Sulfoxide Product Research Articles

Sulfoxidation inside a C3-Vanadium(V) Bowl-Shaped Catalyst

A confined enantiopure oxido-vanadium complex SSS-RRR-1 was synthesized and tested as catalyst for the oxidation of sulfides into sulfoxides. This catalyst is very efficient with a reaction rate more than 300 times higher than the model compound SSS-RRR-3, and a turnover number (TON) close to 10^5 was reached combined with a good selectivity (more than 90%) in the sulfoxide product. Moreover, enantiomerically enriched sulfoxide can be obtained, breaking through the major limitation of the previous chiral vanatrane catalysts that show no detectable enantiomeric excess (ee). Further investigations revealed that the complex SSS-RRR-1 adopts a bowl-shaped structure with an open hydrophobic pocket. The microenvironment of the chiral pocket above the metal center accounts for the strong improvement in catalytic activity and enantioselectivity.

Selective Synthesis of Substituted 3-Aryl-2-phenyl-1,3-thiazolidin-4-one Sulfoxides and Sulfones by S-Oxidation with Oxone

S-oxidation of 3-aryl-2-phenyl-1,3-thiazolidin-4-ones with Oxone® was investigated. For all compounds evaluated, selective oxidation to the sulfoxide was realized using 3 equivalents of Oxone® at room temperature. Alternatively, the sulfone was prepared selectively in most of the compounds evaluated at high temperature by increasing the equivalents of Oxone® used; the extent of this selectivity was affected by the substituent and its position on the N3 aromatic ring. The ratio of the sulfoxide and sulfone products was quantified by isolating the products by liquid chromatography.

Sulfoxide Synthase versus Cysteine Dioxygenase Reactivity in a Nonheme Iron Enzyme

The sulfoxide synthase EgtB represents a unique family of nonheme iron enzymes that catalyze the formation of a C-S bond between N-α-trimethyl histidine and γ-glutamyl cysteine, which is the key step in the biosynthesis of ergothioneine, an important amino acid related to aging. A controversy has arisen regarding its catalytic mechanism related to the function of the active-site Tyr377 residue. The biosynthesis of ergothioneine in EgtB shows structural similarities to cysteine dioxygenase which transfers two oxygen atoms to the thiolate group of cysteine. The question, therefore, is how do EgtB enzymes catalyze the C-S bond-formation reaction, while also preventing a dioxygenation of its cysteinate substrate? In this work we present a quantum mechanics/molecular mechanics study into the mechanism of sulfoxide synthase enzymes as compared to cysteine dioxygenase enzymes and present pathways for both reaction channels in EgtB. We show that EgtB contains a conserved tyrosine residue that reacts via proton-coupled electron transfer with the iron(III)-superoxo species and creates an iron(III)-hydroperoxo intermediate, thereby preventing the possible thiolate dioxygenation side reaction. The nucleophilic C-S bond-formation step happens subsequently concomitant to relay of the proton of the iron(II)-hydroperoxo back to Tyr377. This is the rate-determining step in the reaction cycle and is followed by hydrogen-atom transfer from the CE1-H group of trimethyl histidine substrate to iron(II)-superoxo. In the final step, a quick and almost barrierless sulfoxidation leads to the sulfoxide product complexes. The work highlights a unique machinery and active-site setup of the enzyme that drives the sulfoxide synthase reaction.

Oxidation of β-lactam antibiotics by peracetic acid: Reaction kinetics, product and pathway evaluation

Peracetic acid (PAA) is a disinfection oxidant used in many industries including wastewater treatment. β-Lactams, a group of widely prescribed antibiotics, are frequently detected in wastewater effluents and surface waters. The reaction kinetics and transformation of seven β-lactams (cefalexin (CFX), cefadroxil (CFR), cefapirin (CFP), cephalothin (CFT), ampicillin (AMP), amoxicillin (AMX) and penicillin G (PG)) toward PAA were investigated to elucidate the behavior of β-lactams during PAA oxidation processes. The reaction follows second-order kinetics and is much faster at pH 5 and 7 than at pH 9 due to speciation of PAA. Reactivity to PAA follows the order of CFR ∼ CFX > AMP ∼ AMX > CFT ∼ CFP ∼ PG and is related to β-lactam's nucleophilicity. The thioether sulfur of β-lactams is attacked by PAA to generate sulfoxide products. Presence of the phenylglycinyl amino group on β-lactams can significantly influence electron distribution and the highest occupied molecular orbital (HOMO) location and energy in ways that enhance the reactivity to PAA. Reaction rate constants obtained in clean water matrix can be used to accurately model the decay of β-lactams by PAA in surface water matrix and only slightly overestimate the decay in wastewater matrix. Results of this study indicate that the oxidative transformation of β-lactams by PAA can be expected under appropriate wastewater treatment conditions.

262 - Potential Involvement of Peroxymonocarbonate and SOD in the Oxidation of the Anticancer Drug Metabolite, 6-Mercaptopurine

Introduction 6-mercaptopurine (6MP), an immunosuppressive and cytotoxic metabolite of azathioprine, is used therapeutically in the treatment of many inflammatory and immunological diseases. 6MP is known to undergo metabolism through oxidation by xanthine oxidase, S-methylation via thiopurine methyltransferase, and can be metabolized to form 6-thioguanine, which is believed to be the active metabolite. At sites of inflammation, reactive oxygen species (ROS) are generated, including H2O2 that inactivates superoxide dismutase. In the presence of HCO3-, peroxymonocarbonate (HCO4–) can potentially be produced, which enhances the oxidation potential of H2O2. H2O2 can also produce CO3●– through SOD peroxidase activity. Thiols have been shown to be oxidized by HCO4– or CO3●– but no studies have investigated the effect on 6MP. Hypothesis HCO4– and CO3●– will oxidize 6-mercaptopurine at the sulfur atom, and SOD peroxidase activity will act as a catalyst. Methods and Results UV-Vis spectrometry was used at room temperature to monitor the spectral changes (200 – 500 nm) using 20 µM 6MP and other purine analogs including its parent drug, azathioprine, and related metabolites including 6-methyl-MP, 6-thioguanine, 6-thioxanthine, and 6-thiouric acid. Reactions were run in 0.1 M KPO4 buffer pH 7.4 containing 250 µM DTPA, and were initiated by the addition of 25 mM HCO3– and 1 mM H2O2. The most prominent changes were observed with 6MP and 6-thioguanine; less changes were observed with 6-thioxanthine and 6-thiouric acid. Oxidation of 6MP by H2O2 was observed in the absence of HCO3– but was significantly enhanced using 12.5 and 25 mM HCO3–. The reactions were analyzed by high resolution LC/MS and were compared with reactions that contained SOD to catalyze SOD peroxidase activity. 6MP was detected at its expected m/z (151.0086, C5H4N4S) and the major product peak found corresponded to an m/z of 182.9981 (C5H4N4O2S), representing a sulfoxide product. SOD inclusion in these reactions produced the same products but with only 30 min incubation time vs. 24 h without SOD. The reaction of CO3●– with 6-MP was confirmed by EPR and spectrometric measurements. SOD activity was significantly enhanced by 6-MP but not azathioprine and the CO3●– radicals were scavenged by only 6-MP. 6MP was oxidized by H2O2/HCO3– and treated with HEK293 and HepG2 cells. 6MP-sulfoxide was significantly less cytotoxicity to both cell lines compared to unadulterated 6MP. Conclusions Exposure of 6MP to H2O2/HCO3– with and without SOD significantly enhanced its oxidation, and led to the formation of a 6MP-sulfoxide, which loses its cytotoxic activity and consequently ameliorates SOD activity.

30 - Kinetics and Selectivity of Strained Cycloalkyne-Based Probes with Sulfenic Acids

Protein sulfenic acids are highly reactive intermediates in disulfide formation by biologically relevant reactive oxygen species. Sulfenic acid formation initiates signaling cascades that modulate the function of enzymes and transcription factors. Identifying the site, timing, and conditions of protein sulfenic acid formation remains crucial to understanding cellular redox regulation. Current methods for trapping and analyzing sulfenic acids involve the use of dimedone and other nucleophilic 1, 3-dicarbonyl probes that form covalent adducts with cysteine-derived protein sulfenic acids. As a mechanistic alternative, strained cycloalkynes function effectively as concerted traps of sulfenic acids. We have previously reported that the highly strained bicyclo[6.1.0]nonyne (BCN) reacts with sulfenic acids in proteins and small molecules yielding stable alkenyl sulfoxide products at rates more than 100x greater than 1, 3-dicarbonyl reagents. To better define this class of sulfenic acid traps, we report the reaction kinetics of several commercial and synthetic cycloalkynes, using Fries Acid as a model sulfenic acid, and compare these results to computational models. Further experiments explore the selectivity of these cycloalkynes for sulfenic acids, especially compared to thiols, as well as the ability of these reagents to react with model sulfenamides. The high selectivity and enhanced rate demonstrated by strained alkynes identify them as an emerging class of bioorthogonal probes that complement existing methods for the discovery of sulfenic acid sites and their parent proteins.

Oxidation of cefazolin by potassium permanganate: Transformation products and plausible pathways

Cefazolin was demonstrated to exert high reactivity toward permanganate (Mn(VII)), a common oxidant in water pre-oxidation treatment. In this study, five transformation products were found to be classified into three categories according to the contained characteristic functional groups: three (di-)sulfoxide products, one sulfone product and one di-ketone product. Products analyses showed that two kinds of reactions including oxidation of thioether and the cleavage of unsaturated CC double bond occurred during transformation of cefazolin by Mn(VII). Subsequently, the plausible transformation pathways under different pH conditions were proposed based on the identified products and chemical reaction principles. More importantly, the simulation with real surface water matrix indicated that the proposed transformation pathways of cefazolin could be replayed in real water treatment practices.

Palladium-Catalyzed Arylation of Alkyl Sulfenate Anions.

A unique palladium-catalyzed arylation of alkyl sulfenate anions is introduced that affords aryl alkyl sulfoxides in high yields. Due to the base sensitivity of the starting sulfoxides, sulfenate anion intermediates, and alkyl aryl sulfoxide products, the use of a mild method to generate alkyl sulfenate anions was crucial to the success of this process. Thus, a fluoride triggered elimination strategy was employed with alkyl 2-(trimethylsilyl)ethyl sulfoxides to liberate the requisite alkyl sulfenate anion intermediates. In the presence of palladium catalysts with bulky monodentate phosphines (SPhos and Cy-CarPhos) and aryl bromides or chlorides, alkyl sulfenate anions were readily arylated. Moreover, the thermal fragmentation and the base promoted elimination of alkyl sulfoxides was overridden. The alkyl sulfenate anion arylation exhibited excellent chemoselectivity in the presence of functional groups, such as anilines and phenols, which are also known to undergo palladium catalyzed arylation reactions.

Oxygen-atom transfer reactivity of axially ligated Mn(V)-oxo complexes: evidence for enhanced electrophilic and nucleophilic pathways.

Addition of anionic donors to the manganese(V)–oxo corrolazine complex MnV(O)(TBP8Cz) has a dramatic influence on oxygen-atom transfer (OAT) reactivity with thioether substrates. The six-coordinate anionic [MnV(O)(TBP8Cz)(X)]− complexes (X = F–, N3–, OCN–) exhibit a ∼5 cm–1 downshift of the Mn–O vibrational mode relative to the parent MnV(O)(TBP8Cz) complex as seen by resonance Raman spectroscopy. Product analysis shows that the oxidation of thioether substrates gives sulfoxide product, consistent with single OAT. A wide range of OAT reactivity is seen for the different axial ligands, with the following trend determined from a comparison of their second-order rate constants for sulfoxidation: five-coordinate ≈ thiocyanate ≈ nitrate < cyanate < azide < fluoride ≪ cyanide. This trend correlates with DFT calculations on the binding of the axial donors to the parent MnV(O)(TBP8Cz) complex. A Hammett study was performed with p-X-C6H4SCH3 derivatives and [MnV(O)(TBP8Cz)(X)]− (X = CN– or F–) as the oxidant, and unusual “V-shaped” Hammett plots were obtained. These results are rationalized based upon a change in mechanism that hinges on the ability of the [MnV(O)(TBP8Cz)(X)]− complexes to function as either an electrophilic or weak nucleophilic oxidant depending upon the nature of the para-X substituents. For comparison, the one-electron-oxidized cationic MnV(O)(TBP8Cz•+) complex yielded a linear Hammett relationship for all substrates (ρ = −1.40), consistent with a straightforward electrophilic mechanism. This study provides new, fundamental insights regarding the influence of axial donors on high-valent MnV(O) porphyrinoid complexes.

Structural and Compositional Effect of Heteropolyoxoanions [NiMo&lt;sub&gt;6-x&lt;/sub&gt; W&lt;sub&gt;x&lt;/sub&gt;O&lt;sub&gt;24&lt;/sub&gt;H&lt;sub&gt;6&lt;/sub&gt;]&lt;sup&gt;4-&lt;/sup&gt; on the Catalytic Activity of Clean Selective Oxidation of Diphenylsulfide

Diphenyilsulfide oxidation by H2O2 as oxidant was studied through the structural effect of the isomorphous W-Mo systems, Anderson type, with [Ni(II)Mo(VI)6-xW(VI)xO24H6]4- composition. These phases were proved as alternative catalysts instead of W and Mo conventional systems. The characterization of the substituted phases was carried out by different physico-chemical techniques (AAS, DRS, micro-Raman, XRD, TPR). The catalytic evaluation for the phase NiW6 revealed that the process was selective to the sulfone formation (selectivity ~ 81-88 %) while the Ni-Mo bi-metallic system (NiMo6) was only selective to the sulfoxide production (selectivity 98 %). The activity was 90 % at 60 and 180 min for the NiMo6 and NiW6 respectively, whereas the substituted phases presented intermediate values. The observed differences can be related to the strength of the bridge bonds (Mo-O…Ni and W-O…Ni) associated to the higher electronegativity and ionic potential of Mo with respect to W. Hence, the W-O bond is more reactive by the inductive effect of Ni, which produces a higher oxidation of diphenyilsulfide to give sulfone, considering the electronic mobility in the redox processes. Keywords: Clean oxidation, Diphenylsulfone, Diphenylsulfoxide, Hydrogen peroxide, Selective oxidation, W and Mo heteropolymetalates.

Biotechnological production of chiral organic sulfoxides: current state and perspectives.

Chiral organic sulfoxides (COSs) are important compounds that act as chiral auxiliaries in numerous asymmetric reactions and as intermediates in chiral drug synthesis. In addition to their optical resolution, stereoselective oxidation of sulfides can be used for COS production. This reaction is facilitated by oxygenases and peroxidases from various microbial resources. To meet the current demand for esomeprazole, a proton pump inhibitor used in the treatment of gastric-acid-related disorders, and the (S)-isomer of an organic sulfoxide compound, omeprazole, a successful biotechnological production method using a Baeyer-Villiger monooxygenase (BVMO), was developed. In this review, we summarize the recent advancements in COS production using biocatalysts, including enzyme identification, protein engineering, and process development.

Maintenance of glutathione levels and its importance in epigenetic regulation.

Maintenance of glutathione levels and its importance in epigenetic regulation.

Strained Cycloalkynes as New Protein Sulfenic Acid Traps

Protein sulfenic acids are formed by the reaction of biologically relevant reactive oxygen species with protein thiols. Sulfenic acid formation modulates the function of enzymes and transcription factors either directly or through the subsequent formation of protein disulfide bonds. Identifying the site, timing, and conditions of protein sulfenic acid formation remains crucial to understanding cellular redox regulation. Current methods for trapping and analyzing sulfenic acids involve the use of dimedone and other nucleophilic 1,3-dicarbonyl probes that form covalent adducts with cysteine-derived protein sulfenic acids. As a mechanistic alternative, the present study describes highly strained bicyclo[6.1.0]nonyne (BCN) derivatives as concerted traps of sulfenic acids. These strained cycloalkynes react efficiently with sulfenic acids in proteins and small molecules yielding stable alkenyl sulfoxide products at rates more than 100× greater than 1,3-dicarbonyl reagents enabling kinetic competition with physiological sulfur chemistry. Similar to the 1,3-dicarbonyl reagents, the BCN compounds distinguish the sulfenic acid oxoform from the thiol, disulfide, sulfinic acid, and S-nitrosated forms of cysteine while displaying an acceptable cell toxicity profile. The enhanced rates demonstrated by these strained alkynes identify them as new bioorthogonal probes that should facilitate the discovery of previously unknown sulfenic acid sites and their parent proteins.

The catalytic efficiency of Fe-porphyrins supported on multi-walled carbon nanotubes in the heterogeneous oxidation of hydrocarbons and sulfides in water

Novel recoverable biomimetic catalysts were prepared by the coordinative anchoring of an iron(III) meso-tetraphenyl porphyrin complex [Fe(TPP)Cl] and some derivatives on the activated multi-walled carbon nanotube (AMWCNT) via hydroxyl functionality (Fe-Por–AMWCNT). The simple heterogeneous catalyst [Fe(TPP)Cl–MWCNT] was characterized by powder X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), Raman, FT-IR and UV–vis spectroscopy. The amount of catalyst loading on the nanotubes, was determined by inductively coupled plasma atomic emission spectroscopy (ICP-AES). The thermogravimetric analysis (TGA) demonstrated that the nanocatalyst was thermally stable up to almost 400 °C, exhibiting high thermostability. The epoxidation of olefins and the oxidation of saturated hydrocarbons to the related ketones and also sulfides to the sulfones by aqueous solution of tetra-n-butylammonium peroxomonosulfate (n-Bu4NHSO5, TBAOX) were efficiently enhanced with excellent selectivity under the influence of the separable nanocatalyst with very low catalyst loading. Sulfoxides could also be selectively produced in ethanol, which makes the title methodology a good alternative for both sulfoxide and sulfone production. The separation and recycling of the catalyst and oxidant by-products were simple, effective and economical in this clean oxidation method. The FT-IR, UV–vis and leaching experiments after ten successive cycles showed that the catalyst was most strongly anchored to the MWCNT support.

Clinical Pharmacology of Axitinib

Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 that is approved in the US and several other countries for treatment of patients with advanced renal cell carcinoma after failure of one prior systemic therapy. The recommended clinical starting dose of axitinib is 5mg twice daily, taken with or without food. Dose increase (up to a maximum of 10mg twice daily) or reduction is permitted based on individual tolerability. Axitinib pharmacokinetics are dose-proportional within 1-20mg twice daily, which includes the clinical dose range. Axitinib has a short effective plasma half-life (range 2.5-6.1h), and the plasma accumulation of axitinib is in agreement with what is expected based on the plasma half-life of the drug. Axitinib is absorbed relatively rapidly, reaching maximum observed plasma concentrations (C max) within 4h of oral administration. The mean absolute bioavailability of axitinib is 58%. Axitinib is highly (>99%) bound to human plasma proteins with preferential binding to albumin and moderate binding to α1-acid glycoprotein. In patients with advanced renal cell carcinoma, at the 5-mg twice-daily dose in the fed state, the geometric mean (% coefficient of variation) C max and area under the plasma concentration-time curve (AUC) from time 0-24h (AUC24) were 27.8ng/mL (79%) and 265ng·h/mL (77%), respectively. Axitinib is metabolized primarily in the liver by cytochrome P450 (CYP) 3A4/5 and, to a lesser extent (<10% each), by CYP1A2, CYP2C19, and uridine diphosphate glucuronosyltransferase (UGT) 1A1. The two major human plasma metabolites, M12 (sulfoxide product) and M7 (glucuronide product), are considered pharmacologically inactive. Axitinib is eliminated via hepatobiliary excretion with negligible urinary excretion. Although mild hepatic impairment does not affect axitinib plasma exposures compared with subjects with normal hepatic function, there was a 2-fold increase in AUC from time zero to infinity (AUC∞) following a single 5-mg dose in subjects with moderate hepatic impairment. In the presence of ketoconazole, a strong CYP3A4/5 inhibitor, axitinib C max and AUC∞ increased by 1.5- and 2-fold, respectively, whereas co-administration of rifampin, a strong CYP3A4/5 inducer, resulted in a 71 and 79% decrease in the C max and AUC∞, respectively. Axitinib does not inhibit CYP3A4/5, CYP1A2, CYP2C8, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or UGT1A1 at concentrations obtained with the clinical doses and is not expected to have major interactions with drugs that are metabolized by these enzymes. Axitinib is an inhibitor of the efflux transporter P-glycoprotein (P-gp) in vitro, but is not expected to inhibit P-gp at therapeutic plasma concentrations. A two-compartment population pharmacokinetic model with first-order absorption and lag time was used to describe axitinib pharmacokinetics. No clinically relevant effects of age, sex, body weight, race, renal function, UGT1A1 genotype, or CYP2C19 inferred phenotype on the clearance of axitinib were identified.

Implications of active site orientation in myoglobin for direct electron transfer and electrocatalysis based on monolayer and multilayer covalent immobilization on gold electrodes

Cyclic voltammetry (CV) and atomic force microscopy (AFM) were used to investigate the importance of active site orientation of an immobilized protein for direct electron transfer (DET) and electrocatalysis. While the bioconjugated wild-type myoglobin (WT Mb) was immobilized on the modified gold electrode surface in a random multilayered fashion, the Ser3 replaced with unnatural amino acid, 3-amino-l-tyrosine, (NH2Tyr) mutant Mb was immobilized via a Diels–Alder reaction specific to NH2Tyr residue to form a homogeneous monolayer. Electrochemical calculations for the number of surface exposed redox-active molecules on the electrode surface (Γ) and heterogeneous rate constant for DET were 1.29×10−10molcm−2; 2.3s−1 for the WT Mb and 1.54×10−10molcm−2; 1.3s−1 for the S3NH2Tyr Mb mutant, respectively. Electro-catalytic conversion of thioanisole to sulfoxide products showed similar turnover frequencies (TOF) around 1.9×103s−1 (with 87% conversion) for the WT Mb, and 1.5×103s−1 for the mutant S3NH2Tyr Mb (with 81% conversion). These results indicate that site-directed single monolayer immobilization affords almost the same number of surface exposed Mb active sites as the random multilayer immobilization strategy, though the latter contains a greater number of protein molecules on the electrode surface, as observed from the AFM data.

Mechanism for the reactions of sulfides and sulfoxides with hypochlorites: racemization and oxygen exchange of oxysulfonium salts and sulfoxides

Density functional theory computations have been performed on the oxidations of sulfides and sulfoxides with hypochlorite ion (OCl−), hypochlorous acid, and alkyl hypochlorites to study the mechanism of the reactions. The OCl− anion transforms sulfides to sulfoxides and sulfoxides to sulfones in oxygen transfers. The oxygen atom of QOCl hypochlorites (Q = H, Me, t‐Bu) attacks at the sulfur atom of the substrates, and oxysulfonium cation intermediates are formed; the departure of the leaving Cl− is catalyzed by soft Lewis acids. The structures of the early transition states are determined by highest occupied molecular orbital–lowest unoccupied molecular orbital interactions. The sulfur compounds are the electron acceptors in the reaction with OCl−, but they are the electron donors in the reactions with QOCl. The attack of Cl− at the oxygen atom of oxysulfonium cation intermediates leads to the sulfide and QOCl precursors and can result in racemization, oxygen exchange, and reduction of oxysulfonium salts in reversible reactions. The attack of Cl− at the sulfur atom of oxysulfonium salts produces λ4‐sulfane intermediates. Oxysulfonium cations can be transformed into sulfoxide products with the attack of Cl− or water at the α‐carbon atom of the O‐alkyl group. The attack of water at the sulfur atom of oxysulfonium cation leads to hydrolysis or oxygen exchange reactions. Racemization and oxygen exchange of sulfoxides proceeds in similar reactions, through the formation of hydroxysulfonium cation intermediates in acidic media in the presence of Cl−. Chlorosulfonium cations are of very high energy; their intermediacy can be ruled out in the reactions of sulfides with hypochlorites. Copyright © 2012 John Wiley &amp; Sons, Ltd.

Commentary on: a review on delayed toxic effects of sulfur mustard in Iranian veterans

Dear Editor-in-Chief I read with interest the recent nice article published by Dr Razavi titled “A review on delayed toxic effects of sulfur mustard in Iranian veterans” [1]. Sulfur mustards (SM), commonly known as mustard gas are alkylating agents capable of causing short and long term morbidity [2]. The author stated in Table three that ophthalmic complications in Khateri et al. studies are 93.3% but there is a typesetting problem over there and the correct number is 39.3% [3]. The eyes are the most sensitive organ to SM exposure. Nearly 90% of eye injuries after SM exposure may cause later some kind of ocular disorders [4]. Also, in the paper of Razavi et al. [1], they have highlighted that SM can remain in the battlefields (for example beside the moats in World War I) and can be found in the amount of 1–25 mg/m3 in 6–12 inch depth of the soil. In moderate temperatures with mild winds, SM can remain stable for more than a week but some forms of SM can be stored in the soil for up to 10 years [1]. Natural degradation of SM in soil is a result of chemical hydrolysis and biodegradation. The major product of chemical hydrolysis is thiodiglycol. Chemical hydrolysis of SM and its chlorine derivatives in soil depends on soil type and moisture content, degree of contamination, and temperature. If the moisture content of soil is lower than 50% of its moisture capacity, then chemical hydrolysis in soil does not occur [5]. With higher temperatures and moisture content, the extent of hydrolysis of SM increases, but never to 100% completion. The SM is known to degrade faster in alkaline soils. If SM droplets are considerably below the soil surface, then SM can persist for several years [6,7]. The process of biodegradation of thiodiglycol is still longer [8]. Elimination, hydrolysis and sulfoxide products were also detected in extracts of soil samples from the Iran–Iraq war [9]. SM can be absorbed following inhalation [10] and dermal [10,11] exposure from air and soil. Therefore, although SM is a very reactive substance which hydrolyzing rapidly on contact with water, it may persist in the environment for many years, even decades, longer than expected [12]. Considering all the above facts, the correct assessment of the amount of agent in the air, in nearby water, on equipment, and on the ground (substrates such as soil, grass, concrete and asphalt) is critical to making correct decisions about the need for decontamination. Therefore, testing methods that detect both the SM and its degradation products, some of which may be toxic, since the war zones in our country now are major tourist areas where every year a large number of people travel there, are essential. Again, I would like to thank authors for collecting those valuable data using mostly domestic data and writhing such a nice review.

Self sensitized photooxidation of N-methyl phenothiazine: acidity control of the competition between electron and energy transfer mechanisms

The reaction pathways following electronic excitation of 10-methyl phenothiazine (MPS) in the presence of oxygen have been investigated as a contribution to establish the mechanisms involved in the phototoxic reactions related to phenothiazine drugs. In the context of previously published results, the pathways of oxidation via the radical cation and/or by reactive oxygen species, such as singlet oxygen and superoxide anion, are of particular interest. The effects of polarity of the medium as well as of proton donors on the different reaction pathways, in particular on the formation of reactive oxygen species and the intermediates of the oxidation of 10-methyl phenothiazine, have been investigated. No reaction was observed in non-polar solvents. In polar solvents, both self-sensitized and sensitized singlet oxygen generation lead to the oxidation of MPS and the production of 10-methyl phenothiazine sulfoxide (MPSO) most probably via a zwitterionic persulfoxide. During self-sensitized photooxidation of MPS in the presence of proton donors, such as carboxylic acids, the zwitterionic intermediate is protonated to the corresponding cation that in turn facilitates the reaction with a second molecule of MPS. In the presence of strong acids however, the formation of the radical cation of MPS and of the superoxide anion, by electron transfer from the triplet excited state of MPS to molecular oxygen, competes efficiently with singlet oxygen formation. In this case, the scavenging of the superoxide anion by protons to yield its conjugated acid (hydroperoxyl radical) and the subsequent disproportionation of the latter prevents back electron transfer.

Density Functional Study on the Cytochrome-Mediated S-Oxidation: Identification of Crucial Reactive Intermediate on the Metabolic Path of Thiazolidinediones

S-Oxidation is an important cytochrome P450 (CYP450)-catalyzed reaction, and the structural and energetic details of this process can only be studied by using quantum chemical methods. Thiazolidinedione (TZD) ring metabolism involving initial S-oxidation leads to the generation of reactive metabolites (RMs) and subsequent toxicity forcing the withdrawal of the glitazone class of drugs, thus, the study of the biochemical pathway of TZD ring metabolism is a subject of interest. The S-oxidation of the TZD ring and the formation of the isocyanate intermediate (ISC) was implicated as a possible pathway; however, there are several questions still unanswered in this biochemical pathway. The current study focuses on the CYP450-mediated S-oxidation, fate of the sulfoxide product (TZDSO), ring cleavage to ISC, and formation of nucleophilic adducts. The process of S-oxidation was explored by using Cpd I (iron(IV)-oxo porphyrin, to mimic CYP450) at TZVP/6-311+G(d) basis set. The barriers were calculated after incorporating dispersion and solvent corrections. The metabolic conversion from TZDSO to ISC (studied at B3LYP/6-311++G(2df,3pd)//B3LYP/6-31+G(d)) required a novel protonated intermediate, TZDSOH(+). The effect of higher basis sets (6-311+G(d,p), aug-cc-pvqz) on this conversion was studied. TZDSOH(+) was observed to be more reactive and thermodynamically accessible than ISC, indicating that TZDSOH(+) is the actual reactive intermediate leading to toxicity of the TZD class of compounds.