic sulfoxide reduction using (S)-selective methionine sulfoxide reductases was coupled to an unselective light-dependent sulfoxidation. Protochlorophyllide was established as a new green photocatalyst for the sulfoxidation. Overall, a cyclic deracemization process to produce nonracemic sulfoxides was achieved and the target compounds were obtained with excellent conversions (up to 91 %) and superb optical purity (>99 % ee)., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Sulforaphane (SFN), the main ingredient in broccoli/broccoli sprouts, has a good anticancer effect in a wide variety of tumors, but whether SFN affects acute leukemia is not elucidated. Due to the self-renewal capability for leukemia stem cells, acute leukemia has a high relapse rate. This study explored the effects and related molecular mechanisms of SFN on the proliferation of leukemia stem-like cells in acute myeloid leukemia cells. We found that SFN inhibited the proliferation of leukemia stem-like cells in vitro and in vivo. Meanwhile, we observed that SFN could regulate the stem characteristic of leukemia cells. After SFN treatment, the expression of the key players in the Sonic Hedgehog (Shh) signaling pathway was significantly decreased at the transcriptional and protein levels. To further determine the contribution of the Shh signaling molecular mechanism to SFN-mediated self-renewal capability of LSCs, we then manipulated the Shh gene in the leukemia cells to either overexpress the gene using lentiviral vector transduction or knockdown the gene via siRNA. The results demonstrated that SFN suppressed proliferation in Shh-overexpressed cells more than in Shh-downregulated cells, suggesting that SFN negatively modulates proliferation of leukemia stem-like cells via affecting the Shh signaling pathway. Altogether, these results suggest that SFN is a potent anti-leukemia agent that has inhibitory effects on leukemia stem-like cells' proliferation by regulating the Shh signaling pathway., (Copyright © 2022 Elsevier B.V. All rights reserved.)

In recent years, cross-linking mass spectrometry (XL-MS) has made enormous strides as a technology for probing protein-protein interactions (PPIs) and elucidating architectures of multisubunit assemblies. To define conformational and interaction dynamics of protein complexes under different physiological conditions, various quantitative cross-linking mass spectrometry (QXL-MS) strategies based on stable isotope labeling have been developed. These QXL-MS approaches have effectively allowed comparative analysis of cross-links to determine their relative abundance changes at global scales. Although successful, it remains challenging to consistently obtain quantitative measurements on low-abundant cross-links. Therefore, targeted QXL-MS is needed to enable MS "Western" analysis of cross-links to enhance sensitivity and reliability in quantitation. To this end, we have established a robust parallel reaction monitoring (PRM)-based targeted QXL-MS platform using sulfoxide-containing MS-cleavable cross-linker disuccinimidyl sulfoxide (DSSO), permitting label-free comparative analysis of selected cross-links across multiple samples. In addition, we have applied this methodology to study phosphorylation-dependent conformational dynamics of the human 26S proteasome. The PRM-based targeted QXL-MS analytical platform described here is applicable for all sulfoxide-containing MS-cleavable cross-linkers and can be directly adopted for comparative studies of protein-protein interactions in various cellular contexts.

Sulforaphane (SFN) is an isothiocyanate (ITC) derived from a glucosinolate, glucoraphinin found in cruciferous vegetables. There are few studies that focus on the role of SFN in angiogenesis under hypoxic conditions. The effect of SFN on angiogenesis and the underlying mechanisms including the roles of Nrf2 and mitochondrial dynamics were investigated using cultured human umbilical vein endothelial cells (HUVECs) in hypoxia. SFN at low doses (1.25-5 μM) increased hypoxia-induced HUVEC migration and tube formation, and alleviated hypoxia-induced retarded proliferation, but high doses (≥10 μM) exhibited an opposite effect. Under hypoxia, the expression of Nrf2 and heme oxygenase-1 was up-regulated by SFN treatment. Nrf2 knockdown abrogated SFN (2.5 μM)-induced tube formation and further potentiated the inhibitory effect of SFN (10 μM) on angiogenesis. Meanwhile, the mitochondrial function, morphology and expression of dynamic-related proteins suggested that low-dose SFN protected against hypoxia-induced mitochondrial injury and alleviated hypoxia-induced fission Nrf2-dependently without affecting the expression of key effector proteins (Drp1, Fis1, Mfn1/2 and Opa1), while high concentrations (≥10 μM SFN) aggravated hypoxia-induced mitochondrial injury, fission and Drp1 expression, and inhibited Mfn1/2 expression. These findings suggest that SFN biphasically affected the angiogenic capacity of hypoxia challenged HUVECs potentially via mechanisms involving an integrated modulation of Nrf2 and mitochondrial dynamics.

For decades, various plants have been studied as sources of biologically active compounds. Compounds with anticancer and antimicrobial properties are the most frequently desired. Cruciferous plants, including Brussels sprouts, broccoli, and wasabi, have a special role in the research studies. Studies have shown that consumption of these plants reduce the risk of lung, breast, and prostate cancers. The high chemopreventive and anticancer potential of cruciferous plants results from the presence of a large amount of glucosinolates, which, under the influence of myrosinase, undergo an enzymatic transformation to biologically active isothiocyanates (ITCs). Natural isothiocyanates, such as benzyl isothiocyanate, phenethyl isothiocyanate, or the best-tested sulforaphane, possess anticancer activity at all stages of the carcinogenesis process, show antibacterial activity, and are used in organic synthesis. Methods of synthesis of sulforaphane, as well as its natural or synthetic bifunctional analogues with sulfinyl, sulfanyl, sulfonyl, phosphonate, phosphinate, phosphine oxide, carbonyl, ester, carboxamide, ether, or additional isothiocyanate functional groups, and with the unbranched alkyl chain containing 2-6 carbon atoms, are discussed in this review. The biological activity of these compounds are also reported. In the first section, glucosinolates, isothiocyanates, and mercapturic acids (their metabolites) are briefly characterized. Additionally, the most studied anticancer and antibacterial mechanisms of ITC actions are discussed.

Intestinal inflammation represented by inflammatory bowel disease (IBD) has become a global epidemic disease and the number of patients with IBD continues to increase. This digestive tract disease not only affects the absorption of food components by destroying the intestinal epithelial structure, but also can induce diseases in remote organs via the gut-organ axis, seriously harming human health. Nowadays, increasing attention is being paid to the nutritional and medicinal value of food components with increasing awareness among the general public regarding health. As an important member of the isothiocyanates, sulforaphane (SFN) is abundant in cruciferous plants and is famous for its excellent anti-cancer effects. With the development of clinical research, more physiological activities of SFN, such as antidepressant, hypoglycemic and anti-inflammatory activities, have been discovered, supporting the fact that SFN and SFN-rich sources have great potential to be dietary supplements that are beneficial to health. This review summarizes the characteristics of intestinal inflammation, the anti-inflammatory mechanism of SFN and its various protective effects on intestinal inflammation, and the possible future applications of SFN for promoting intestinal health have also been discussed.

In this study, we developed a novel colorimetric chemosensor for selective and sensitive recognition of Glutathione (GSH) using a simple binary mixture of commercially accessible and inexpensive metal receptors with names, Bromo Pyrogallol Red (BPR) and Xylenol Orange (XO). This procedure is based on the synergistic coordination of BPR and XO with cerium ion (Ce3+) for the recognition of GSH over other available competitive amino acids (AAs) especially thiol species in aqueous media. Generally, cysteine (Cys) and homocysteine (hCys) can seriously interfere with the detection of GSH among common biological species because they possess similar chemical behavior. Using all the information from 1HNMR and FT-IR studies, the proposed interaction is presented in which GSH acts as a tri-dentate ligand with three N donor atoms in conjunction with BPR and XO as mono and bi-dentate ligands respectively. This approach opens a path for selective detection of other AAs by argumentatively selecting the ensemble of mixed organic ligands from commercially available reagents, thereby eliminating the need for developing synthetic receptors, sample preparation, organic solvent mixtures, and expensive equipment. Evaluating the feasibility of the existing method was led to the determination of GSH in human plasma samples., (Copyright © 2021. Published by Elsevier Inc.)

Enzymatic oxidations of thiophenes, including thiophene-containing drugs, are important for biodesulfurization of crude oil and drug metabolism of mono- and poly-cyclic thiophenes. Thiophene oxidative dearomatization pathways involve reactive metabolites, whose detection is important in the pharmaceutical industry, and are catalyzed by monooxygenase (sulfoxidation, epoxidation) and dioxygenase (sulfoxidation, dihydroxylation) enzymes. Sulfoxide and epoxide metabolites of thiophene substrates are often unstable, and, while cis -dihydrodiol metabolites are more stable, significant challenges are presented by both types of metabolite. Prediction of the structure, relative and absolute configuration, and enantiopurity of chiral metabolites obtained from thiophene enzymatic oxidation depends on the substrate, type of oxygenase selected, and molecular docking results. The racemization and dimerization of sulfoxides, cis / trans epimerization of dihydrodiol metabolites, and aromatization of epoxides are all factors associated with the mono- and di-oxygenase-catalyzed metabolism of thiophenes and thiophene-containing drugs and their applications in chemoenzymatic synthesis and medicine.

Type 2 transglutaminase (TG2) functions as an important cancer cell survival protein in a range of cancers including epidermal squamous cell carcinoma. TG2 exists in open and closed conformations each of which has a distinct and mutually exclusive activity. The closed conformation has GTP-binding/GTPase activity while the open conformation functions as a transamidase to catalyze protein-protein crosslinking. GTP-binding/GTPase activity is required for TG2 maintenance of the aggressive cancer phenotype. Thus, identifying agents that convert TG2 from the closed to the open GTP-binding/GTPase inactive conformation is an important cancer prevention/treatment strategy. Sulforaphane (SFN) is an important diet-derived cancer prevention agent that is known to possess a reactive isothiocyanate group and has potent anticancer activity. Using a biotin-tagged SFN analog (Biotin-ITC) and kinetic analysis we show that SFN covalently and irreversibly binds to recombinant TG2 to inhibit transamidase activity and shift TG2 to an open/extended conformation, leading to a partial inhibition of GTP binding. We also show that incubation of cancer cells or cancer cell extract with Biotin-ITC results in formation of a TG2/Biotin-ITC complex and that SFN treatment of cancer cells inhibits TG2 transamidase activity and shifts TG2 to an open/extended conformation. These findings identify TG2 as a direct SFN anticancer target in epidermal squamous cell carcinoma., (© 2021 Wiley Periodicals LLC.)

Biaryl synthesis continues to occupy a central role in chemical synthesis. From blockbuster drug molecules to organic electronics, biaryls present numerous possibilities and new applications continue to emerge. Transition-metal-catalyzed coupling reactions represent the gold standard for biaryl synthesis and the mechanistic steps, such as reductive elimination, are well established. Developing routes that exploit alternative mechanistic scenarios could give unprecedented biaryl structures and expand the portfolio of biaryl applications. We have developed metal-free C-H/C-H couplings of aryl sulfoxides with phenols to afford 2-hydroxy-2'-sulfanylbiaryls. This cascade strategy consists of an interrupted Pummerer reaction and [3,3] sigmatropic rearrangement. Our method enables the synthesis of intriguing aromatic molecules, including oligoarenes, enantioenriched dihetero[8]helicenes, and polyfluorobiaryls. From our successes in aryl sulfoxide/phenol couplings and a deeper understanding of sigmatropic rearrangements for biaryl synthesis, we have established related methods, such as aryl sulfoxide/aniline and aryl iodane/phenol couplings. Overall, our fundamental interests in underexplored reaction mechanisms have led to various methods for accessing important biaryl architectures.

A linear polyamidoamine (PAA) named BAC-EDDS, containing metal chelating repeat units composed of two tert -amines and four carboxylic groups, has been prepared by the aza-Michael polyaddition of ethylendiaminodisuccinic (EDDS) with 2,2-bis(acrylamido)acetic acid (BAC). It was characterized by size exclusion chromatography (SEC), FTIR, UV-Vis and NMR spectroscopies. The pK a values of the ionizable groups of the repeat unit were estimated by potentiometric titration, using a purposely synthesized molecular ligand (Agly-EDDS) mimicking the structure of the BAC-EDDS repeat unit. Dynamic light scattering (DLS) and ζ-potential analyses revealed the propensity of BAC-EDDS to form stable nanoaggregates with a diameter of approximately 150 nm at pH 5 and a net negative charge at physiological pH, in line with an isoelectric point <2. BAC-EDDS stably chelated Gd (III) ions with a molar ratio of 0.5:1 Gd (III)/repeat unit. The stability constant of the molecular model Gd-Agly-EDDS (log K = 17.43) was determined as well, by simulating the potentiometric titration through the use of Hyperquad software. In order to comprehend the efficiency of Gd-BAC-EDDS in contrasting magnetic resonance images, the nuclear longitudinal ( r 1 ) and transverse ( r 2 ) relaxivities as a function of the externally applied static magnetic field were investigated and compared to the ones of commercial contrast agents. Furthermore, a model derived from the Solomon-Bloembergen-Morgan theory for the field dependence of the NMR relaxivity curves was applied and allowed us to evaluate the rotational correlation time of the complex ( τ = 0.66 ns). This relatively high value is due to the dimensions of Gd-BAC-EDDS, and the associated rotational motion causes a peak in the longitudinal relaxivity at ca. 75 MHz, which is close to the frequencies used in clinics. The good performances of Gd-BAC-EDDS as a contrast agent were also confirmed through in vitro magnetic resonance imaging experiments with a 0.2 T magnetic field.

Investigations regarding the feasibility, reliability, and accuracy of Fricke gel dosimeter layers for stereotactic radiosurgery are presented. A representative radiosurgery plan consisting of two targets has been investigated. Absorbed dose distributions measured using radiochromic films and gelatin Fricke Gel dosimetry in layers have been compared with dose distributions calculated by using a treatment planning system and Monte Carlo simulations. The different dose distributions have been compared by means of the gamma index demonstrating that gelatin Fricke gel dosimeter layers showed agreements of 100%, 100%, and 93%, with dose and distance tolerances of 2% and 2 mm, with respect to film dosimetry, treatment planning system and Monte Carlo simulations, respectively. The capability of the developed system for three-dimensional dose mapping was shown, obtaining promising results when compared with well-established dosimetry methods. The obtained results support the viability of Fricke gel dosimeter layers analyzed by optical methods for stereotactic radiosurgery., (Copyright © 2021 Elsevier Ltd. All rights reserved.)