Phenyl Vinyl Sulfone Research Articles

ROLE OF APOPTOSIS IN EXPERIMENTAL CRYPTOSPORIDIUM PARVUM INFECTED ALBINO MICE

Cryptosporidium is one of the commonest opportunistic parasites. But, its chemotherapeuticoptions are limited, with controversy about the role of apoptosis in cryptosporidiosis. Caspasesare key molecules of apoptosis. The study assessed the role of apoptosis in cryptosporidiosisby studying the relationship between the effects of phenyl vinyl sulfone (PVS), nitazoxanide(NTZ) and combined therapy on Cryptosporidium parvum infection and caspase 3immunostaining. Ninety female laboratory bred Swiss Albino mice were divided into twomajor groups; immunocompetent and immunosuppressed. Both groups were divided into thefollowing subgroups, for each one respectively: negative control (1 & 6), infected control (2& 7), infected treated with PVS (3 & 8), infected treated with NTZ (4 & 9) and infected treatedcombined (5 & 10). Sacrification were done on 18th day post infection.Histopathological study of ileum was done and endogenous developmental stages werecounted. Also, caspase 3 immunohistochemical staining was carried out on ileal sections.Combined therapy in groups 5 &10 showed the highest reduction in mean number of endogenousdevelopmental stages as in G10 (P <0.05). Caspase expression in PVS treated groups (3& 8) showed significant decrease when compared to their control groups (P < 0.05). Whilethere were significant increase in caspase expression in groups treated with NTZ (4 & 9)when compared to their contorls (P < 0.05). Caspase 3 epithelial overexpression was evidentin infected immunocompetent G2 than immunosuppressed G7 (P<0.05).

A novel LC-MS method development and validation for the determination of phenyl vinyl sulfone in eletriptan hydrobromide

BackgroundThe aim of the present method is to develop and validate a specific, sensitive, precise, and accurate liquid chromatography-mass spectrometry (LC-MS) method for the estimation of the phenyl vinyl sulfone in the eletriptan hydrobromide. The effective separation of the phenyl vinyl sulfone was achieved by the Symmetry C18 (50 × 4.6 mm, 3.5 μm) column and a mobile phase composition of 0.1%v/v ammonia buffer to methanol (5:95 v/v), using 0.45 ml/min flow rate and 20 μl of injection volume, with methanol used as diluent. The phenyl vinyl sulfone was monitored on atomic pressure chemical ionization mode mass spectrometer with positive polarity mode.ResultsThe retention time of phenyl vinyl sulfone was found at 2.13 min. The limit of detection (LOD) and limit of quantification (LOQ) were observed at 1.43 ppm and 4.77 ppm concentration respectively; the linear range was found in the concentration ranges from 4.77 to 27.00 ppm with regression coefficient of 0.9990 and accuracy in the range of 97.50–102.10%. The percentage relative standard deviation (% RSD) for six replicates said to be injections were less than 10%.ConclusionThe proposed method was validated successfully as per ICH guidelines. Hence, this is employed for the determination of phenyl vinyl sulfone in the eletriptan hydrobromide.

Synthesis, Molecular Docking, Druglikeness Analysis, and ADMET Prediction of the Chlorinated Ethanoanthracene Derivatives as Possible Antidepressant Agents

Ethanoanthracene cycloadducts (5–7) anti, (5–7) syn, and (5–7) dec have been synthesized from the Diels–Alder (DA) reaction of diene 1,8-dichloroanthracene 2, with the dienophiles; acrylonitrile 3, 1-cynavinyl acetate 4, and phenyl vinyl sulfone 5, individually. The steric effect of dienophile substituents were more favorable toward the anti-isomer formation as deduced from 1H-NMR spectrum. The cheminformatics prediction for (5–7) anti and (5–7) syn was investigated. The in silico anticipated anti-depression activity of the (5–7) anti and (5–7) syn compounds were investigated and compared to maprotiline 9 as reference anti-depressant drug. The study showed that steric interactions play a crucial role in the binding affinity of these compounds to the representative models; 4xnx, 2QJU, and 3GWU. The pharmacokinetic and drug-like properties of (5–7) anti and (5–7) syn exhibited that these compounds could be represented as potential candidates for further development into antidepressant-like agents.

Microwave-assisted regioselective synthesis of substituted-9-bromo-9,10-dihydro-9,10-ethanoanthracenes via Diels-Alder cycloaddition

The substituted-9-bromo-9,10-dihydro-9,10-ethanoanthracenes ortho8a-12a and meta8b-13b have been synthesized via Diels-Alder reaction under microwave conditions. The cycloadduct isomers ortho8a-11a and meta8b-11b, with priority to ortho8a-11a, were obtained from the reaction of 9-bromoanthracene 1 with acrylonitrile 2, 2-chloroacrylonitrile 3, methacryloyl chloride 4 and acrylic acid 5, while ortho12a and meta12b, with priority to meta12b, was obtained from the reaction of 9-bromoanthracene 1 with 1-cynao vinyl acetate 6. Interestingly, the only isomer meta13b was obtained from the reaction of 9-bromoanthracene 1 with phenyl vinyl sulfone 7. The results proved that the steric or/and electronic nature of the dienophile substituent is/are playing significant roles in the regioselectivity and isomers ratio.

Olefin‐Oriented Selective Synthesis of Linear and Branched N‐Alkylated Heterocycles by Hydroamination

An effective base‐induced selective approach for the synthesis of linear and branched N‐alkylated heterocycles by hydroamination of olefins has been described. The designed C–N bond formation method was directed through the olefin, as with styrenes only linear N‐alkylated product was obtained, and acrylates gave linear as well as branched alkylated heterocycles. This protocol provided the synthesis of exclusive N‐alkylated product instead of the C‐3 Michael addition product. The reaction was also compatible with phenyl vinyl sulfone, thus leading to the formation of sulfone substituted heterocycles in good yield. Further, the method was utilized for the synthesis of medicinally important analogs of CB1 Cannabinoid receptor and Dimebon analogue in short reaction sequence.

Characterization of the sortase A from Lactobacillus acidophilus ATCC 4356 involved in adherence to intestinal cells.

Aim: Confirmation of the enzymatic activity of Class A sortase (SrtA) in probiotic strain Lactobacillus acidophilus associated with the adhesion properties. Materials & methods: SrtA from L. acidophilus ATCC 4356 was purified and its enzymatic properties was investigated by site-directed mutagenesis approach and the sensitivity to metal ions was also detected. Results: SrtA of L. acidophilus ATCC4356 can recognize LPxTG and LPxTD sorting motifs. The active sites of SrtA include His137, Cys198 and Arg205. Furthermore, acacetin can increase the activity of SrtA, while phenyl vinyl sulfone could effectively inhibit the activity of SrtA with an IC50 of 143.32μg/ml. The adhesion ability of L. acidophilus was also decreased resulting from the inhibition of SrtA activity. Conclusion: The unique properties of SrtA of L. acidophilus can provide some insights into the development of high-adhesion Lactobacillus strains in the GI tract.

Synthesis and chromatographic evaluation of a new stationary phase based on mild thiol-Michael addition reaction

Click chemistry has attracted increasing attention for the synthesis of novel stationary phases. Considering the advantage of click chemistry, a strategy based on thiol-Michael addition was developed for the preparation of a new stationary phase herein, and a phenyl vinyl sulfone stationary phase (M-PVS) was prepared. The resulting M-PVS bonded silica was characterized by elemental analysis, solid-state 13C cross-polarization/magic-angle spinning NMR and infrared spectroscopy, confirming the successful immobilization of phenyl vinyl sulfone on the silica support. The retention properties of M-PVS were investigated and exhibited unambiguous reversed phase retention characteristics. Moreover, shape selectivity and silanol activity were studied to reveal the diverse interactions of M-PVS, including hydrophobic, π–π, hydrogen bonding, and ion-exchange interactions. In addition, de-wetting tolerance and hydrophilic properties were evaluated and a pronounced “U” retention curves were obtained, indicating enhanced retention for polar analytes and transitions of different interaction modes. Selectivity differences between M-PVS column, phenyl column and conventional C18 column were examined using series natural standards. The diverse interactions of M-PVS demonstrated its improved selectivity for the compounds with similar hydrophobic skeleton but different polar substituents.

Targeting protein tyrosine phosphatase PTP-PEST (PTPN12) for therapeutic intervention in acute myocardial infarction.

The myocardial ischaemia/reperfusion (I/R) injury is almost inevitable since reperfusion is the only established treatment for acute myocardial infarction (AMI). To date there is no effective strategy available for reducing the I/R injury. Our aim was to elucidate the mechanisms underlying myocardial I/R injury and to develop a new strategy for attenuating the damage it causes. Using a mouse model established by ligation of left anterior descending artery, we found an increase in activity of protein tyrosine phosphatases (PTPs) in myocardium during I/R. Treating the I/R-mice with a pan-PTP inhibitor phenyl vinyl sulfone attenuated I/R damage, suggesting PTP activation to be harmful in I/R. Through analysing RNAseq data, we showed PTPs being abundantly expressed in mouse myocardium. By exposing primary cardiomyocytes ablated with specific endogenous PTPs by RNAi to hypoxia/reoxygenation (H/R), we found a role that PTP-PEST (PTPN12) plays to promote cell death under H/R stress. Auranofin, a drug being used in clinical practice for treating rheumatoid arthritis, may target PTP-PEST thus suppressing its activity. We elucidated the molecular basis for Auranofin-induced inactivation of PTP-PEST by structural studies, and then examined its effect on myocardial I/R injury. In the mice receiving Auranofin before reperfusion, myocardial PTP activity was suppressed, leading to restored phosphorylation of PTP-PEST substrates, including ErbB-2 that maintains the survival signalling of the heart. In line with the inhibition of PTP-PEST activity, the Auranofin-treated I/R-mice had smaller infarct size and better cardiac function. PTP-PEST contributes to part of the damages resulting from myocardial I/R. The drug Auranofin, potentially acting through the PTP-PEST-ErbB-2 signalling axis, reduces myocardial I/R injury. Based on this finding, Auranofin could be used in the development of new treatments that manage I/R injury in patients with AMI.

Efficiency and Selectivity Aspects in the C–H Functionalization of Aliphatic Oxygen Heterocycles by Photocatalytic Hydrogen Atom Transfer

The C–H to C–C conversion in aliphatic oxygen heterocycles (dioxolanes, 1,3-dioxane, or cyclic carbonates) by photocatalytic hydrogen atom transfer and subsequent trapping of the resulting radical with phenyl vinyl sulfone was investigated. The performance of three different photocatalysts, namely tetrabutylammonium decatungstate and the aromatic ketones thioxanthone and 9-fluorenone, was compared. The UV-light-absorbing decatungstate anion is more efficient and permits the use of a smaller excess of hydrogen donor than the aromatic ketones, although the ketones could be excited by visible light. Further intramolecular selectivity studies revealed that aromatic ketones afforded a higher proportion of functionalization at the acetalic versus the ethereal positions than did the decatungstate anion.

Abstract 297: Old Drug New Tricks: Repurposing Auranofin for Acute Myocardial Infarction by Targeting Protein Tyrosine Phosphatase PTP-PEST

Rationale: Myocardial ischemia/reperfusion (I/R) injury is almost unavoidable since reperfusion is the only established treatment for acute myocardial infarction (AMI). To date there has no effective strategies available for reducing I/R injury. Objective: To elucidate the mechanisms underlying myocardial I/R injury and to develop new strategies for attenuating the damage it causes. Methods and Results: Using I/R-mice model created by ligation of left anterior descending (LAD) artery, we found increases in activity of protein tyrosine phosphatases (PTPs) in myocardium during I/R. Treating the I/R-mice with a pan-PTP inhibitor PVS (phenyl vinyl sulfone) attenuated I/R damage, suggesting PTPs activation to be harmful in I/R. Through analyzing myocardial RNAseq data, we showed PTPs that are abundantly expressed in the myocardium. By exposing cardiomyocytes ablated with specific endogenous PTPs to hypoxia/reoxygenation (H/R), we found a role that PTP-PEST (PTPn12) plays to promote cell death under H/R stress. Auranofin, a drug being used in clinical practice for treating rheumatoid arthritis, may target PTP-PEST thus suppressing its activity. We recapitulated the function of auranofin as a PTP-PEST inhibitor by in vitro studies, and then examined its effect on myocardial I/R injury. In the mice receiving auranofin before reperfusion, myocardial PTP activity was suppressed, leading to restored phosphorylation of PTP-PEST substrates, including ErbB-2 that maintains survival signaling of the heart. In line with the suppression of PTP-PEST activity, the auranofin-treated I/R-mice had smaller infarct size and better cardiac function. Conclusions: PTP-PEST contributes to part of the damages resulting from myocardial I/R. The PTP inhibitor auranofin, acting through the PTP-PEST-ErbB-2 signaling axis, reduces myocardial I/R injury. Based on the finding, auranofin could potentially be used in the development of treatments to manage I/R injury in patients with AMI.

Multi‐Step Continuous Flow Synthesis of β/γ‐Substituted Ketones

AbstractThe smooth preparation of β/γ‐substituted ketones has been carried out by using a three‐step continuous flow synthesis involving the initial photocatalyzed addition of an aldehyde onto phenyl vinyl sulfone. The resulting β‐ketosulfones were then elaborated in flow to prepare in situ an enone upon basic elimination of the sulfonyl group and then to give γ‐nitroketones, a 4‐chromanone, and β‐(3‐indolyl)ketones in moderate to good yields.

Therapeutic effect of phenyl vinyl sulfone and nitazoxanide on experimentally infected mice with cryptosporidiosis

Objective Evaluation of the therapeutic effect of phenyl vinyl sulfone (PVS) as cysteine protease inhibitors, nitazoxanide (NTZ), and combined therapy on Cryptosporidium parvum infection regarding the parasitological and histopathological parameters. Background Cryptosporidium spp. had been identified as the second most important diarrheal pathogen after rotavirus in young children. The immune status of the host plays a critical role. There is no reliable treatment for cryptosporidiosis, as the only approved drug NTZ provides no benefit for immunocompromised patients. Materials and methods A total of 180 female laboratory-bred Swiss albino mice were divided into two major divisions, immunocompetent and immunosuppressed, with the following groups for each one, respectively: negative control (I and VI), infected control (II and VII), infected treated with PVS (III and VIII), infected treated with NTZ (IV and IX), and infected treated combined (V and X). Stool examination for oocyst shedding was done at different days postinfection, and mice were killed at 18 and 30 days postinfection (groups A and B, respectively). Histopathological assessment of the ileum was done, and the endogenous developmental stages of the parasite were counted. Results Combined therapy in groups V and X resulted in the highest reduction in Cryptosporidium spp. oocysts shedding (P = 0.044 and Conclusion Combined therapy is more effective than either NTZ or PVS used alone. NTZ is still a better treatment option than PVS.

1,3-Dipolar cycloadditions with azomethine ylide species generated from aminocyclopropanes

Two types of bicyclic N-cyclopropyl glycine ester derivatives have been prepared and put under scrutiny as possible precursors of azomethine ylides. The results demonstrate that they can indeed participate in 1,3-dipolar cycloaddition reactions with dipolarophiles, as illustrated in the cases of phenyl vinyl sulfone, N-phenylmaleimide, diethyl fumarate and diethyl maleate. The relative configurations of the major diastereoisomers produced are consistent with the predicted generation of azomethine ylide species, reacting in concerted cycloaddition processes. This unprecedented way of generating such 1,3-dipoles provides access to functionalised pyrrolizidine and pyrrolidine derivatives, that would be difficult to make directly by more classic methods. It was also found that using phenyl vinyl sulfone or N-phenylmaleimide as the dipolarophile reactant, a domino nucleophilic conjugate addition/1,3-dipolar cycloaddition process may operate competitively.

Synthesis and kinetic evaluation of ethyl acrylate and vinyl sulfone derived inhibitors for human cysteine cathepsins

A series of inhibitors targeting human cathepsins have been designed and synthesized following a combinatorial approach. The compounds bear an α,β-unsaturated phenyl vinyl sulfone or ethyl acrylate warhead and a peptidomimetic portion aligned to the non-primed binding region. Biochemical evaluation toward four human cathepsins was carried out and the kinetic characterization confirmed an irreversible mode of inhibition. Compound 6c combining the most advantageous building blocks for cathepsin S inhibition was identified as a potent cathepsin S inactivator exhibiting a second-order rate constant of 30600 M−1 s−1.

Target identification reveals protein arginine methyltransferase 1 is a potential target of phenyl vinyl sulfone and its derivatives.

Phenyl vinyl sulfone (PVS) and phenyl vinyl sulfonate (PVSN) inactivate protein tyrosine phosphatases (PTPs) by mimicking the phosphotyrosine structure and providing a Michael addition acceptor for the active-site cysteine residue of PTPs, thus forming covalent adducts between PVS (or PVSN) and PTPs. We developed a specific antiserum against PVS. This antiserum can be used in general antibody-based assays such as immunoblotting, immunofluorescence staining, and immunoprecipitation. Target identification through immunoprecipitation and mass spectrometry analysis reveals potential targets of PVS, mostly proteins with reactive cysteine residues or low-pKa cysteine residues that are prone to reversible redox modifications. Target identification of PVSN has been conducted because the anti-PVS antiserum can also recognize PVSN. Among the targets, protein arginine methyltransferase 1 (PRMT1), inosine-5′-monophosphate dehydrogenase 1, vimentin, and glutathione reductase (GR) were further confirmed by immunoprecipitation followed by immunoblotting. In addition, PVSN and Bay11-7082 inhibited GR activity, and PVS, PVSN, and Bay 11-7082 inhibited PRMT1 activity in in vitro assays. In addition, treatment of PVSN, Bay11-7082, or Bay 11-7085 in cultured HeLa cells can cause the quick decline in the levels of protein asymmetric dimethylarginine. These results indicate that the similar moiety among PVS, PVSN, Bay 11-7082, and Bay 11-7085 can be the key structure of lead compounds of PRMT1. Therefore, we expect to use this approach in the identification of potential targets of other covalent drugs.

Abstract 149: Targeting Protein Tyrosine Phosphatase PTP-PEST for Therapeutic Interventions in Acute Myocardial Infarction

Introduction: To date reperfusion remains the only established clinical management to salvage ischemic myocardium. However, reperfusion also results in additional damage. New interventions that prevent myocardial injury caused by ischemia/reperfusion (I/R) are the unmet clinical need. A hallmark of I/R-induced cardiac signaling perturbation is dysregulation of protein tyrosine phosphorylation (pTyr), which is dynamically controlled by protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs). Recent works showed that forced activation of myocardial PTKs reduces I/R injury to the heart, suggesting a detrimental effect of protein tyrosine dephosphorylation by PTPs on the survival of myocardium. However, the role of PTPs in this disease context has never been explored. Hypothesis: PTPs may act to promote I/R-induced injury to the heart. Methods: Mice received the surgery for myocardial ischemia (1 h) followed by reperfusion (4 h). We measured the myocardial PTP activity, the pTyr level of cardiac proteins, and the degree of heart injury. To suppress endogenous PTP activity, mice were treated with phenyl vinyl sulfone (PVS), a pan-PTP inhibitor. Results: We found that the overall myocardial PTP activity was significantly elevated after ischemia and I/R, in line with a decrease of pTyr in cardiac proteins. Interestingly, PTP-PEST, which is abundantly expressed in myocardium, underwent protease-processed activation in the heart exposed to I/R. Consistently, the pTyr of paxillin and p130CAS, both which are the substrates of PTP-PEST, was significantly diminished. Treatment of the mice with PVS, an inhibitor that inactivates PTP-PEST, protected the heart from I/R injury. Conclusion: Our finding suggests that PTP-PEST may be a new target against myocardial I/R injury. The current focus is to validate the role of PTP-PEST in cardiac I/R damage and to test the therapeutic effect of drugable PTP-PEST inhibitors. New pharmacological interventions may be designed for improving the outcome of myocardial infarction.

Novel sydnone derivatives carrying azidomethyl-1,2, 4-oxadiazole unit and their 1,3-dipolar cycloadditions

ABSTRACTA series of 1,2,4-oxadiazolymethyl sydnones carrying azido group were synthesized and subjected to react with a variety of alkenic and acetylenic dipolarophilic reagents; N-phenyl maleimide, phenyl vinyl sulfone, and phenyl propiolic acid. All the new products are identified by spectral/physical data including high-resolution mass measurements and X-ray diffraction data.

Crystal structure of (2R*,3aR*)-2-phenyl-sulfonyl-2,3,3a,4,5,6-hexa-hydro-pyrrolo-[1,2-b]isoxazole.

The title compound, C12H15NO3S, was prepared by 1,3-dipolar cyclo-addition of 3,4-di-hydro-2H-pyrrole 1-oxide and phenyl vinyl sulfone. In the mol-ecule, both fused five-membered rings display a twisted conformation. In the crystal, C-H⋯O hydrogen bonds link neighbouring mol-ecules, forming chains running parallel to the b axis.

One-pot Synthesis of Highly Functionalizable 3-(Phenylsulfonyl)-2,3-dihydro-4(1H)-quinolinones via a Cu-catalyzed Aza-Michael Addition/Cyclization Reaction

A straightforward and mild one-pot method used for the synthesis of 3-(phenylsulfonyl)-2,3-dihydro-4(1H)-quinolinones via a Cu-catalyzed aza-Michael addition/base-mediated cyclization reaction is described. Addition of a range of readily available 2-aminobenzoates to phenyl vinyl sulfone was catalyzed by 5 mol % of a Cu complex at ambient temperature, followed by cyclization with KOt-Bu at 0 °C to afford new versatile 3-sulfonyl-substituted-2,3-dihydro-4(1H)-quinolinones in good yield (53–99%).

Expanding the Potential of Heteroaryl Vinyl Sulfones.

The easily available vinyl sulfone 3 showed great potential for new applications in several fields such as organic synthesis and bioconjugate formation. This was demonstrated by performing a systematic assessment of its reactivity in Michael, radical, and cycloaddition reactions. Heteroaryl vinyl sulfone 3 presented excellent output in terms of reactivity and selectivity, proving superior to phenyl vinyl sulfone 1 and with clear advantages over bis-sulfone 2. This behavior might be due to the conformational and orbital control exerted by the tetrazole unit according to DFT calculations. Moreover, some alternative transformations to the Julia-Kocienski olefination on the obtained products are also described.