Privileged Electrophile Sensors: A Resource for Covalent Drug Development.

PubMed

Long, Marcus John Curtis; Aye, Yimon

2017-07-20

This Perspective delineates how redox signaling affects the activity of specific enzyme isoforms and how this property may be harnessed for rational drug design. Covalent drugs have resurged in recent years and several reports have extolled the general virtues of developing irreversible inhibitors. Indeed, many modern pharmaceuticals contain electrophilic appendages. Several invoke a warhead that hijacks active-site nucleophiles whereas others take advantage of spectator nucleophilic side chains that do not participate in enzymatic chemistry, but are poised to bind/react with electrophiles. The latest data suggest that innate electrophile sensing-which enables rapid reaction with an endogenous signaling electrophile-is a quintessential resource for the development of covalent drugs. For instance, based on recent work documenting isoform-specific electrophile sensing, isozyme non-specific drugs may be converted to isozyme-specific analogs by hijacking privileged first-responder electrophile-sensing cysteines. Because this approach targets functionally relevant cysteines, we can simultaneously harness previously untapped moonlighting roles of enzymes linked to redox sensing. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Generalizable Platform for Interrogating Target- and Signal-Specific Consequences of Electrophilic Modifications in Redox-Dependent Cell Signaling

PubMed Central

Lin, Hong-Yu; Haegele, Joseph A.; Disare, Michael T.; Lin, Qishan; Aye, Yimon

2015-01-01

Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target-protein-personalized “electrophile toolbox” with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology—T-REX (targetable reactive electrophiles & oxidants)—is established by: (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein—one of several redox-sensitive regulators of the Nrf2–ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2–ARE induction. T-REX is also able to elicit cell activation in cases in which whole-cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein-target-specific electrophilic modifications in an otherwise unaffected cellular background. PMID:25909755

A generalizable platform for interrogating target- and signal-specific consequences of electrophilic modifications in redox-dependent cell signaling.

PubMed

Lin, Hong-Yu; Haegele, Joseph A; Disare, Michael T; Lin, Qishan; Aye, Yimon

2015-05-20

Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target-protein-personalized "electrophile toolbox" with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology, T-REX (targetable reactive electrophiles and oxidants), is established by (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept, which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein, one of several redox-sensitive regulators of the Nrf2-ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2-ARE induction. T-REX is also able to elicit cell activation in cases in which whole-cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein-target-specific electrophilic modifications in an otherwise unaffected cellular background.

Enolate-Forming Phloretin Pharmacophores: Hepatoprotection in an Experimental Model of Drug-Induced Toxicity.

PubMed

Geohagen, Brian C; Vydyanathan, Amaresh; Kosharskyy, Boleslav; Shaparin, Naum; Gavin, Terrence; LoPachin, Richard M

2016-06-01

Drug-induced toxicity is often mediated by electrophilic metabolites, such as bioactivation of acetaminophen (APAP) to N-acetyl-p-benzoquinone imine (NAPQI). We have shown that APAP hepatotoxicity can be prevented by 2-acetylcyclopentanone (2-ACP). This 1,3-dicarbonyl compound ionizes to form an enolate nucleophile that scavenges NAPQI and other electrophilic intermediates. In this study, we expanded our investigation of enolate-forming compounds to include analyses of the phloretin pharmacophores, 2',4',6'-trihydroxyacetophenone (THA) and phloroglucinol (PG). Studies in a mouse model of APAP overdose showed that THA provided hepatoprotection when given either by intraperitoneal injection or oral administration, whereas PG was hepatoprotective only when given intraperitoneally. Corroborative research characterized the molecular pharmacology (efficacy, potency) of 2-ACP, THA, and PG in APAP-exposed isolated mouse hepatocytes. For comparative purposes, N-acetylcysteine (NAC) cytoprotection was also evaluated. Measurements of multiple cell parameters (e.g., cell viability, mitochondrial membrane depolarization) indicated that THA and, to a lesser extent, PG provided concentration-dependent protection against APAP toxicity, which exceeded that of 2-ACP or NAC. The enolate-forming compounds and NAC truncated ongoing APAP exposure and thereby returned intoxicated hepatocytes toward normal viability. The superior ability of THA to protect is related to multifaceted modes of action that include metal ion chelation, free radical trapping, and scavenging of NAPQI and other soft electrophiles involved in oxidative stress. The rank order of potency for the tested cytoprotectants was consistent with that determined in a parallel mouse model. These data suggest that THA or a derivative might be useful in treating drug-induced toxicities and other conditions that involve electrophile-mediated pathogenesis. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Enolate-Forming Phloretin Pharmacophores: Hepatoprotection in an Experimental Model of Drug-Induced Toxicity

PubMed Central

Geohagen, Brian C.; Vydyanathan, Amaresh; Kosharskyy, Boleslav; Shaparin, Naum; Gavin, Terrence

2016-01-01

Drug-induced toxicity is often mediated by electrophilic metabolites, such as bioactivation of acetaminophen (APAP) to N-acetyl-p-benzoquinone imine (NAPQI). We have shown that APAP hepatotoxicity can be prevented by 2-acetylcyclopentanone (2-ACP). This 1,3-dicarbonyl compound ionizes to form an enolate nucleophile that scavenges NAPQI and other electrophilic intermediates. In this study, we expanded our investigation of enolate-forming compounds to include analyses of the phloretin pharmacophores, 2′,4′,6′-trihydroxyacetophenone (THA) and phloroglucinol (PG). Studies in a mouse model of APAP overdose showed that THA provided hepatoprotection when given either by intraperitoneal injection or oral administration, whereas PG was hepatoprotective only when given intraperitoneally. Corroborative research characterized the molecular pharmacology (efficacy, potency) of 2-ACP, THA, and PG in APAP-exposed isolated mouse hepatocytes. For comparative purposes, N-acetylcysteine (NAC) cytoprotection was also evaluated. Measurements of multiple cell parameters (e.g., cell viability, mitochondrial membrane depolarization) indicated that THA and, to a lesser extent, PG provided concentration-dependent protection against APAP toxicity, which exceeded that of 2-ACP or NAC. The enolate-forming compounds and NAC truncated ongoing APAP exposure and thereby returned intoxicated hepatocytes toward normal viability. The superior ability of THA to protect is related to multifaceted modes of action that include metal ion chelation, free radical trapping, and scavenging of NAPQI and other soft electrophiles involved in oxidative stress. The rank order of potency for the tested cytoprotectants was consistent with that determined in a parallel mouse model. These data suggest that THA or a derivative might be useful in treating drug-induced toxicities and other conditions that involve electrophile-mediated pathogenesis. PMID:27029584

Accumulation of electrophilic aldehydes during postovulatory aging of mouse oocytes causes reduced fertility, oxidative stress, and apoptosis.

PubMed

Lord, Tessa; Martin, Jacinta H; Aitken, R John

2015-02-01

With increasing periods of time following ovulation, the metaphase II (MII)-stage oocyte experiences overproduction of reactive oxygen species and elevated levels of lipid peroxidation that are implicitly linked with functional deficiencies acquired during postovulatory oocyte aging. We have demonstrated that the electrophilic aldehydes 4-hydroxynonenal (4HNE), malondialdehyde, and acrolein are by-products of nonenzymatic lipid peroxidation in the murine MII-stage oocyte, adducting to multiple proteins within the cell. The covalent modification of oocyte proteins by these aldehydes increased with extended periods of time postovulation; the mitochondrial protein succinate dehydrogenase (SDHA) was identified as a primary target for 4HNE adduction. Time- and dose-dependent studies revealed that exposure to elevated levels of electrophilic aldehydes causes mitochondrial reactive oxygen species production, lipid peroxidation, loss of mitochondrial membrane potential, and eventual apoptosis within the MII oocyte, presumably as a consequence of electron transport chain collapse following SDHA adduction. Additionally, we have determined that short-term exposure to low doses of 4HNE dramatically impairs the oocyte's ability to participate in fertilization and support embryonic development; however, this loss of functionality can be prevented by supplementation with the antioxidant penicillamine. In conclusion, this study has revealed that the accumulation of electrophilic aldehydes is linked to postovulatory oocyte aging, causing reduced fertility, oxidative stress, and apoptosis of this highly specialized cell. These data highlight the importance of timely fertilization of the mammalian oocyte postovulation and emphasize the potential advantages associated with antioxidant supplementation of oocyte culture medium in circumstances where reinsemination of oocytes may be desirable (i.e., rescue intracytoplasmic sperm injection), or where in vitro fertilization may be delayed. © 2015 by the Society for the Study of Reproduction, Inc.

The Die Is Cast: Precision Electrophilic Modifications Contribute to Cellular Decision Making

PubMed Central

2016-01-01

This perspective sets out to critically evaluate the scope of reactive electrophilic small molecules as unique chemical signal carriers in biological information transfer cascades. We consider these electrophilic cues as a new volatile cellular currency and compare them to canonical signaling circulation such as phosphate in terms of chemical properties, biological specificity, sufficiency, and necessity. The fact that nonenzymatic redox sensing properties are found in proteins undertaking varied cellular tasks suggests that electrophile signaling is a moonlighting phenomenon manifested within a privileged set of sensor proteins. The latest interrogations into these on-target electrophilic responses set forth a new horizon in the molecular mechanism of redox signal propagation wherein direct low-occupancy electrophilic modifications on a single sensor target are biologically sufficient to drive functional redox responses with precision timing. We detail how the various mechanisms through which redox signals function could contribute to their interesting phenotypic responses, including hormesis. PMID:27617777

The Die Is Cast: Precision Electrophilic Modifications Contribute to Cellular Decision Making.

PubMed

Long, Marcus J C; Aye, Yimon

2016-10-02

This perspective sets out to critically evaluate the scope of reactive electrophilic small molecules as unique chemical signal carriers in biological information transfer cascades. We consider these electrophilic cues as a new volatile cellular currency and compare them to canonical signaling circulation such as phosphate in terms of chemical properties, biological specificity, sufficiency, and necessity. The fact that nonenzymatic redox sensing properties are found in proteins undertaking varied cellular tasks suggests that electrophile signaling is a moonlighting phenomenon manifested within a privileged set of sensor proteins. The latest interrogations into these on-target electrophilic responses set forth a new horizon in the molecular mechanism of redox signal propagation wherein direct low-occupancy electrophilic modifications on a single sensor target are biologically sufficient to drive functional redox responses with precision timing. We detail how the various mechanisms through which redox signals function could contribute to their interesting phenotypic responses, including hormesis.

Ionic liquid-functionalized mesoporous sorbents and their use in the capture of polluting gases

DOEpatents

Lee, Jong Suk; Koros, William J.; Bhuwania, Nitesh; Hillesheim, Patrick C.; Dai, Sheng

2016-01-12

A composite structure for capturing a gaseous electrophilic species, the composite structure comprising mesoporous refractory sorbent particles on which an ionic liquid is covalently attached, wherein said ionic liquid includes an accessible functional group that is capable of binding to said gaseous electrophilic species. In particular embodiments, the mesoporous sorbent particles are contained within refractory hollow fibers. Also described is a method for capturing a gaseous electrophilic species by use of the above-described composite structure, wherein the gaseous electrophilic species is contacted with the composite structure. In particular embodiments thereof, cooling water is passed through the refractory hollow fibers containing the IL-functionalized sorbent particles in order to facilitate capture of the gaseous electrophilic species, and then steam is passed through the refractory hollow fibers to facilitate release of the gaseous electrophilic species such that the composite structure can be re-used to capture additional gas.

Analysis of Drosophila TRPA1 reveals an ancient origin for human chemical nociception.

PubMed

Kang, Kyeongjin; Pulver, Stefan R; Panzano, Vincent C; Chang, Elaine C; Griffith, Leslie C; Theobald, Douglas L; Garrity, Paul A

2010-03-25

Chemical nociception, the detection of tissue-damaging chemicals, is important for animal survival and causes human pain and inflammation, but its evolutionary origins are largely unknown. Reactive electrophiles are a class of noxious compounds humans find pungent and irritating, such as allyl isothiocyanate (in wasabi) and acrolein (in cigarette smoke). Diverse animals, from insects to humans, find reactive electrophiles aversive, but whether this reflects conservation of an ancient sensory modality has been unclear. Here we identify the molecular basis of reactive electrophile detection in flies. We demonstrate that Drosophila TRPA1 (Transient receptor potential A1), the Drosophila melanogaster orthologue of the human irritant sensor, acts in gustatory chemosensors to inhibit reactive electrophile ingestion. We show that fly and mosquito TRPA1 orthologues are molecular sensors of electrophiles, using a mechanism conserved with vertebrate TRPA1s. Phylogenetic analyses indicate that invertebrate and vertebrate TRPA1s share a common ancestor that possessed critical characteristics required for electrophile detection. These findings support emergence of TRPA1-based electrophile detection in a common bilaterian ancestor, with widespread conservation throughout vertebrate and invertebrate evolution. Such conservation contrasts with the evolutionary divergence of canonical olfactory and gustatory receptors and may relate to electrophile toxicity. We propose that human pain perception relies on an ancient chemical sensor conserved across approximately 500 million years of animal evolution.

Molecular Mechanisms of Aldehyde Toxicity: A Chemical Perspective

PubMed Central

2015-01-01

Aldehydes are electrophilic compounds to which humans are pervasively exposed. Despite a significant health risk due to exposure, the mechanisms of aldehyde toxicity are poorly understood. This ambiguity is likely due to the structural diversity of aldehyde derivatives and corresponding differences in chemical reactions and biological targets. To gain mechanistic insight, we have used parameters based on the hard and soft, acids and bases (HSAB) theory to profile the different aldehyde subclasses with respect to electronic character (softness, hardness), electrophilic reactivity (electrophilic index), and biological nucleophilic targets. Our analyses indicate that short chain aldehydes and longer chain saturated alkanals are hard electrophiles that cause toxicity by forming adducts with hard biological nucleophiles, e.g., primary nitrogen groups on lysine residues. In contrast, α,β-unsaturated carbonyl derivatives, alkenals, and the α-oxoaldehydes are soft electrophiles that preferentially react with soft nucleophilic thiolate groups on cysteine residues. The aldehydes can therefore be grouped into subclasses according to common electronic characteristics (softness/hardness) and molecular mechanisms of toxicity. As we will discuss, the toxic potencies of these subgroups are generally related to corresponding electrophilicities. For some aldehydes, however, predictions of toxicity based on electrophilicity are less accurate due to inherent physicochemical variables that limit target accessibility, e.g., steric hindrance and solubility. The unsaturated aldehydes are also members of the conjugated type-2 alkene chemical class that includes α,β-unsaturated amide, ketone, and ester derivatives. Type-2 alkenes are electrophiles of varying softness and electrophilicity that share a common mechanism of toxicity. Therefore, exposure to an environmental mixture of unsaturated carbonyl derivatives could cause “type-2 alkene toxicity” through additive interactions. Finally, we propose that environmentally derived aldehydes can accelerate diseases by interacting with endogenous aldehydes generated during oxidative stress. This review provides a basis for understanding aldehyde mechanisms and environmental toxicity through the context of electronic structure, electrophilicity, and nucleophile target selectivity. PMID:24911545

Structure-activity relationship between the 3D distribution of the electrophilicity of sugar derivatives and their cytotoxic and antiviral properties

NASA Astrophysics Data System (ADS)

Ricca, Alessandra; Tronchet, Jean M. J.; Weber, Jacques

1992-12-01

The cytotoxic activities of a series of sugar derivatives bearing electrophilic groups (1-cyanovinyl, 4-cyanochromen-2-yl and 3-nitrochromen-2-yl) have been correlated with their electrophilic properties. To this end, an electrophilic index was defined as an isovalue surface where the interaction energy with an incoming model nucelophile (H-) was equal to a predefined value. This index, calculated from extended Hückel wave functions, allows one to quantify the electrophilic character of the substrates and to describe its spatial localization within the molecular volume (at Michael acceptor sites or on other parts of the molecules). Only sugars for which Michael acceptor reactivity was predicted were retained, and they were subdivided into two groups: those showing antiviral activity against a retrovirus and those devoid of such activity. Under these conditions, good correlations between cytotoxic activity and electrophilic reactivity-positive for the first group, negative for the second-were found. In addition, the ratio electrophilicity/sum of the absolute value of the dipole plus its projection along the principal axis of inertia, Z, of the molecule allows one to predict to which of these groups a sugar derivative belongs.

A Green Starting Material for Electrophilic Aromatic Substitution for the Undergraduate Organic Laboratory

ERIC Educational Resources Information Center

Jones-Wilson, T. Michelle; Burtch, Elizabeth A.

2005-01-01

Electrophilic aromatic substitution (EAS) experiment is designed for the second-semester and undergraduate organic chemistry laboratory. In the EAS experiment, the principles of green chemistry are discussed and illustrated in conjunction with the presentation of electrophilic aromatic substitution.

Multiplexed Thiol Reactivity Profiling for Target Discovery of Electrophilic Natural Products.

PubMed

Tian, Caiping; Sun, Rui; Liu, Keke; Fu, Ling; Liu, Xiaoyu; Zhou, Wanqi; Yang, Yong; Yang, Jing

2017-11-16

Electrophilic groups, such as Michael acceptors, expoxides, are common motifs in natural products (NPs). Electrophilic NPs can act through covalent modification of cysteinyl thiols on functional proteins, and exhibit potent cytotoxicity and anti-inflammatory/cancer activities. Here we describe a new chemoproteomic strategy, termed multiplexed thiol reactivity profiling (MTRP), and its use in target discovery of electrophilic NPs. We demonstrate the utility of MTRP by identifying cellular targets of gambogic acid, an electrophilic NP that is currently under evaluation in clinical trials as anticancer agent. Moreover, MTRP enables simultaneous comparison of seven structurally diversified α,β-unsaturated γ-lactones, which provides insights into the relative proteomic reactivity and target preference of diverse structural scaffolds coupled to a common electrophilic motif and reveals various potential druggable targets with liganded cysteines. We anticipate that this new method for thiol reactivity profiling in a multiplexed manner will find broad application in redox biology and drug discovery. Copyright © 2017 Elsevier Ltd. All rights reserved.

Copper(II)-catalyzed electrophilic amination of quinoline N-oxides with O-benzoyl hydroxylamines.

PubMed

Li, Gang; Jia, Chunqi; Sun, Kai; Lv, Yunhe; Zhao, Feng; Zhou, Kexiao; Wu, Hankui

2015-03-21

Copper acetate-catalyzed C-H bond functionalization amination of quinoline N-oxides was achieved using O-benzoyl hydroxylamine as an electrophilic amination reagent, thereby affording the desired products in moderate to excellent yields. Electrophilic amination can also be performed in good yield on a gram scale.

A Green, Guided-Inquiry Based Electrophilic Aromatic Substitution for the Organic Chemistry Laboratory

ERIC Educational Resources Information Center

Eby, Eric; Deal, S. Todd

2008-01-01

We developed an alternative electrophilic aromatic substitution reaction for the organic chemistry teaching laboratory. The experiment is an electrophilic iodination reaction of salicylamide, a popular analgesic, using environmentally friendly reagents--sodium iodide and household bleach. Further, we designed the lab as a guided-inquiry…

Studies Towards the Leucetta-derived Alkaloids Spirocalcaridine A and B - Possible Biosynthetic Implications.

PubMed

Koswatta, Panduka B; Das, Jayanta; Yousufuddin, Muhammed; Lovely, Carl J

2015-04-01

An exploration of an abiotic approach to spirocalcaridines A and B is described centered on electrophile-induced dearomatizing spirocyclization of aryl enyne derivatives. Elaboration of the α-iodoenone via an Ullmann-like, copper-catalyzed amidation provided a formamide which upon treatment with methylamine undergoes a dienol-arene rearrangement, providing the corresponding kealiinine-like framework. This observation suggests a possible biosynthetic links between the spirocalcaridines and the naphthimidazole group of Leucetta alkaloids.

Precision Electrophile Tagging in Caenorhabditis elegans

PubMed Central

2017-01-01

Adduction of an electrophile to privileged sensor proteins and the resulting phenotypically dominant responses are increasingly appreciated as being essential for metazoan health. Functional similarities between the biological electrophiles and electrophilic pharmacophores commonly found in covalent drugs further fortify the translational relevance of these small-molecule signals. Genetically encodable or small-molecule-based fluorescent reporters and redox proteomics have revolutionized the observation and profiling of cellular redox states and electrophile–sensor proteins, respectively. However, precision mapping between specific redox-modified targets and specific responses has only recently begun to be addressed, and systems tractable to both genetic manipulation and on-target redox signaling in vivo remain largely limited. Here we engineer transgenic Caenorhabditis elegans expressing functional HaloTagged fusion proteins and use this system to develop a generalizable light-controlled approach to tagging a prototypical electrophile–sensor protein with native electrophiles in vivo. The method circumvents issues associated with low uptake/distribution and toxicity/promiscuity. Given the validated success of C. elegans in aging studies, this optimized platform offers a new lens with which to scrutinize how on-target electrophile signaling influences redox-dependent life span regulation. PMID:28857552

Studies Towards the Leucetta-derived Alkaloids Spirocalcaridine A and B – Possible Biosynthetic Implications

PubMed Central

Koswatta, Panduka B.; Das, Jayanta; Yousufuddin, Muhammed; Lovely, Carl J.

2015-01-01

An exploration of an abiotic approach to spirocalcaridines A and B is described centered on electrophile-induced dearomatizing spirocyclization of aryl enyne derivatives. Elaboration of the α–iodoenone via an Ullmann-like, copper-catalyzed amidation provided a formamide which upon treatment with methylamine undergoes a dienol-arene rearrangement, providing the corresponding kealiinine-like framework. This observation suggests a possible biosynthetic links between the spirocalcaridines and the naphthimidazole group of Leucetta alkaloids. PMID:26257576

Chemoproteomic profiling and discovery of protein electrophiles in human cells

NASA Astrophysics Data System (ADS)

Matthews, Megan L.; He, Lin; Horning, Benjamin D.; Olson, Erika J.; Correia, Bruno E.; Yates, John R.; Dawson, Philip E.; Cravatt, Benjamin F.

2017-03-01

Activity-based protein profiling (ABPP) serves as a chemical proteomic platform to discover and characterize functional amino acids in proteins on the basis of their enhanced reactivity towards small-molecule probes. This approach, to date, has mainly targeted nucleophilic functional groups, such as the side chains of serine and cysteine, using electrophilic probes. Here we show that 'reverse-polarity' (RP)-ABPP using clickable, nucleophilic hydrazine probes can capture and identify protein-bound electrophiles in cells. Using this approach, we demonstrate that the pyruvoyl cofactor of S-adenosyl-L-methionine decarboxylase (AMD1) is dynamically controlled by intracellular methionine concentrations. We also identify a heretofore unknown modification—an N-terminally bound glyoxylyl group—in the poorly characterized protein secernin-3. RP-ABPP thus provides a versatile method to monitor the metabolic regulation of electrophilic cofactors and discover novel types of electrophilic modifications on proteins in human cells.

Precise through-space control of an abiotic electrophilic aromatic substitution reaction

NASA Astrophysics Data System (ADS)

Murphy, Kyle E.; Bocanegra, Jessica L.; Liu, Xiaoxi; Chau, H.-Y. Katharine; Lee, Patrick C.; Li, Jianing; Schneebeli, Severin T.

2017-04-01

Nature has evolved selective enzymes for the efficient biosynthesis of complex products. This exceptional ability stems from adapted enzymatic pockets, which geometrically constrain reactants and stabilize specific reactive intermediates by placing electron-donating/accepting residues nearby. Here we perform an abiotic electrophilic aromatic substitution reaction, which is directed precisely through space. Ester arms--positioned above the planes of aromatic rings--enable it to distinguish between nearly identical, neighbouring reactive positions. Quantum mechanical calculations show that, in two competing reaction pathways, both [C-H...O]-hydrogen bonding and electrophile preorganization by coordination to a carbonyl group likely play a role in controlling the reaction. These through-space-directed mechanisms are inspired by dimethylallyl tryptophan synthases, which direct biological electrophilic aromatic substitutions by preorganizing dimethylallyl cations and by stabilizing reactive intermediates with [C-H...N]-hydrogen bonding. Our results demonstrate how the third dimension above and underneath aromatic rings can be exploited to precisely control electrophilic aromatic substitutions.

Detection of Electrophilic and Nucleophilic Chemical Agents

DOEpatents

McElhanon, James R.; Shepodd, Timothy J.

2008-11-11

A "real time" method for detecting electrophilic and nucleophilic species generally by employing tunable, precursor sensor materials that mimic the physiological interaction of these agents to form highly florescent berberine-type alkaloids that can be easily and rapidly detected. These novel precursor sensor materials can be tuned for reaction with both electrophilic (chemical species, toxins) and nucleophilic (proteins and other biological molecules) species.

Direct Functionalization of Kevlar (registered trademark) with Copolymers Containing Sulfonyl Nitrene

DTIC Science & Technology

2016-01-01

phenylene terephthalamide) (Kevlar®) fibers via thermal generation of an electrophilic nitrene, while preserving the mechanical properties of the...poly(p-phenylene terephthalamide) (Kevlar®) fibers via thermal generation of an electrophilic nitrene, while preserving the mechanical properties of...radiation, plasma, or chemical radical generation,12 conventional solution-based electrophilic aromatic substitution,13 silanation,14 or hydrolysis with

Monohalogenated acetamide-induced cellular stress and genotoxicity are related to electrophilic softness and thiol/thiolate reactivity.

PubMed

Pals, Justin A; Wagner, Elizabeth D; Plewa, Michael J; Xia, Menghang; Attene-Ramos, Matias S

2017-08-01

Haloacetamides (HAMs) are cytotoxic, genotoxic, and mutagenic byproducts of drinking water disinfection. They are soft electrophilic compounds that form covalent bonds with the free thiol/thiolate in cysteine residues through an S N 2 reaction mechanism. Toxicity of the monohalogenated HAMs (iodoacetamide, IAM; bromoacetamide, BAM; or chloroacetamide, CAM) varied depending on the halogen substituent. The aim of this research was to investigate how the halogen atom affects the reactivity and toxicological properties of HAMs, measured as induction of oxidative/electrophilic stress response and genotoxicity. Additionally, we wanted to determine how well in silico estimates of electrophilic softness matched thiol/thiolate reactivity and in vitro toxicological endpoints. Each of the HAMs significantly induced nuclear Rad51 accumulation and ARE signaling activity compared to a negative control. The rank order of effect was IAM>BAM>CAM for Rad51, and BAM≈IAM>CAM for ARE. In general, electrophilic softness and in chemico thiol/thiolate reactivity provided a qualitative indicator of toxicity, as the softer electrophiles IAM and BAM were more thiol/thiolate reactive and were more toxic than CAM. Copyright © 2017. Published by Elsevier B.V.

Molecular Mechanism of Acrylamide Neurotoxicity: Lessons Learned from Organic Chemistry

PubMed Central

Gavin, Terrence

2012-01-01

Background: Acrylamide (ACR) produces cumulative neurotoxicity in exposed humans and laboratory animals through a direct inhibitory effect on presynaptic function. Objectives: In this review, we delineate how knowledge of chemistry provided an unprecedented understanding of the ACR neurotoxic mechanism. We also show how application of the hard and soft, acids and bases (HSAB) theory led to the recognition that the α,β-unsaturated carbonyl structure of ACR is a soft electrophile that preferentially forms covalent bonds with soft nucleophiles. Methods: In vivo proteomic and in chemico studies demonstrated that ACR formed covalent adducts with highly nucleophilic cysteine thiolate groups located within active sites of presynaptic proteins. Additional research showed that resulting protein inactivation disrupted nerve terminal processes and impaired neurotransmission. Discussion: ACR is a type-2 alkene, a chemical class that includes structurally related electrophilic environmental pollutants (e.g., acrolein) and endogenous mediators of cellular oxidative stress (e.g., 4-hydroxy-2-nonenal). Members of this chemical family produce toxicity via a common molecular mechanism. Although individual environmental concentrations might not be toxicologically relevant, exposure to an ambient mixture of type-2 alkene pollutants could pose a significant risk to human health. Furthermore, environmentally derived type-2 alkenes might act synergistically with endogenously generated unsaturated aldehydes to amplify cellular damage and thereby accelerate human disease/injury processes that involve oxidative stress. Conclusions: These possibilities have substantial implications for environmental risk assessment and were realized through an understanding of ACR adduct chemistry. The approach delineated here can be broadly applied because many toxicants of different chemical classes are electrophiles that produce toxicity by interacting with cellular proteins. PMID:23060388

Knock-Down of the IFR1 Protein Perturbs the Homeostasis of Reactive Electrophile Species and Boosts Photosynthetic Hydrogen Production in Chlamydomonas reinhardtii

PubMed Central

Venkanna, Deepak; Südfeld, Christian; Baier, Thomas; Homburg, Sarah V.; Patel, Anant V.; Wobbe, Lutz; Kruse, Olaf

2017-01-01

The protein superfamily of short-chain dehydrogenases/reductases (SDR), including members of the atypical type (aSDR), covers a huge range of catalyzed reactions and in vivo substrates. This superfamily also comprises isoflavone reductase-like (IRL) proteins, which are aSDRs highly homologous to isoflavone reductases from leguminous plants. The molecular function of IRLs in non-leguminous plants and green microalgae has not been identified as yet, but several lines of evidence point at their implication in reactive oxygen species homeostasis. The Chlamydomonas reinhardtii IRL protein IFR1 was identified in a previous study, analyzing the transcriptomic changes occurring during the acclimation to sulfur deprivation and anaerobiosis, a condition that triggers photobiological hydrogen production in this microalgae. Accumulation of the cytosolic IFR1 protein is induced by sulfur limitation as well as by the exposure of C. reinhardtii cells to reactive electrophile species (RES) such as reactive carbonyls. The latter has not been described for IRL proteins before. Over-accumulation of IFR1 in the singlet oxygen response 1 (sor1) mutant together with the presence of an electrophile response element, known to be required for SOR1-dependent gene activation as a response to RES, in the promoter of IFR1, indicate that IFR1 expression is controlled by the SOR1-dependent pathway. An implication of IFR1 into RES homeostasis, is further implied by a knock-down of IFR1, which results in a diminished tolerance toward RES. Intriguingly, IFR1 knock-down has a positive effect on photosystem II (PSII) stability under sulfur-deprived conditions used to trigger photobiological hydrogen production, by reducing PSII-dependent oxygen evolution, in C. reinhardtii. Reduced PSII photoinhibition in IFR1 knock-down strains prolongs the hydrogen production phase resulting in an almost doubled final hydrogen yield compared to the parental strain. Finally, IFR1 knock-down could be successfully used to further increase hydrogen yields of the high hydrogen-producing mutant stm6, demonstrating that IFR1 is a promising target for genetic engineering approaches aiming at an increased hydrogen production capacity of C. reinhardtii cells. PMID:28824682

Knock-Down of the IFR1 Protein Perturbs the Homeostasis of Reactive Electrophile Species and Boosts Photosynthetic Hydrogen Production in Chlamydomonas reinhardtii.

PubMed

Venkanna, Deepak; Südfeld, Christian; Baier, Thomas; Homburg, Sarah V; Patel, Anant V; Wobbe, Lutz; Kruse, Olaf

2017-01-01

The protein superfamily of short-chain dehydrogenases/reductases (SDR), including members of the atypical type (aSDR), covers a huge range of catalyzed reactions and in vivo substrates. This superfamily also comprises isoflavone reductase-like (IRL) proteins, which are aSDRs highly homologous to isoflavone reductases from leguminous plants. The molecular function of IRLs in non-leguminous plants and green microalgae has not been identified as yet, but several lines of evidence point at their implication in reactive oxygen species homeostasis. The Chlamydomonas reinhardtii IRL protein IFR1 was identified in a previous study, analyzing the transcriptomic changes occurring during the acclimation to sulfur deprivation and anaerobiosis, a condition that triggers photobiological hydrogen production in this microalgae. Accumulation of the cytosolic IFR1 protein is induced by sulfur limitation as well as by the exposure of C. reinhardtii cells to reactive electrophile species (RES) such as reactive carbonyls. The latter has not been described for IRL proteins before. Over-accumulation of IFR1 in the singlet oxygen response 1 ( sor1 ) mutant together with the presence of an electrophile response element, known to be required for SOR1-dependent gene activation as a response to RES, in the promoter of IFR1 , indicate that IFR1 expression is controlled by the SOR1-dependent pathway. An implication of IFR1 into RES homeostasis, is further implied by a knock-down of IFR1 , which results in a diminished tolerance toward RES. Intriguingly, IFR1 knock-down has a positive effect on photosystem II (PSII) stability under sulfur-deprived conditions used to trigger photobiological hydrogen production, by reducing PSII-dependent oxygen evolution, in C. reinhardtii . Reduced PSII photoinhibition in IFR1 knock-down strains prolongs the hydrogen production phase resulting in an almost doubled final hydrogen yield compared to the parental strain. Finally, IFR1 knock-down could be successfully used to further increase hydrogen yields of the high hydrogen-producing mutant stm6 , demonstrating that IFR1 is a promising target for genetic engineering approaches aiming at an increased hydrogen production capacity of C. reinhardtii cells.

Simple ortho- and para-hydroquinones as compounds neuroprotective against oxidative stress in a manner associated with specific transcriptional activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Satoh, Takumi; Saitoh, Sachie; Hosaka, Manami

2009-02-06

Electrophilic compounds protect neurons through the activation of the Keap1/Nrf2 pathway and the induction of phase-2 enzymes [T. Satoh, S.A. Lipton, Redox regulation of neuronal survival by electrophilic compounds, Trends Neurosci. 30 (2007) 38-45; T. Satoh, S. Okamoto, J. Cui, Y. Watanabe, K. Furuta, M. Suzuki, K. Tohyama, S.A. Lipton, Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic phase II inducers. Proc. Natl. Acad. Sci. USA 103 (2006) 768-773]. Hydroquinone-type electrophilic compounds such as tert-butyl hydroquinone (TBHQ) and carnosic acid (CA) have attracted special attention, because the oxidative conversion of 'hydroquinone' to 'quinone' is essential for the transcriptional activationmore » of the above-mentioned enzymes [T. Satoh, K. Kosaka, K. Itoh, A. Kobayashi, M. Yamamoto, Y. Shimojo, C. Kitajima, J. Cui, J. Kamins, S. Okamoto, T. Shirasawa, S.A. Lipton, Carnosic acid, a catechol-type electrophilic compound, protect neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of specific cysteine, J. Neurochem. 104 (2008) 1161-1131; A.D. Kraft, D.A. Johnson, J.A. Johnson, Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult, J. Neurosci. 24 (2004) 1101-1112]. In the present study, we examined the relationship between electrophilicity and the protective effects afforded by electrophilic compounds. Electrophilicity was assessed in terms of the ability of a compound to bind to a cysteine on bovine serum albumin, by which we found that neuroprotective hydroquinones [TBHQ (para-) and CA (ortho-)] had distinctive patterns of cysteine binding compared with other electrophilic compounds. Further, we found that isomers of simple ortho- and para-hydroquinones such as 2-methylhydroquinone (para-) and 4-methyl-catechol (ortho-) [not in abstract] had similar properties of cysteine binding as TBHQ and CA, which compounds were associated with the transcriptional activation and an increase in the level of reduced glutathione. These results suggest that para- and ortho-dihydroquinones may be neuroprotective compounds active against oxidative stress.« less

A new scale of electronegativity based on electrophilicity index.

PubMed

Noorizadeh, Siamak; Shakerzadeh, Ehsan

2008-04-17

By calculating the energies of neutral and different ionic forms (M2+, M+, M, M-, and M2-) of 32 elements (using B3LYP/6-311++G** level of theory) and taking energy (E) to be a Morse-like function of the number of electrons (N), the electrophilicity values (omega) are calculated for these atoms. The obtained electrophilicities show a good linearity with some commonly used electronegativity scales such as Pauling and Allred-Rochow. Using these electrophilicities, the ionicities of some diatomic molecules are calculated, which are in good agreement with the experimental data. Therefore, these electrophilicities are introduced as a new scale for atomic electronegativity, chi(omega)0. The same procedure is also performed for some simple polyatomic molecules. It is shown that the new scale successfully obeys Sanderson's electronegativity equalization principle and for those molecules which have the same number of atoms, the ratio of the change in electronegativity during the formation of a molecule from its elements to the molecular electronegativity (Delta chi/chi omega) is the same.

Application of the Hard and Soft, Acids and Bases (HSAB) theory to toxicant--target interactions.

PubMed

Lopachin, Richard M; Gavin, Terrence; Decaprio, Anthony; Barber, David S

2012-02-20

Many chemical toxicants and/or their active metabolites are electrophiles that cause cell injury by forming covalent bonds with nucleophilic targets on biological macromolecules. Covalent reactions between nucleophilic and electrophilic reagents are, however, discriminatory since there is a significant degree of selectivity associated with these interactions. Over the course of the past few decades, the theory of Hard and Soft, Acids and Bases (HSAB) has proven to be a useful tool in predicting the outcome of such reactions. This concept utilizes the inherent electronic characteristic of polarizability to define, for example, reacting electrophiles and nucleophiles as either hard or soft. These HSAB definitions have been successfully applied to chemical-induced toxicity in biological systems. Thus, according to this principle, a toxic electrophile reacts preferentially with biological targets of similar hardness or softness. The soft/hard classification of a xenobiotic electrophile has obvious utility in discerning plausible biological targets and molecular mechanisms of toxicity. The purpose of this perspective is to discuss the HSAB theory of electrophiles and nucleophiles within a toxicological framework. In principle, covalent bond formation can be described by using the properties of their outermost or frontier orbitals. Because these orbital energies for most chemicals can be calculated using quantum mechanical models, it is possible to quantify the relative softness (σ) or hardness (η) of electrophiles or nucleophiles and to subsequently convert this information into useful indices of reactivity. This atomic level information can provide insight into the design of corroborative laboratory research and thereby help investigators discern corresponding molecular sites and mechanisms of toxicant action. The use of HSAB parameters has also been instrumental in the development and identification of potential nucleophilic cytoprotectants that can scavenge toxic electrophiles. Clearly, the difficult task of delineating molecular sites and mechanisms of toxicant action can be facilitated by the application of this quantitative approach.

APPLICATION OF THE HARD AND SOFT, ACIDS AND BASES (HSAB) THEORY TO TOXICANT-TARGET INTERACTIONS

PubMed Central

LoPachin, Richard M.; Gavin, Terrence; DeCaprio, Anthony; Barber, David S.

2011-01-01

Many chemical toxicants and/or their active metabolites are electrophiles that cause cell injury by forming covalent bonds with nucleophilic targets on biological macromolecules. Covalent reactions between nucleophilic and electrophilic reagents are however discriminatory, since there is a significant degree of selectivity associated with these interactions. Over the course of the past few decades, the theory of Hard and Soft, Acid and Bases (HSAB) has proven to be a useful tool in predicting the outcome of such reactions. This concept utilizes the inherent electronic characteristic of polarizability to define, for example, reacting electrophiles and nucleophiles as either hard or soft. These HSAB definitions have been successfully applied to chemical-induced toxicity in biological systems. Thus, according to this principle, a toxic electrophile reacts preferentially with biological targets of similar hardness or softness. The soft/hard classification of a xenobiotic electrophile has obvious utility in discerning plausible biological targets and molecular mechanisms of toxicity. The purpose of this Perspective is to discuss the HSAB theory of electrophiles and nucleophiles within a toxicological framework. In principle, covalent bond formation can be described by using the properties of their outermost or frontier orbitals. Because these orbital energies for most chemicals can be calculated using quantum mechanical models, it is possible to quantify the relative softness (σ) or hardness (η) of electrophiles or nucleophiles and to subsequently convert this information into useful indices of reactivity. This atomic level information can provide insight into the design of corroborative laboratory research and thereby help investigators discern corresponding molecular sites and mechanisms of toxicant action. The use of HSAB parameters has also been instrumental in the development and identification of potential nucleophilic cytoprotectants that can scavenge toxic electrophiles. Clearly, the difficult task of delineating molecular sites and mechanisms of toxicant action can be facilitated by the application of this quantitative approach. PMID:22053936

Titanocene(III)-Catalyzed Three-Component Reaction of Secondary Amides, Aldehydes, and Electrophilic Alkenes.

PubMed

Zheng, Xiao; He, Jiang; Li, Heng-Hui; Wang, Ao; Dai, Xi-Jie; Wang, Ai-E; Huang, Pei-Qiang

2015-11-09

An umpolung Mannich-type reaction of secondary amides, aliphatic aldehydes, and electrophilic alkenes has been disclosed. This reaction features the one-pot formation of C-N and C-C bonds by a titanocene-catalyzed radical coupling of the condensation products, from secondary amides and aldehydes, with electrophilic alkenes. N-substituted γ-amido-acid derivatives and γ-amido ketones can be efficiently prepared by the current method. Extension to the reaction between ketoamides and electrophilic alkenes allows rapid assembly of piperidine skeletons with α-amino quaternary carbon centers. Its synthetic utility has been demonstrated by a facile construction of the tricyclic core of marine alkaloids such as cylindricine C and polycitorol A. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Complexes of metal chlorides with proton donors — promising polyfunctional catalysts for electrophilic processes

NASA Astrophysics Data System (ADS)

Minsker, Karl S.; Ivanova, S. R.; Biglova, Raisa Z.

1995-05-01

The Bronsted acids formed as a result of the interaction of aluminium chlorides with Group I and II metal chlorides in the presence of proton-donating compounds are promising polyfunctional catalysts for electrophilic processes (polymerisation, depolymerisation and degradation of macromolecules, alkylation, desulfurisation, and hydrogenation). The factor determing the electrophilic activity and selectivity of the action of the catalysts is their acidity. This makes it possible to predict the direction of the changes in the activity and selectivity of the catalyst in specific chemical processes in conformity with the opposite variation rule: with increase in the acidity of the electrophilic catalyst, their activity increases but the selectivity of their action diminishes. The bibliography includes 72 references.

Chiral Brønsted Base-Promoted Nitroalkane Alkylation: Enantioselective Synthesis of sec-Alkyl-3-Substituted Indoles

PubMed Central

Dobish, Mark C.; Johnston, Jeffrey N.

2010-01-01

A Brønsted base-catalyzed reaction of nitroalkanes with alkyl electrophiles provides indole heterocycles substituted at C3 bearing a sec-alkyl group with good enantioselectivity (up to 90% ee). Denitration by hydrogenolysis provides a product with equally high ee. An indolenine intermediate is implicated in the addition step, and surprisingly, water cosolvent was found to have a beneficial effect in this step, leading to a one-pot protocol for elimination/enantioselective addition using PBAM, a bis(amidine) chiral nonracemic base. PMID:21090654

redox Signaling by 8-nitro-cyclic guanosine monophosphate: nitric oxide- and reactive oxygen species-derived electrophilic messenger.

PubMed

Fujii, Shigemoto; Akaike, Takaaki

2013-10-10

Emerging evidence has revealed that nitric oxide (NO)- and reactive oxygen species (ROS)-derived electrophiles formed in cells mediate signal transduction for responses to oxidative stress. The cyclic nucleotide with a nitrated guanine moiety-8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP)-first identified in 2007 as a second messenger for NO and ROS-has certain unique properties that its parental cGMP lacks. For example, it can react with particular protein Cys thiols because of its electrophilicity and can cause unique post-translational modifications of redox-sensor proteins such as Keap1 and H-Ras. Site-specific S-guanylation of Keap1 at Cys434 induced NO- and ROS-mediated adaptive responses to oxidative stress. H-Ras Cys184 S-guanylation was recently found to be involved in activation of mitogen-activated protein kinase cascades as manifested by cellular senescence and heart failure in mouse cardiac hypertrophy models. The latest finding related to the concept of electrophile-based redox signaling is a potent regulatory function of endogenously produced hydrogen sulfide for redox signaling via 8-nitro-cGMP. Electrophile modification of 8-nitro-cGMP, as a second messenger for NO and ROS, by hydrogen sulfide (i.e., electrophile sulfhydration) can most likely effect physiological regulation of cellular redox signaling. Continued investigation of the precise function of cellular hydrogen sulfide that may control electrophile-dependent redox cellular signaling, most typically via 8-nitro-cGMP formation, may provide novel insights into the molecular mechanisms of oxidative stress responses, oxidative stress-related pathology and disease control, and development of therapeutics for various diseases.

Cross-Electrophile Coupling: Principles of Reactivity and Selectivity

PubMed Central

2015-01-01

A critical overview of the catalytic joining of two different electrophiles, cross-electrophile coupling (XEC), is presented with an emphasis on the central challenge of cross-selectivity. Recent synthetic advances and mechanistic studies have shed light on four possible methods for overcoming this challenge: (1) employing an excess of one reagent; (2) electronic differentiation of starting materials; (3) catalyst–substrate steric matching; and (4) radical chain processes. Each method is described using examples from the recent literature. PMID:24820397

Identification of novel malarial cysteine protease inhibitors using structure-based virtual screening of a focused cysteine protease inhibitor library.

PubMed

Shah, Falgun; Mukherjee, Prasenjit; Gut, Jiri; Legac, Jennifer; Rosenthal, Philip J; Tekwani, Babu L; Avery, Mitchell A

2011-04-25

Malaria, in particular that caused by Plasmodium falciparum , is prevalent across the tropics, and its medicinal control is limited by widespread drug resistance. Cysteine proteases of P. falciparum , falcipain-2 (FP-2) and falcipain-3 (FP-3), are major hemoglobinases, validated as potential antimalarial drug targets. Structure-based virtual screening of a focused cysteine protease inhibitor library built with soft rather than hard electrophiles was performed against an X-ray crystal structure of FP-2 using the Glide docking program. An enrichment study was performed to select a suitable scoring function and to retrieve potential candidates against FP-2 from a large chemical database. Biological evaluation of 50 selected compounds identified 21 diverse nonpeptidic inhibitors of FP-2 with a hit rate of 42%. Atomic Fukui indices were used to predict the most electrophilic center and its electrophilicity in the identified hits. Comparison of predicted electrophilicity of electrophiles in identified hits with those in known irreversible inhibitors suggested the soft-nature of electrophiles in the selected target compounds. The present study highlights the importance of focused libraries and enrichment studies in structure-based virtual screening. In addition, few compounds were screened against homologous human cysteine proteases for selectivity analysis. Further evaluation of structure-activity relationships around these nonpeptidic scaffolds could help in the development of selective leads for antimalarial chemotherapy.

Electrophilic surface sites as precondition for the chemisorption of pyrrole on GaAs(001) surfaces

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bruhn, Thomas; Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., Albert-Einstein-Str.9, 12489 Berlin; Fimland, Bjørn-Ove

We report how the presence of electrophilic surface sites influences the adsorption mechanism of pyrrole on GaAs(001) surfaces. For this purpose, we have investigated the adsorption behavior of pyrrole on different GaAs(001) reconstructions with different stoichiometries and thus different surface chemistries. The interfaces were characterized by x-ray photoelectron spectroscopy, scanning tunneling microscopy, and by reflectance anisotropy spectroscopy in a spectral range between 1.5 and 5 eV. On the As-rich c(4 × 4) reconstruction that exhibits only nucleophilic surface sites, pyrrole was found to physisorb on the surface without any significant modification of the structural and electronic properties of the surface. Onmore » the Ga-rich GaAs(001)-(4 × 2)/(6 × 6) reconstructions which exhibit nucleophilic as well as electrophilic surface sites, pyrrole was found to form stable covalent bonds mainly to the electrophilic (charge deficient) Ga atoms of the surface. These results clearly demonstrate that the existence of electrophilic surface sites is a crucial precondition for the chemisorption of pyrrole on GaAs(001) surfaces.« less

Alkylation Damage by Lipid Electrophiles Targets Functional Protein Systems*

PubMed Central

Codreanu, Simona G.; Ullery, Jody C.; Zhu, Jing; Tallman, Keri A.; Beavers, William N.; Porter, Ned A.; Marnett, Lawrence J.; Zhang, Bing; Liebler, Daniel C.

2014-01-01

Protein alkylation by reactive electrophiles contributes to chemical toxicities and oxidative stress, but the functional impact of alkylation damage across proteomes is poorly understood. We used Click chemistry and shotgun proteomics to profile the accumulation of proteome damage in human cells treated with lipid electrophile probes. Protein target profiles revealed three damage susceptibility classes, as well as proteins that were highly resistant to alkylation. Damage occurred selectively across functional protein interaction networks, with the most highly alkylation-susceptible proteins mapping to networks involved in cytoskeletal regulation. Proteins with lower damage susceptibility mapped to networks involved in protein synthesis and turnover and were alkylated only at electrophile concentrations that caused significant toxicity. Hierarchical susceptibility of proteome systems to alkylation may allow cells to survive sublethal damage while protecting critical cell functions. PMID:24429493

Ubiquitin C-terminal electrophiles are activity-based probes for identification and mechanistic study of ubiquitin conjugating machinery.

PubMed

Love, Kerry Routenberg; Pandya, Renuka K; Spooner, Eric; Ploegh, Hidde L

2009-04-17

Protein modification by ubiquitin (Ub) and ubiquitin-like modifiers (Ubl) requires the action of activating (E1), conjugating (E2), and ligating (E3) enzymes and is a key step in the specific destruction of proteins. Deubiquitinating enzymes (DUBs) deconjugate substrates modified with Ub/Ubl's and recycle Ub inside the cell. Genome mining based on sequence homology to proteins with known function has assigned many enzymes to this pathway without confirmation of either conjugating or DUB activity. Function-dependent methodologies are still the most useful for rapid identification or assessment of biological activity of expressed proteins from cells. Activity-based protein profiling uses chemical probes that are active-site-directed for the classification of protein activities in complex mixtures. Here we show that the design and use of an expanded set of Ub-based electrophilic probes allowed us to recover and identify members of each enzyme class in the ubiquitin-proteasome system, including E3 ligases and DUBs with previously unverified activity. We show that epitope-tagged Ub-electrophilic probes can be used as activity-based probes for E3 ligase identification by in vitro labeling and activity studies of purified enzymes identified from complex mixtures in cell lysate. Furthermore, the reactivity of our probe with the HECT domain of the E3 Ub ligase ARF-BP1 suggests that multiple cysteines may be in the vicinity of the E2-binding site and are capable of the transfer of Ub to self or to a substrate protein.

Detection of electrophilic and nucleophilic chemical agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

McElhanon, James R.; Shepodd, Timothy J.

2014-08-12

A "real time" method for detecting chemical agents generally and particularly electrophilic and nucleophilic species by employing tunable, precursor sensor materials that mimic the physiological interaction of these agents to form highly florescent berberine-type alkaloids that can be easily and rapidly detected. These novel precursor sensor materials can be tuned for reaction with both electrophilic (chemical species, toxins) and nucleophilic (proteins and other biological molecules) species. By bonding or otherwise attaching these precursor molecules to a surface or substrate they can be used in numerous applications.

Cu/Mn bimetallic catalysis enables carbonylative Suzuki-Miyaura coupling with unactivated alkyl electrophiles.

PubMed

Pye, Dominic R; Cheng, Li-Jie; Mankad, Neal P

2017-07-01

A bimetallic system consisting of Cu-carbene and Mn-carbonyl co-catalysts was employed for carbonylative C-C coupling of arylboronic esters with alkyl halides, allowing for the convergent synthesis of ketones. The system operates under mild conditions and exhibits complementary reactivity to Pd catalysis. The method is compatible with a wide range of arylboronic ester nucleophiles and proceeds smoothly for both primary and secondary alkyl iodide electrophiles. Preliminary mechanistic experiments corroborate a hypothetical catalytic mechanism consisting of co-dependent cycles wherein the Cu-carbene co-catalyst engages in transmetallation to generate an organocopper nucleophile, while the Mn-carbonyl co-catalyst activates the alkyl halide electrophile by single-electron transfer and then undergoes reversible carbonylation to generate an acylmanganese electrophile. The two cycles then intersect with a heterobimetallic, product-releasing C-C coupling step.

Recent aspects of nitration: New preparative methods and mechanistic studies (A Review)

PubMed Central

Olah, George A.; Narang, Subhash C.; Olah, Judith A.; Lammertsma, Koop

1982-01-01

New preparative methods of electrophilic nitration and transfer nitration are reviewed, including reactions relating to the ambident reactivity of the nitronium ion. Recent aspects of the mechanism of electrophilic aromatic substitution are discussed.

Reference scales for the characterization of cationic electrophiles and neutral nucleophiles.

PubMed

Mayr, H; Bug, T; Gotta, M F; Hering, N; Irrgang, B; Janker, B; Kempf, B; Loos, R; Ofial, A R; Remennikov, G; Schimmel, H

2001-10-03

Twenty-three diarylcarbenium ions and 38 pi-systems (arenes, alkenes, allyl silanes and stannanes, silyl enol ethers, silyl ketene acetals, and enamines) have been defined as basis sets for establishing general reactivity scales for electrophiles and nucleophiles. The rate constants of 209 combinations of these benzhydrylium ions and pi-nucleophiles, 85 of which are first presented in this article, have been subjected to a correlation analysis to determine the electrophilicity parameters E and the nucleophilicity parameters N and s as defined by the equation log k(20 degrees C) = s(N + E) (Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938-957). Though the reactivity scales thus obtained cover more than 16 orders of magnitude, the individual rate constants are reproduced with a standard deviation of a factor of 1.19 (Table 1). It is shown that the reactivity parameters thus derived from the reactions of diarylcarbenium ions with pi-nucleophiles (Figure 3) are also suitable for characterizing the nucleophilic reactivities of alkynes, metal-pi-complexes, and hydride donors (Table 2) and for characterizing the electrophilic reactivities of heterosubstituted and metal-coordinated carbenium ions (Table 3). The reactivity parameters in Figure 3 are, therefore, recommended for the characterization of any new electrophiles and nucleophiles in the reactivity range covered. The linear correlation between the electrophilicity parameters E of benzhydryl cations and the corresponding substituent constants sigma(+) provides Hammett sigma(+) constants for 10 substituents from -1.19 to -2.11, i.e., in a range with only very few previous entries.

Facile synthesis of electrophilic vinyl boranes: reactions of alkynyl-borates and diazonium salts.

PubMed

Zhao, Xiaoxi; Liang, Liyuan; Stephan, Douglas W

2012-10-21

Reactions of alkynylborate salts, easily derived from reaction of frustrated Lewis pairs with terminal alkynes, with diazonium salts to induce 1,1-carboboration affording a facile and efficient route to substituted electrophilic vinyl boranes.

Fingerprinting the reactive toxicity pathways of 50 drinking water disinfection by-products.

PubMed

Stalter, Daniel; O'Malley, Elissa; von Gunten, Urs; Escher, Beate I

2016-03-15

A set of nine in vitro cellular bioassays indicative of different stages of the cellular toxicity pathway was applied to 50 disinfection by-products (DBPs) to obtain a better understanding of the commonalities and differences in the molecular mechanisms of reactive toxicity of DBPs. An Eschericia coli test battery revealed reactivity towards proteins/peptides for 64% of the compounds. 98% activated the NRf2-mediated oxidative stress response and 68% induced an adaptive stress response to genotoxic effects as indicated by the activation of the tumor suppressor protein p53. All DBPs reactive towards DNA in the E. coli assay and activating p53 also induced oxidative stress, confirming earlier studies that the latter could trigger DBP's carcinogenicity. The energy of the lowest unoccupied molecular orbital ELUMO as reactivity descriptor was linearly correlated with oxidative stress induction for trihalomethanes (r(2)=0.98) and haloacetamides (r(2)=0.58), indicating that potency of these DBPs is connected to electrophilicity. However, the descriptive power was poor for haloacetic acids (HAAs) and haloacetonitriles (r(2) (<) 0.06). For HAAs, we additionally accounted for speciation by including the acidity constant with ELUMO in a two-parameter multiple linear regression model. This increased r(2) to >0.80, indicating that HAAs' potency is connected to both, electrophilicity and speciation. Based on the activation of oxidative stress response and the soft electrophilic character of most tested DBPs we hypothesize that indirect genotoxicity-e.g., through oxidative stress induction and/or enzyme inhibition-is more plausible than direct DNA damage for most investigated DBPs. The results provide not only a mechanistic understanding of the cellular effects of DBPs but the effect concentrations may also serve to evaluate mixture effects of DBPs in water samples. Copyright © 2016 Elsevier Ltd. All rights reserved.

LC-MS/MS screening strategy for unknown adducts to N-terminal valine in hemoglobin applied to smokers and nonsmokers.

PubMed

Carlsson, Henrik; von Stedingk, Hans; Nilsson, Ulrika; Törnqvist, Margareta

2014-12-15

Electrophilically reactive compounds have the ability to form adducts with nucleophilic sites in DNA and proteins, constituting a risk for toxic effects. Mass spectrometric detection of adducts to N-terminal valine in hemoglobin (Hb) after detachment by modified Edman degradation procedures is one approach for in vivo monitoring of exposure to electrophilic compounds/metabolites. So far, applications have been limited to one or a few selected reactive species, such as acrylamide and its metabolite glycidamide. This article presents a novel screening strategy for unknown Hb adducts to be used as a basis for an adductomic approach. The method is based on a modified Edman procedure, FIRE, specifically developed for LC-MS/MS analysis of N-terminal valine adducts in Hb detached as fluorescein thiohydantoin (FTH) derivatives. The aim is to detect and identify a priori unknown Hb adducts in human blood samples. Screening of valine adducts was performed by stepwise scanning of precursor ions in small mass increments, monitoring four fragments common for the FTH derivative of valine with different N-substitutions in the multiple-reaction mode, covering a mass range of 135 Da (m/z 503-638). Samples from six smokers and six nonsmokers were analyzed. Control experiments were performed to compare these results with known adducts and to check for artifactual formation of adducts. In all samples of smokers and nonsmokers, seven adducts were identified, of which six have previously been studied. Nineteen unknown adducts were observed, and 14 of those exhibited fragmentation patterns similar to earlier studied FTH derivatives of adducts to valine. Identification of the unknown adducts will be the focus of future work. The presented methodology is a promising screening tool using Hb adducts to indicate exposure to potentially toxic electrophilic compounds and metabolites.

Electrophilic and Redox Properties of Diesel Exhaust Particles

EPA Science Inventory

The adverse health effects of air pollutants have been associated with their redox and electrophilic properties. Although the specific chemical species involved in these effects are not known, the characterization of their general physical and chemical-properties is important to ...

Ube2V2 Is a Rosetta Stone Bridging Redox and Ubiquitin Codes, Coordinating DNA Damage Responses.

PubMed

Zhao, Yi; Long, Marcus J C; Wang, Yiran; Zhang, Sheng; Aye, Yimon

2018-02-28

Posttranslational modifications (PTMs) are the lingua franca of cellular communication. Most PTMs are enzyme-orchestrated. However, the reemergence of electrophilic drugs has ushered mining of unconventional/non-enzyme-catalyzed electrophile-signaling pathways. Despite the latest impetus toward harnessing kinetically and functionally privileged cysteines for electrophilic drug design, identifying these sensors remains challenging. Herein, we designed "G-REX"-a technique that allows controlled release of reactive electrophiles in vivo. Mitigating toxicity/off-target effects associated with uncontrolled bolus exposure, G-REX tagged first-responding innate cysteines that bind electrophiles under true k cat / K m conditions. G-REX identified two allosteric ubiquitin-conjugating proteins-Ube2V1/Ube2V2-sharing a novel privileged-sensor-cysteine. This non-enzyme-catalyzed-PTM triggered responses specific to each protein. Thus, G-REX is an unbiased method to identify novel functional cysteines. Contrasting conventional active-site/off-active-site cysteine-modifications that regulate target activity, modification of Ube2V2 allosterically hyperactivated its enzymatically active binding-partner Ube2N, promoting K63-linked client ubiquitination and stimulating H2AX-dependent DNA damage response. This work establishes Ube2V2 as a Rosetta-stone bridging redox and ubiquitin codes to guard genome integrity.

Introducing Aliphatic Substitution with a Discovery Experiment Using Competing Electrophiles

ERIC Educational Resources Information Center

Curran, Timothy P.; Mostovoy, Amelia J.; Curran, Margaret E.; Berger, Clara

2016-01-01

A facile, discovery-based experiment is described that introduces aliphatic substitution in an introductory undergraduate organic chemistry curriculum. Unlike other discovery-based experiments that examine substitution using two competing nucleophiles with a single electrophile, this experiment compares two isomeric, competing electrophiles…

Modeling of Toxicity-Relevant Electrophilic Reactivity for Guanine with Epoxides: Estimating the Hard and Soft Acids and Bases (HSAB) Parameter as a Predictor.

PubMed

Zhang, Jing; Wang, Chenchen; Ji, Li; Liu, Weiping

2016-05-16

According to the electrophilic theory in toxicology, many chemical carcinogens in the environment and/or their active metabolites are electrophiles that exert their effects by forming covalent bonds with nucleophilic DNA centers. The theory of hard and soft acids and bases (HSAB), which states that a toxic electrophile reacts preferentially with a biological macromolecule that has a similar hardness or softness, clarifies the underlying chemistry involved in this critical event. Epoxides are hard electrophiles that are produced endogenously by the enzymatic oxidation of parent chemicals (e.g., alkenes and PAHs). Epoxide ring opening proceeds through a SN2-type mechanism with hard nucleophile DNA sites as the major facilitators of toxic effects. Thus, the quantitative prediction of chemical reactivity would enable a predictive assessment of the molecular potential to exert electrophile-mediated toxicity. In this study, we calculated the activation energies for reactions between epoxides and the guanine N7 site for a diverse set of epoxides, including aliphatic epoxides, substituted styrene oxides, and PAH epoxides, using a state-of-the-art density functional theory (DFT) method. It is worth noting that these activation energies for diverse epoxides can be further predicted by quantum chemically calculated nucleophilic indices from HSAB theory, which is a less computationally demanding method than the exacting procedure for locating the transition state. More importantly, the good qualitative/quantitative correlations between the chemical reactivity of epoxides and their bioactivity suggest that the developed model based on HSAB theory may aid in the predictive hazard evaluation of epoxides, enabling the early identification of mutagenicity/carcinogenicity-relevant SN2 reactivity.

Electronic Structure Principles and Aromaticity

ERIC Educational Resources Information Center

Chattaraj, P. K.; Sarkar, U.; Roy, D. R.

2007-01-01

The relationship between aromaticity and stability in molecules on the basis of quantities such as hardness and electrophilicity is explored. The findings reveal that aromatic molecules are less energetic, harder, less polarizable, and less electrophilic as compared to antiaromatic molecules, as expected from the electronic structure principles.

Iterative Coupling of Two Different Enones by Nitromethane Using Bifunctional Thiourea Organocatalysts. Stereocontrolled Assembly of Cyclic and Acyclic Structures.

PubMed

Varga, Szilárd; Jakab, Gergely; Csámpai, Antal; Soós, Tibor

2015-09-18

An organocatalytic iterative assembly line has been developed in which nitromethane was sequentially coupled with two different enones using a combination of pseudoenantiomeric cinchona-based thiourea catalysts. Application of unsaturated aldehydes and ketones in the second step of the iterative sequence allows the construction of cyclic syn-ketols and acyclic compounds with multiple contiguous stereocenters. The combination of the multifunctional substrates and ambident electrophiles rendered some organocatalytic transformations possible that have not yet been realized in bifunctional noncovalent organocatalysis.

Advances in Nucleophilic Phosphine Catalysis of Alkenes, Allenes, Alkynes, and MBHADs

PubMed Central

Fan, Yi Chiao

2014-01-01

In nucleophilic phosphine catalysis, tertiary phosphines undergo conjugate additions to activated carbon–carbon multiple bonds to form β-phosphonium enolates, β-phosphonium dienolates, β-phosphonium enoates, and vinyl phosphonium ylides as intermediates. When these reactive zwitterionic species react with nucleophiles and electrophiles, they may generate carbo- and heterocycles with multifarious molecular architectures. This Article describes the reactivities of these phosphonium zwitterions, the applications of phosphine catalysis in the syntheses of biologically active compounds and natural products, and recent developments in the enantioselective phosphine catalysis. PMID:24196409

One electron oxidation of 3-methylcholanthrene: A chemical model for its mechanism of carcinogenesis

NASA Astrophysics Data System (ADS)

Lehner, Andreas F.; Horn, Jamie; Flesher, James W.

2017-06-01

One electron transfer oxidation has long been proposed as a route to the ultimate electrophilic and carcinogenic metabolites of both methylated and non-methylated polycyclic aromatic hydrocarbons (PAH). The carcinogenic hydrocarbon 3-methylcholanthrene (3-MC) has a methyl-analogous function at its meso-anthracenic center in the form of a dimethylene bridge, and treatment of this compound with the one electron transfer oxidizing reagent ferric ferricyanide, FeIII(FeIII(CN)6), in mixed aqueous-organic media generated multiple oxygenated species, many of which duplicate those found in mammalian metabolism including known carcinogens 1-hydroxy-3MC and 1-keto-3MC. These results are in agreement with a Unified Theory for PAH Carcinogenicity which predicts in vivo generation of a proximate benzylic alcohol metabolite from the 3-MC procarcinogen and conjugation with a moiety such as sulfate intended for rapid urinary excretion. The sulfate instead acts as a leaving group and generates an electrophilic carbocation capable of reacting with sensitive nucleophiles such as DNA in cellular nuclei. The products of one electron transfer oxidation align well with predictions of the Unified Theory since in many cases these products provide substrates or precursors for conjugation reactions.

Phosphonium-based ionic liquids and their use in the capture of polluting gases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dai, Sheng; Wang, Congmin; Luo, Huimin

2017-06-06

An ionic liquid composition having the following chemical structural formula: ##STR00001## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently selected from hydrocarbon groups containing at least 1 and up to 20 carbon atoms, and X.sup.- is a cyclic anion that possesses a negatively-charged group reactive with a gaseous electrophilic species, particularly carbon dioxide or sulfur dioxide. Methods for capturing a gaseous electrophilic species, such as CO.sub.2 or SO.sub.2, by contacting the gaseous electrophilic species with an ionic liquid according to Formula (1) are also described.

Catalytic intermolecular carbon electrophile induced semipinacol rearrangement.

PubMed

Zhang, Qing-Wei; Zhang, Xiao-Bo; Li, Bao-Sheng; Xiang, Kai; Zhang, Fu-Min; Wang, Shao-Hua; Tu, Yong-Qiang

2013-02-25

A catalytic intermolecular carbon electrophile induced semipinacol rearrangement was realized and the asymmetric version was also preliminarily accomplished with 92% and 82% ee. The complex tricyclic system architecture with four continuous stereogenic centers could be achieved from simple starting materials in a single step under mild conditions.

Chemical reactivities of ambient air samples in three Southern California communities

PubMed Central

Eiguren-Fernandez, Arantza; Di Stefano, Emma; Schmitz, Debra A.; Guarieiro, Aline Lefol Nani; Salinas, Erika M.; Nasser, Elina; Froines, John R.; Cho, Arthur K.

2015-01-01

The potential adverse health effects of PM2.5 and vapor samples from three communities that neighbor railyards, Commerce (CM), Long Beach (LB), and San Bernardino (SB), were assessed by determination of chemical reactivities attributed to the induction of oxidative stress by air pollutants. The assays used were dithiothreitol (DTT) and dihydrobenzoic acid (DHBA) based procedures for prooxidant content and a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) assay for electrophiles. Prooxidants and electrophiles have been proposed as the reactive chemical species responsible for the induction of oxidative stress by air pollution mixtures. The PM2.5 samples from CM and LB sites showed seasonal differences in reactivities with higher levels in the winter whereas the SB sample differences were reversed. The reactivities in the vapor samples were all very similar, except for the summer SB samples, which contained higher levels of both prooxidants and electrophiles. The results suggest the observed reactivities reflect general geographical differences rather than direct effects of the railyards. Distributional differences in reactivities were also observed with PM2.5 fractions containing most of the prooxidants (74–81%) and the vapor phase most of the electrophiles (82–96%). The high levels of the vapor phase electrophiles and their potential for adverse biological effects point out the importance of the vapor phase in assessing the potential health effects of ambient air. PMID:25947123

Carbocation Rearrangement in An Electrophilic Aromatic Substitution Discovery Laboratory

ERIC Educational Resources Information Center

Polito, Victoria; Hamann, Christian S.; Rhile, Ian J.

2010-01-01

In this discovery laboratory, students performed electrophilic aromatic substitution reactions between 1,4-dimethoxybenzene and either 2-methyl-2-butanol or 3-methyl-2-butanol with sulfuric acid as a catalyst. The carbocation from 3-methyl-2-butanol undergoes a hydride shift, and hence, both reactions afford…

Cross-coupling of alkenyl/aryl carboxylates with Grignard reagent via Fe-catalyzed C-O bond activation.

PubMed

Li, Bi-Jie; Xu, Li; Wu, Zhen-Hua; Guan, Bing-Tao; Sun, Chang-Liang; Wang, Bi-Qin; Shi, Zhang-Jie

2009-10-21

Iron-catalyzed cross-coupling of alkenyl/aryl carboxylates with primary alkyl Grignard reagent was described. This reaction brought a new family of electrophiles to iron catalysis. The combination of an inexpensive carboxylate electrophile and an iron catalyst would generate ample advantages.

Synthesis of substituted tetrahydroisoquinolines by lithiation then electrophilic quench.

PubMed

Talk, Ruaa A; Duperray, Alexia; Li, Xiabing; Coldham, Iain

2016-06-07

Substituted N-tert-butoxycarbonyl (Boc)-1,2,3,4-tetrahydroisoquinolines were prepared and treated with n-butyllithium in THF at -50 °C to test the scope of the metallation and electrophilic quench. The lithiation was optimised by using in situ ReactIR spectroscopy and the rate of rotation of the carbamate was determined. The 1-lithiated intermediates could be trapped with a variety of electrophiles to give good yields of 1-substituted tetrahydroisoquinoline products. Treatment with acid or reduction with LiAlH4 allows conversion to the N-H or N-Me compound. The chemistry was applied to the efficient total syntheses of the alkaloids (±)-crispine A and (±)-dysoxyline.

An Overview of the Chemistry and Biology of Reactive Aldehydes

PubMed Central

Fritz, Kristofer S.; Petersen, Dennis R.

2012-01-01

The non-enzymatic free radical generation of reactive aldehydes is known to contribute to diseases of sustained oxidative stress including rheumatoid arthritis, atherosclerosis, neurodegenerative and a number of liver diseases. At the same time, the accumulation of lipid electrophiles has been demonstrated to play a role in cell signaling events through modification of proteins critical for cellular homeostasis. Given the broad scope of reactivity profiles and the ability to modify numerous proteomic and genomic processes, new emphasis is being placed on a systems-based analysis of the consequences of electrophilic adduction. This review focuses on the generation and chemical reactivity of lipid-derived aldehydes with a special focus on the homeostatic responses to electrophilic stress. PMID:22750507

Organic Chemistry Students' Ideas about Nucleophiles and Electrophiles: The Role of Charges and Mechanisms

ERIC Educational Resources Information Center

Anzovino, Mary E.; Bretz, Stacey Lowery

2015-01-01

Organic chemistry students struggle with reaction mechanisms and the electron-pushing formalism (EPF) used by practicing organic chemists. Faculty have identified an understanding of nucleophiles and electrophiles as one conceptual prerequisite to mastery of the EPF, but little is known about organic chemistry students' knowledge of nucleophiles…

Evaluation of the Commercial off-the-shelf (COTS) Low Temperature Powder Coating (LTPC)

DTIC Science & Technology

2017-11-15

isothiazolin- 3-one (OIT) 26530-20-1 120°C 4.9x10-3 (25°C) Isothiazolinone; Mode of Action: Electrophilic active agent. Reacts with nucleophiles (e.g...Action: Electrophilic active agent with activated N-S bond and vinyl activated halogens; reacts with nucleophilic elements of cell proteins

Synthesis of Triarylmethane and Xanthene Dyes Using Electrophilic Aromatic Substitution Reactions

ERIC Educational Resources Information Center

McCullagh, James V.; Daggett, Kelly A.

2007-01-01

The synthesis of dyes has long been a popular topic in organic chemistry laboratory experiments because it allows students to see first hand that reactions learned in class can be used to make compounds with useful applications. In this experiment electrophilic aromatic substitution reactions are used to synthesize several triarylmethane and…

Nucleophile sensitivity of Drosophila TRPA1 underlies light-induced feeding deterrence

PubMed Central

Du, Eun Jo; Ahn, Tae Jung; Wen, Xianlan; Seo, Dae-Won; Na, Duk L; Kwon, Jae Young; Choi, Myunghwan; Kim, Hyung-Wook; Cho, Hana; Kang, KyeongJin

2016-01-01

Solar irradiation including ultraviolet (UV) light causes tissue damage by generating reactive free radicals that can be electrophilic or nucleophilic due to unpaired electrons. Little is known about how free radicals induced by natural sunlight are rapidly detected and avoided by animals. We discover that Drosophila Transient Receptor Potential Ankyrin 1 (TRPA1), previously known only as an electrophile receptor, sensitively detects photochemically active sunlight through nucleophile sensitivity. Rapid light-dependent feeding deterrence in Drosophila was mediated only by the TRPA1(A) isoform, despite the TRPA1(A) and TRPA1(B) isoforms having similar electrophile sensitivities. Such isoform dependence re-emerges in the detection of structurally varied nucleophilic compounds and nucleophilicity-accompanying hydrogen peroxide (H2O2). Furthermore, these isoform-dependent mechanisms require a common set of TRPA1(A)-specific residues dispensable for electrophile detection. Collectively, TRPA1(A) rapidly responds to natural sunlight intensities through its nucleophile sensitivity as a receptor of photochemically generated radicals, leading to an acute light-induced behavioral shift in Drosophila. DOI: http://dx.doi.org/10.7554/eLife.18425.001 PMID:27656903

Dual nickel and Lewis acid catalysis for cross-electrophile coupling: the allylation of aryl halides with allylic alcohols† †Electronic supplementary information (ESI) available. CCDC 1515176. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7sc03140h

PubMed Central

Jia, Xue-Gong; Guo, Peng; Duan, Jicheng

2017-01-01

Controlling the selectivity in cross-electrophile coupling reactions is a significant challenge, particularly when one electrophile is much more reactive. We report a general and practical strategy to address this problem in the reaction between reactive and unreactive electrophiles by a combination of nickel and Lewis acid catalysis. This strategy is used for the coupling of aryl halides with allylic alcohols to form linear allylarenes selectively. The reaction tolerates a wide range of functional groups (e.g. silanes, boronates, anilines, esters, alcohols, and various heterocycles) and works with various allylic alcohols. Complementary to most current routes for the C3 allylation of an unprotected indole, this method provides access to C2 and C4–C7 allylated indoles. Preliminary mechanistic experiments reveal that the reaction might start with an aryl nickel intermediate, which then reacts with Lewis acid activated allylic alcohols in the presence of Mn. PMID:29629130

Thiol-Based Probe for Electrophilic Natural Products Reveals That Most of the Ammosamides Are Artifacts.

PubMed

Reimer, Daniela; Hughes, Chambers C

2017-01-27

To date, 16 members of the ammosamide family of natural products have been discovered, and except for ammosamide D each of these metabolites is characterized by an unusual chlorinated pyrrolo[4,3,2-de]quinoline skeleton. Several ammosamides have been shown to inhibit quinone reductase 2, a flavoenzyme responsible for quelling toxic oxidative species in cells or for killing cancer cells outright. Treatment of the extract from an ammosamide-producing culture (Streptomyces strain CNR-698) with a thiol-based reagent designed to label electrophilic natural products produced an ammosamide C-thiol adduct. This observation led us to hypothesize, and then demonstrate through experimentation, that all of the other ammosamides are derived from ammosamide C via nonenzymatic processes involving exposure to nucleophiles, air, and light. Like many established electrophilic natural products, reaction with the thiol probe suggests that ammosamide C is itself an electrophilic natural product. Although ammosamide C did not show substantial cytotoxicity against cancer cells, its activity against a marine Bacillus bacterial strain may reflect its ecological role.

Electronic forces as descriptors of nucleophilic and electrophilic regioselectivity and stereoselectivity.

PubMed

Liu, Shubin; Rong, Chunying; Lu, Tian

2017-01-04

One of the main tasks of theoretical chemistry is to rationalize computational results with chemical insights. Key concepts of such nature include nucleophilicity, electrophilicity, regioselectivity, and stereoselectivity. While computational tools are available to predict barrier heights and other reactivity properties with acceptable accuracy, a conceptual framework to appreciate above quantities is still lacking. In this work, we introduce the electronic force as the fundamental driving force of chemical processes to understand and predict molecular reactivity. It has three components but only two are independent. These forces, electrostatic and steric, can be employed as reliable descriptors for nucleophilic and electrophilic regioselectivity and stereoselectivity. The advantages of using these forces to evaluate molecular reactivity are that electrophilic and nucleophilic attacks are featured by distinct characteristics in the electrostatic force and no knowledge of quantum effects included in the kinetic and exchange-correlation energies is required. Examples are provided to highlight the validity and general applicability of these reactivity descriptors. Possible applications in ambident reactivity, σ and π holes, frustrated Lewis pairs, and stereoselective reactions are also included in this work.

Phase I Metabolic Stability and Electrophilic Reactivity of 2-Phenylaminophenylacetic Acid Derived Compounds.

PubMed

Pang, Yi Yun; Tan, Yee Min; Chan, Eric Chun Yong; Ho, Han Kiat

2016-07-18

Diclofenac and lumiracoxib are two highly analogous 2-phenylaminophenylacetic acid anti-inflammatory drugs exhibiting occasional dose-limiting hepatotoxicities. Prior data indicate that bioactivation and reactive metabolite formation play roles in the observed toxicity, but the exact chemical influence of the substituents remains elusive. In order to elucidate the role of chemical influence on metabolism related toxicity, metabolic stability and electrophilic reactivity were investigated for a series of structurally related analogues and their resulting metabolites. The resulting analogues embody progressive physiochemical changes through varying halogeno- and aliphatic substituents at two positions and were subjected to in vitro human liver microsomal metabolic stability and cell-based GSH depletion assays (to measure electrophilic reactivity). LC-MS/MS analysis of the GSH trapped reactive intermediates derived from the analogues was then used to identify the putative structures of reactive metabolites. We found that chemical modifications of the structural backbone led to noticeable perturbations of metabolic stability, electrophilic reactivity, and structures and composition of reactive metabolites. With the acquired data, the relationships between stability, reactivity, and toxicity were investigated in an attempt to correlate between Phase I metabolism and in vitro toxicity. A positive correlation was identified between reactivity and in vitro toxicity, indicating that electrophilic reactivity can be an indicator for in vitro toxicity. All in all, the effect of substituents on the structures and reactivity of the metabolites, however subtle the changes, should be taken into consideration during future drug design involving similar chemical features.

A quantitative approach to nucleophilic organocatalysis

PubMed Central

Lakhdar, Sami; Maji, Biplab; Ofial, Armin R

2012-01-01

Summary The key steps in most organocatalytic cyclizations are the reactions of electrophiles with nucleophiles. Their rates can be calculated by the linear free-energy relationship log k(20 °C) = s N(E + N), where electrophiles are characterized by one parameter (E) and nucleophiles are characterized by the solvent-dependent nucleophilicity (N) and sensitivity (s N) parameters. Electrophilicity parameters in the range –10 < E < –5 were determined for iminium ions derived from cinnamaldehyde and common organocatalysts, such as pyrrolidines and imidazolidinones, by studying the rates of their reactions with reference nucleophiles. Iminium activated reactions of α,β-unsaturated aldehydes can, therefore, be expected to proceed with nucleophiles of 2 < N < 14, because such nucleophiles are strong enough to react with iminium ions but weak enough not to react with their precursor aldehydes. With the N parameters of enamines derived from phenylacetaldehyde and MacMillan’s imidazolidinones one can rationalize why only strong electrophiles, such as stabilized carbenium ions (–8 < E < –2) or hexachlorocyclohexadienone (E = –6.75), are suitable electrophiles for enamine activated reactions with imidazolidinones. Several mechanistic controversies concerning iminium and enamine activated reactions could thus be settled by studying the reactivities of independently synthesized intermediates. Kinetic investigations of the reactions of N-heterocyclic carbenes (NHCs) with benzhydrylium ions showed that they have similar nucleophilicities to common organocatalysts (e.g., PPh3, DMAP, DABCO) but are much stronger (100–200 kJ mol–1) Lewis bases. While structurally analogous imidazolylidenes and imidazolidinylidenes have comparable nucleophilicities and Lewis basicities, the corresponding deoxy Breslow intermediates differ dramatically in reactivity. The thousand-fold higher nucleophilicity of 2-benzylidene-imidazoline relative to 2-benzylidene-imidazolidine is explained by the gain of aromaticity during electrophilic additions to the imidazoline derivatives. O-Methylated Breslow intermediates are a hundred-fold less nucleophilic than deoxy Breslow intermediates. PMID:23019481

Crystallization-induced dynamic resolution of Fox chiral auxiliary and application to the diastereoselective electrophilic fluorination of amide enolates.

PubMed

Lubin, Hodney; Dupuis, Christophe; Pytkowicz, Julien; Brigaud, Thierry

2013-04-05

A highly efficient crystallization-induced dynamic resolution (CIDR) of trans-Fox (fluorinated oxazolidine) chiral auxiliary is reported. This chiral auxiliary was used for highly diastereoselective (>98% de) electrophilic fluorination of amide enolates. After removal of the chiral auxiliary, highly valuable enantiopure α-fluorocarboxylic acids and β-fluoroalcohols are obtained.

Palladium-Catalyzed Asymmetric Allylic Alkylation of Electron-Deficient Pyrroles with Meso Electrophiles

PubMed Central

Osipov, Maksim; Dong, Guangbin

2012-01-01

Pyrroles can serve as competent nucleophiles with meso electrophiles in the Pd-catalyzed asymmetric allylic alkylation. The products from this transformation were obtained as a single regio- and diastereomer in high yield and enantiopurity. A nitropyrrole-containing nucleoside analogue was synthesized in 7 steps to demonstrate the synthetic utility of this transformation. PMID:22506671

Electrophilic acid gas-reactive fluid, proppant, and process for enhanced fracturing and recovery of energy producing materials

DOEpatents

Fernandez, Carlos A.; Heldebrant, David J.; Bonneville, Alain H. R.; Jung, Hun Bok; Carroll, Kenneth

2016-09-20

An electrophilic acid gas-reactive fracturing and recovery fluid, proppant, and process are detailed. The fluid expands in volume to provide rapid and controlled increases in pressure that enhances fracturing in subterranean bedrock for recovery of energy-producing materials. Proppants stabilize openings in fractures and fissures following fracturing.

Molecular Modeling of an Electrophilic Addition Reaction with "Unexpected" Regiochemistry

ERIC Educational Resources Information Center

Best, Katherine T.; Li, Diana; Helms, Eric D.

2017-01-01

The electrophilic addition of a hydrohalic acid (HX) to an alkene is often one of the first reactions learned in second-year undergraduate organic chemistry classes. During the ensuing discussion of the mechanism, it is shown that this reaction follows Markovnikov's rule, which states that the hydrogen atom will attach to the carbon with fewer…

General synthesis of C-glycosyl amino acids via proline-catalyzed direct electrophilic alpha-amination of C-glycosylalkyl aldehydes.

PubMed

Nuzzi, Andrea; Massi, Alessandro; Dondoni, Alessandro

2008-10-16

Non-natural axially and equatorially linked C-glycosyl alpha-amino acids (glycines, alanines, and CH2-serine isosteres) with either S or R alpha-configuration were prepared by D- and L-proline-catalyzed (de >95%) alpha-amination of C-glycosylalkyl aldehydes using dibenzyl azodicarboxylate as the electrophilic reagent.

Copper-Catalyzed SN2'-Selective Allylic Substitution Reaction of gem-Diborylalkanes.

PubMed

Zhang, Zhen-Qi; Zhang, Ben; Lu, Xi; Liu, Jing-Hui; Lu, Xiao-Yu; Xiao, Bin; Fu, Yao

2016-03-04

A Cu/(NHC)-catalyzed SN2'-selective substitution reaction of allylic electrophiles with gem-diborylalkanes is reported. Different substituted gem-diborylalkanes and allylic electrophiles can be employed in this reaction, and various synthetic valuable functional groups can be tolerated. The asymmetric version of this reaction was initially researched with chiral N-heterocyclic carbene (NHC) ligands.

Transition-Metal Catalysis of Nucleophilic Substitution Reactions: A Radical Alternative to SN1 and SN2 Processes.

PubMed

Fu, Gregory C

2017-07-26

Classical methods for achieving nucleophilic substitutions of alkyl electrophiles (S N 1 and S N 2) have limited scope and are not generally amenable to enantioselective variants that employ readily available racemic electrophiles. Radical-based pathways catalyzed by chiral transition-metal complexes provide an attractive approach to addressing these limitations.

Transition-Metal Catalysis of Nucleophilic Substitution Reactions: A Radical Alternative to SN1 and SN2 Processes

PubMed Central

2017-01-01

Classical methods for achieving nucleophilic substitutions of alkyl electrophiles (SN1 and SN2) have limited scope and are not generally amenable to enantioselective variants that employ readily available racemic electrophiles. Radical-based pathways catalyzed by chiral transition-metal complexes provide an attractive approach to addressing these limitations. PMID:28776010

Prediction of the chemo- and regioselectivity of Diels-Alder reactions of o-benzoquinone derivatives with thiophenes by means of DFT-based reactivity indices

NASA Astrophysics Data System (ADS)

Ghomri, Amina; Mekelleche, Sidi Mohamed

2014-03-01

Global and local reactivity indices derived from density functional theory were used to elucidate the regio- and chemoselectivity of Diels-Alder reactions of masked o-benzoquinones with thiophenes acting as dienophiles. The polarity of the studied reactions is evaluated in terms of the difference of electrophilicity powers between the diene and dienophile partners. Preferential cyclisation modes of these cycloadditions are predicted using Domingo's polar model based on the local electrophilicity index, ωk, of the electrophile and the local nucleophilicity index, Nuk, of the nucleophile. The theoretical calculations, carried out at the B3LYP/6-311G(d,p) level of theory, are in good agreement with experimental findings.

Generation and exploitation of acyclic azomethine imines in chiral Brønsted acid catalysis

NASA Astrophysics Data System (ADS)

Hashimoto, Takuya; Kimura, Hidenori; Kawamata, Yu; Maruoka, Keiji

2011-08-01

Successful implementation of a catalytic asymmetric synthesis strategy to produce enantiomerically enriched compounds requires the adoption of suitable prochiral substrates. The combination of an azomethine imine electrophile with various nucleophiles could give straightforward access to a number of synthetically useful chiral hydrazines, but is used rarely. Here we report the exploitation of acyclic azomethine imines as a new type of prochiral electrophile. They can be generated in situ by the condensation of N‧-benzylbenzoylhydrazide with a variety of aldehydes in the presence of a catalytic amount of an axially chiral dicarboxylic acid. By trapping these electrophiles with alkyl diazoacetate or (diazomethyl)phosphonate nucleophiles, we produced a diverse array of chiral α-diazo-β-hydrazino esters and phosphonates with excellent enantioselectivities.

2-Diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one: Another Utility for Electrophilic Trifluoromethylthiolation Reactions.

PubMed

Huang, Zhongyan; Okuyama, Kenta; Wang, Chen; Tokunaga, Etsuko; Li, Xiaorui; Shibata, Norio

2016-06-01

2-Diazo-1-phenyl-2-((trifluoromethyl)sulfonyl)ethan-1-one (diazo-triflone) ( 2 ) is not only a building block but also a reagent. In this study, diazo-triflone, which was originally used for the synthesis of β-lactam triflones as a trifluoromethanesulfonyl (SO 2 CF 3 ) building block under catalyst-free thermal conditions, is redisclosed as an effective electrophilic trifluoromethylthiolation reagent under copper catalysis. A broad set of enamines, indoles, β-keto esters, pyrroles, and anilines were nicely transformed into corresponding trifluoromethylthio (SCF 3 ) compounds in good to high yields by diazo-triflone under copper catalysis via an electrophilic-type reaction. A coupling-type trifluoromethylthiolation reaction of aryl iodides was also realized by diazo-triflone in acceptable yields.

Nitrates and NO-NSAIDs in Cancer Chemoprevention & Therapy: In Vitro Evidence Querying the NO Donor Functionality

PubMed Central

Dunlap, Tareisha; Abdul-Hay, Samer; Chandrasena, R. Esala P.; Hagos, Ghenet K; Sinha, Vaishali; Wang, Zhiqiang; Wang, Huali; Thatcher, Gregory R. J.

2008-01-01

Properties of the NO-ASA family of NO-donating NSAIDs (NO-NSAIDs), notably NCX 4016 (mNO-ASA) and NCX 4040 (pNO-ASA), reported in more than a hundred publications, have included positive preclinical data in cancer chemoprevention and therapy. Evidence is presented that the antiproliferative, the chemopreventive (antioxidant/electrophile response element (ARE) activation), and the anti-inflammatory activity of NO-ASA in cell cultures is replicated by X-ASA derivatives that are incapable of acting as NO donors. pBr-ASA and mBr-ASA are conisogenic with NO-ASA, but are not NO donors. The biological activity of pNO-ASA is replicated by pBr-ASA; and both pNO-ASA and pBr-ASA are bioactivated to the same quinone methide electrophile. The biological activity of mNO-ASA is replicated by mBr-ASA; mNO-ASA and mBr-ASA are bioactivated to different benzyl electrophiles. The observed activity is likely initiated by trapping of thiol biomolecules by the quinone and benzyl electrophiles, leading to depletion of GSH and modification of Cys-containing sensor proteins. Whereas all NO-NSAIDs containing the same structural “linker” as NCX 4040 and NCX 4016 are anticipated to possess activity resulting from bioactivation to electrophilic metabolites, this expectation does not extend to other linker structures. Nitrates require metabolic bioactivation to liberate NO bioactivity, which is often poorly replicated in vitro, and NO bioactivity provided by NO-NSAIDs in vivo provides proven therapeutic benefits in mitigation of NSAID gastrotoxicity. The in vivo properties of X-ASA drugs await discovery. PMID:18485921

Nitrates and NO-NSAIDs in cancer chemoprevention and therapy: in vitro evidence querying the NO donor functionality.

PubMed

Dunlap, Tareisha; Abdul-Hay, Samer O; Chandrasena, R Esala P; Hagos, Ghenet K; Sinha, Vaishali; Wang, Zhiqiang; Wang, Huali; Thatcher, Gregory R J

2008-09-01

Properties of the NO-ASA family of NO-donating NSAIDs (NO-NSAIDs), notably NCX 4016 (mNO-ASA) and NCX 4040 (pNO-ASA), reported in more than one hundred publications, have included positive preclinical data in cancer chemoprevention and therapy. Evidence is presented that the antiproliferative, the chemopreventive (antioxidant/electrophile response element (ARE) activation), and the anti-inflammatory activity of NO-ASA in cell cultures is replicated by X-ASA derivatives that are incapable of acting as NO donors. pBr-ASA and mBr-ASA are conisogenic with NO-ASA, but are not NO donors. The biological activity of pNO-ASA is replicated by pBr-ASA; and both pNO-ASA and pBr-ASA are bioactivated to the same quinone methide electrophile. The biological activity of mNO-ASA is replicated by mBr-ASA; mNO-ASA and mBr-ASA are bioactivated to different benzyl electrophiles. The observed activity is likely initiated by trapping of thiol biomolecules by the quinone and benzyl electrophiles, leading to depletion of GSH and modification of Cys-containing sensor proteins. Whereas all NO-NSAIDs containing the same structural "linker" as NCX 4040 and NCX 4016 are anticipated to possess activity resulting from bioactivation to electrophilic metabolites, this expectation does not extend to other linker structures. Nitrates require metabolic bioactivation to liberate NO bioactivity, which is often poorly replicated in vitro, and NO bioactivity provided by NO-NSAIDs in vivo provides proven therapeutic benefits in mitigation of NSAID gastrotoxicity. The in vivo properties of X-ASA drugs await discovery.

CuH-catalysed hydroamination of arylalkynes with hydroxylamine esters – a computational scrutiny of rival mechanistic pathways† †Electronic supplementary information (ESI) available: Complete account of all examined pathways, computational details, full description of reported key species (energies and Cartesian coordinates in angstroms). See DOI: 10.1039/c7sc01107e Click here for additional data file.

PubMed Central

Tobisch, Sven

2017-01-01

An in-depth computational mechanistic probe of the CuH-mediated hydroamination of internal arylalkynes with an archetype hydroxylamine ester and hydrosilane by a (Xantphos)CuH catalyst (Xantphos ≡ {P^P} ≡ 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) is presented. This first comprehensive computational study of the CuH-mediated electrophilic alkyne hydroamination has identified the most accessible pathway for the rival avenues for direct and reductive hydroamination. The mechanistic picture derived from smooth energy profiles obtained by employing a reliable computational protocol applied to a realistic catalyst model conforms to all available experimental data. The crucial vinyl- and alkylcopper intermediates were found to display a distinct chemodivergence in their reactivity towards amine electrophile and alcohol, which ensures the successful formation of α-branched alkylamines together with (E)-enamines. On the one hand, the vinylcopper is somewhat preferably approached by the alcohol, thereby rendering the reductive hydroamination avenue favourable in the presence of both amine electrophile and alcohol. In contrast, the greater kinetic demands for protonation versus electrophilic amination predicted for the alkylcopper prevents the reductive hydroamination avenue to become non-productive. Electronically modified hydroxylamine esters are found to influence the chemoselectivity in reactivity towards amine electrophile and alcohol achievable for the vinyl- and alkylcopper, thereby offering an opportunity for process improvement. PMID:28660063

Screening for Natural Chemoprevention Agents that Modify Human Keap1

PubMed Central

Hu, Chenqi; Nikolic, Dejan; Eggler, Aimee L.; Mesecar, Andrew D.; van Breemen, Richard B.

2012-01-01

Upregulation of cytoprotective enzymes by therapeutic agents to prevent damage by reactive oxygen species and xenobiotic electrophiles is a strategy for cancer chemoprevention. The Kelch-like ECH-associated protein 1 (Keap1) and its binding partner, transcription factor NF-E2-related factor-2 (Nrf2), are chemoprevention targets because of their role in regulating the antioxidant response element (ARE) in response to oxidative stress and exposure to electrophiles. Modification of the sensor protein Keap1 by electrophiles such as the isothiocyanate sulforaphane can direct Nrf2 accumulation in the nucleus and subsequent ARE activation. Since our previous matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF MS)-based screening method to discover natural products that modify Keap1 does not detect covalent modification of Keap1 by some highly reversible agents such as sulforaphane, a more sensitive screening assay was developed. In this new assay, electrophiles that have reversibly modified Keap1 can be released, trapped and detected as β-mercaptoethanol adducts by mass spectrometry. Isoliquiritigenin and sulforaphane, known ARE activators that target Keap1, were used to validate the assay. To determine the ability of the assay to identify electrophiles in complex matrixes that modify Keap1, sulforaphane was spiked into a cocoa extract, and LC-MS/MS using high resolution mass spectrometry with accurate mass measurement was used to identify β-mercaptoethanol adducts of sulforaphane that had been released from Keap1. This screening assay permits identification of potential chemoprevention agents in complex natural product mixtures that reversibly modify Keap1 but cannot be detected using MALDI-TOF MS. PMID:22074792

Catalytic Ketone Hydrodeoxygenation Mediated by Highly Electrophilic Phosphonium Cations.

PubMed

Mehta, Meera; Holthausen, Michael H; Mallov, Ian; Pérez, Manuel; Qu, Zheng-Wang; Grimme, Stefan; Stephan, Douglas W

2015-07-06

Ketones are efficiently deoxygenated in the presence of silane using highly electrophilic phosphonium cation (EPC) salts as catalysts, thus affording the corresponding alkane and siloxane. The influence of distinct substitution patterns on the catalytic effectiveness of several EPCs was evaluated. The deoxygenation mechanism was probed by DFT methods. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Estrogen Receptor Driven Inhibitor Synthesis

DTIC Science & Technology

2006-09-01

labeling thiols in cellular pro- tein extracts [6,7]. But because these probes are based on nonspecific electrophiles , they are inherently less...selective electrophiles such as maleimide, alkyl halides, and iodoacetamide [5,25,26]. Conclusions DSSA probes composed of fluorescein tethered to rho...Haugland, F. Mao, Fluorinated xanthene derivatives, US patent. 6 (162), (2000) 931. [21] T. Nguyen, M.B. Francis, Practical route to functionalized rhoda

Catalytic stereoselective synthesis of highly substituted indanones via tandem Nazarov cyclization and electrophilic fluorination trapping.

PubMed

Nie, Jing; Zhu, Hong-Wei; Cui, Han-Feng; Hua, Ming-Qing; Ma, Jun-An

2007-08-02

A new catalytic stereoselective tandem transformation via Nazarov cyclization/electrophilic fluorination has been accomplished. This sequence is efficiently catalyzed by a Cu(II) complex to afford fluorine-containing 1-indanone derivatives with two new stereocenters with high diastereoselectivity (trans/cis up to 49/1). Three examples of catalytic enantioselective tandem transformation are presented.

Electrophilic acid gas-reactive fluid, proppant, and process for enhanced fracturing and recovery of energy producing materials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fernandez, Carlos A.; Heldebrant, David J.; Bonneville, Alain

An electrophilic acid gas-reactive fracturing fluid, proppant, and process are detailed. The fluid expands in volume to provide rapid and controlled increases in pressure that enhances fracturing in subterranean bedrock for recovery of energy-producing materials. The proppant stabilizes fracture openings in the bedrock to enhance recovery of energy-producing materials.

Assessing the superelectrophilic dimension through sigma-complexation, SNAr and Diels-Alder reactivity.

PubMed

Buncel, Erwin; Terrier, François

2010-05-21

In the domain of organic chemistry, S(N)Ar substitutions represent a class of reactions of overwhelming importance, both in synthesis and in the understanding of structure-reactivity relationships, especially the role of sigma-complex intermediates. The primary factor necessary for achievement of S(N)Ar reactions is the presence of a good leaving group, which allows facile rearomatization of the ring undergoing nucleophilic attack. Consistent is the finding that the superelectrophilic chloronitrobenzofuroxans--or furazans--exhibit a very high S(N)Ar reactivity, allowing a number of C-C, C-N, C-O couplings to be achieved that are not accessible with the classical series of nitro-substituted aromatics. Of particular interest is the synthesis of a number of indoles, indolizines, pyrroles and extended pi-excessive aromatic structures like azulene substituted by superelectrophilic moieties. The remarkable driving force for the facile completion of these reactions is the 10 orders of magnitude greater reactivity of 10pi-electron-deficient heteroaromatics such as 4,6-dinitrobenzofuroxan (DNBF) than of the most reactive trinitrobenzene derivatives in sigma-adduct complexation. Among the factors that have been recognized as governing superelectrophilicity, there is the poor aromaticity of 6-membered 10pi-electron structures investigated, with a common origin for sigma-complexation and pericyclic processes. A remarkable capacity of these structures is actually to contribute to a variety of Diels-Alder reactions. As an example, the DNBF molecule formally behaves as a nitroalkene, being susceptible to act as a dienophile as well as a heterodiene. Another remarkable Diels-Alder pathway is the capacity of the 6-membered carbocyclic ring of DNBF to act as a carbodiene. Also noteworthy is the successful Diels-Alder trapping of the dinitroso intermediate associated with 1-oxide/3-oxide tautomerism of the furoxan moiety of 4-aza-6-nitrobenzofuroxan. A point of fundamental importance in taking advantage of the reactivity of superelectrophilic structures at hand has been a successful calibration of their reactivity within the electrophilicity E scale developed by Mayr to describe nucleophile-electrophile combinations in general. It has thus been established that the E parameters measuring the electrophilicity of neutral heteroaromatics lie in the same region of the E scale as a number of highly reactive cationic reagents. Besides a reactivity rather similar to that of the 4-nitrobenzenediazonium cation (vide supra), the most electrophilic neutral molecules (DNBF, DNTP, DNBZ) are as electrophilic as tropylium cations or a number of metal-coordinated carbenium ions. Furthermore, there is a remarkable link between the pK(a)(H(2)O) and E scales, as evidenced by the existence of a unique linear relationship spanning more than 20 orders of reactivity. This relationship appears as being a nice probe to predict the feasibility of S(N)Ar substitutions and related sigma-complexation processes. Also revealing in terms of feasibility of the reactions is the existence of a close correlation between the electrochemical oxidation potential E degrees of sigma-adducts and their positioning on the pK(a)(H(2)O) scale. Our data can also be used to evaluate the potential of a theoretical model recently derived from DFT calculations, namely the global electrophilicity index omega, for the description of nucleophile-electrophile combinations. While showing several significant deviations, a reasonably linear omega vs. pK(a)(H(2)O) relationship is obtained when restricting the correlation to structurally similar electrophilic moieties. On this basis, valuable information could be derived regarding the polar character of some DA reactions. Overall, the global electrophilicity (omega) approach may be a promising avenue in future work of electrophile-nucleophile combinations.

Akt3 is a privileged first responder in isozyme-specific electrophile response.

PubMed

Long, Marcus J C; Parvez, Saba; Zhao, Yi; Surya, Sanjna L; Wang, Yiran; Zhang, Sheng; Aye, Yimon

2017-03-01

Isozyme-specific post-translational regulation fine tunes signaling events. However, redundancy in sequence or activity renders links between isozyme-specific modifications and downstream functions uncertain. Methods to study this phenomenon are underdeveloped. Here we use a redox-targeting screen to reveal that Akt3 is a first-responding isozyme sensing native electrophilic lipids. Electrophile modification of Akt3 modulated downstream pathway responses in cells and Danio rerio (zebrafish) and markedly differed from Akt2-specific oxidative regulation. Digest MS sequencing identified Akt3 C119 as the privileged cysteine that senses 4-hydroxynonenal. A C119S Akt3 mutant was hypomorphic for all downstream phenotypes shown by wild-type Akt3. This study documents isozyme-specific and chemical redox signal-personalized physiological responses.

Electrophilic activation and cycloisomerization of enynes: a new route to functional cyclopropanes.

PubMed

Bruneau, Christian

2005-04-15

Transformations of enynes in the presence of transition-metal catalysts have played an important role in the preparation of a variety of cyclic compounds. Recent developments in the activation of triple carbon-carbon bonds by electrophilic metal centers have provided a new entry to the selective synthesis of cyclopropane derivatives from enynes. The mechanisms of these reactions involve catalytic species with both ionic and cyclopropylcarbenoid character. This type of activation will undoubtedly be further developed for application to other unsaturated hydrocarbons and inspire new catalytic cascade reaction sequences. This Minireview discusses the recent developments in electrophilic activation of enynes and shows that simple catalysts such as [Ru(3)(CO)(12)], PtCl(2), and cationic gold complexes are efficient precursors to promote the formation of functional polyclic compounds.

Dimethyl Fumarate Inhibits the Nuclear Factor κB Pathway in Breast Cancer Cells by Covalent Modification of p65 Protein.

PubMed

Kastrati, Irida; Siklos, Marton I; Calderon-Gierszal, Esther L; El-Shennawy, Lamiaa; Georgieva, Gergana; Thayer, Emily N; Thatcher, Gregory R J; Frasor, Jonna

2016-02-12

In breast tumors, activation of the nuclear factor κB (NFκB) pathway promotes survival, migration, invasion, angiogenesis, stem cell-like properties, and resistance to therapy--all phenotypes of aggressive disease where therapy options remain limited. Adding an anti-inflammatory/anti-NFκB agent to breast cancer treatment would be beneficial, but no such drug is approved as either a monotherapy or adjuvant therapy. To address this need, we examined whether dimethyl fumarate (DMF), an anti-inflammatory drug already in clinical use for multiple sclerosis, can inhibit the NFκB pathway. We found that DMF effectively blocks NFκB activity in multiple breast cancer cell lines and abrogates NFκB-dependent mammosphere formation, indicating that DMF has anti-cancer stem cell properties. In addition, DMF inhibits cell proliferation and significantly impairs xenograft tumor growth. Mechanistically, DMF prevents p65 nuclear translocation and attenuates its DNA binding activity but has no effect on upstream proteins in the NFκB pathway. Dimethyl succinate, the inactive analog of DMF that lacks the electrophilic double bond of fumarate, is unable to inhibit NFκB activity. Also, the cell-permeable thiol N-acetyl l-cysteine, reverses DMF inhibition of the NFκB pathway, supporting the notion that the electrophile, DMF, acts via covalent modification. To determine whether DMF interacts directly with p65, we synthesized and used a novel chemical probe of DMF by incorporating an alkyne functionality and found that DMF covalently modifies p65, with cysteine 38 being essential for the activity of DMF. These results establish DMF as an NFκB inhibitor with anti-tumor activity that may add therapeutic value in the treatment of aggressive breast cancers. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Copper-Catalyzed Electrophilic Amination of Organoaluminum Nucleophiles with O-Benzoyl Hydroxylamines.

PubMed

Zhou, Shuangliu; Yang, Zhiyong; Chen, Xu; Li, Yimei; Zhang, Lijun; Fang, Hong; Wang, Wei; Zhu, Xiancui; Wang, Shaowu

2015-06-19

A copper-catalyzed electrophilic amination of aryl and heteroaryl aluminums with N,N-dialkyl-O-benzoyl hydroxylamines that affords the corresponding anilines in good yields has been developed. The catalytic reaction proceeds very smoothly under mild conditions and exhibits good substrate scope. Moreover, the developed catalytic system is also well suited for heteroaryl aluminum nucleophiles, providing facile access to heteroaryl amines.

Enantioselective Cobalt-Catalyzed Sequential Nazarov Cyclization/Electrophilic Fluorination: Access to Chiral α-Fluorocyclopentenones.

PubMed

Zhang, Heyi; Cheng, Biao; Lu, Zhan

2018-06-20

A newly designed thiazoline iminopyridine ligand for enantioselective cobalt-catalyzed sequential Nazarov cyclization/electrophilic fluorination was developed. Various chiral α-fluorocyclopentenones were prepared with good yields and diastereo- and enantioselectivities. Further derivatizations could be easily carried out to provide chiral cyclopentenols with three contiguous stereocenters. Furthermore, a direct deesterification of fluorinated products could afford chiral α-single fluorine-substituted cyclopentenones.

Stereospecific Ni-Catalyzed Cross-Coupling of Potassium Alkenyltrifluoroborates with Alkyl Halides

PubMed Central

2015-01-01

A general method for the alkenylation of alkyl electrophiles using nearly stoichiometric amounts of the air- and moisture-stable potassium organotrifluoroborates has been developed. Various functional groups were tolerated on both the nucleophilic and electrophilic partner. Reactions of highly substituted E- and Z-alkenyltrifluoroborates, as well as vinyl- and propenyltrifluoroborates, were successful, and no loss of stereochemistry or regiochemistry was observed. PMID:24666316

Generation and dietary modulation of anti-inflammatory electrophilic omega-3 fatty acid derivatives.

PubMed

Cipollina, Chiara; Salvatore, Sonia R; Muldoon, Matthew F; Freeman, Bruce A; Schopfer, Francisco J

2014-01-01

Dietary ω-3 polyunsaturated fatty acids (PUFAs) decrease cardiovascular risk via suppression of inflammation. The generation of electrophilic α,β-unsaturated ketone derivatives of the ω-3 PUFAs docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) in activated human macrophages is catalyzed by cyclooxygenase-2 (Cox-2). These derivatives are potent pleiotropic anti-inflammatory signaling mediators that act via mechanisms including the activation of Nrf2-dependent phase 2 gene expression and suppression of pro-inflammatory NF-κB-driven gene expression. Herein, the endogenous generation of ω-3 PUFAs electrophilic ketone derivatives and their hydroxy precursors was evaluated in human neutrophils. In addition, their dietary modulation was assessed through a randomized clinical trial. Endogenous generation of electrophilic omega-3 PUFAs and their hydroxy precursors was evaluated by mass spectrometry in neutrophils isolated from healthy subjects, both at baseline and upon stimulation with calcium ionophore. For the clinical trial, participants were healthy adults 30-55 years of age with a reported EPA+DHA consumption of ≤300 mg/day randomly assigned to parallel groups receiving daily oil capsule supplements for a period of 4 months containing either 1.4 g of EPA+DHA (active condition, n = 24) or identical appearing soybean oil (control condition, n = 21). Participants and laboratory technicians remained blinded to treatment assignments. 5-lypoxygenase-dependent endogenous generation of 7-oxo-DHA, 7-oxo-DPA and 5-oxo-EPA and their hydroxy precursors is reported in human neutrophils stimulated with calcium ionophore and phorbol 12-myristate 13-acetate (PMA). Dietary EPA+DHA supplementation significantly increased the formation of 7-oxo-DHA and 5-oxo-EPA, with no significant modulation of arachidonic acid (AA) metabolite levels. The endogenous detection of these electrophilic ω-3 fatty acid ketone derivatives supports the precept that the benefit of ω-3 PUFA-rich diets can be attributed to the generation of electrophilic oxygenated metabolites that transduce anti-inflammatory actions rather than the suppression of pro-inflammatory AA metabolites. ClinicalTrials.gov NCT00663871.

Redox homeostasis: The Golden Mean of healthy living

PubMed Central

Ursini, Fulvio; Maiorino, Matilde; Forman, Henry Jay

2016-01-01

The notion that electrophiles serve as messengers in cell signaling is now widely accepted. Nonetheless, major issues restrain acceptance of redox homeostasis and redox signaling as components of maintenance of a normal physiological steady state. The first is that redox signaling requires sudden switching on of oxidant production and bypassing of antioxidant mechanisms rather than a continuous process that, like other signaling mechanisms, can be smoothly turned up or down. The second is the misperception that reactions in redox signaling involve “reactive oxygen species” rather than reaction of specific electrophiles with specific protein thiolates. The third is that hormesis provides protection against oxidants by increasing cellular defense or repair mechanisms rather than by specifically addressing the offset of redox homeostasis. Instead, we propose that both oxidant and antioxidant signaling are main features of redox homeostasis. As the redox shift is rapidly reversed by feedback reactions, homeostasis is maintained by continuous signaling for production and elimination of electrophiles and nucleophiles. Redox homeostasis, which is the maintenance of nucleophilic tone, accounts for a healthy physiological steady state. Electrophiles and nucleophiles are not intrinsically harmful or protective, and redox homeostasis is an essential feature of both the response to challenges and subsequent feedback. While the balance between oxidants and nucleophiles is preserved in redox homeostasis, oxidative stress provokes the establishment of a new radically altered redox steady state. The popular belief that scavenging free radicals by antioxidants has a beneficial effect is wishful thinking. We propose, instead, that continuous feedback preserves nucleophilic tone and that this is supported by redox active nutritional phytochemicals. These nonessential compounds, by activating Nrf2, mimic the effect of endogenously produced electrophiles (parahormesis). In summary, while hormesis, although globally protective, results in setting up of a new phenotype, parahormesis contributes to health by favoring maintenance of homeostasis. PMID:26820564

A competing, dual mechanism for catalytic direct benzene hydroxylation from combined experimental-DFT studies.

PubMed

Vilella, Laia; Conde, Ana; Balcells, David; Díaz-Requejo, M Mar; Lledós, Agustí; Pérez, Pedro J

2017-12-01

A dual mechanism for direct benzene catalytic hydroxylation is described. Experimental studies and DFT calculations have provided a mechanistic explanation for the acid-free, Tp x Cu-catalyzed hydroxylation of benzene with hydrogen peroxide (Tp x = hydrotrispyrazolylborate ligand). In contrast with other catalytic systems that promote this transformation through Fenton-like pathways, this system operates through a copper-oxyl intermediate that may interact with the arene ring following two different, competitive routes: (a) electrophilic aromatic substitution, with the copper-oxyl species acting as the formal electrophile, and (b) the so-called rebound mechanism, in which the hydrogen is abstracted by the Cu-O moiety prior to the C-O bond formation. Both pathways contribute to the global transformation albeit to different extents, the electrophilic substitution route seeming to be largely favoured.

Chemical reactivity indices for the complete series of chlorinated benzenes: solvent effect.

PubMed

Padmanabhan, J; Parthasarathi, R; Subramanian, V; Chattaraj, P K

2006-03-02

We present a comprehensive analysis to probe the effect of solvation on the reactivity of the complete series of chlorobenzenes through the conceptual density functional theory (DFT)-based global and local descriptors. We propose a multiphilic descriptor in this study to explore the nature of attack at a particular site in a molecule. It is defined as the difference between nucleophilic and electrophilic condensed philicity functions. This descriptor is capable of explaining both the nucleophilicity and electrophilicity of the given atomic sites in the molecule simultaneously. The predictive ability of this descriptor is tested on the complete series of chlorobenzenes in gas and solvent media. A structure-toxicity analysis of these entire sets of chlorobenzenes toward aquatic organisms demonstrates the importance of the electrophilicity index in the prediction of the reactivity/toxicity.

Mechanism of Electrophilic Fluorination with Pd(IV): Fluoride Capture and Subsequent Oxidative Fluoride Transfer†, ‡

PubMed Central

Brandt, Jochen R.; Lee, Eunsung; Boursalian, Gregory B.

2013-01-01

Electrophilic fluorinating reagents derived from fluoride are desirable for the synthesis of 18F-labeled molecules for positron emission tomography (PET). Here, we study the mechanism by which a Pd(IV)-complex captures fluoride and subsequently transfers it to nucleophiles. The intermediate Pd(IV)-F is formed with high rates even at the nano- to micromolar fluoride concentrations typical for radiosyntheses with 18F due to fast formation of an outer-sphere complex between fluoride and Pd(IV). The subsequent fluorine transfer from the Pd(IV)-F complex is proposed to proceed through an unusual SET/fluoride transfer/SET mechanism. The findings detailed in this manuscript provide a theoretical foundation suitable for addressing a more general approach for electrophilic fluorination with high specific activity 18F PET imaging. PMID:24376910

Use of Aryl Chlorides as Electrophiles in Pd-Catalyzed Alkene Difunctionalization Reactions

PubMed Central

Rosen, Brandon R.; Ney, Joshua E.; Wolfe, John P.

2010-01-01

The development of conditions that allow use of inexpensive aryl chlorides as electrophiles in Pd-catalyzed alkene carboamination and carboetherification reactions is described. A catalyst composed of Pd(OAc)2 and S-Phos minimizes N-arylation of the substrate and prevents formation of mixtures of regioisomeric products. A number of heterocycles, including pyrrolidines, isoxazolidines, tetrahydrofurans, and pyrazolidines, are efficiently generated with this method. PMID:20297834

Finite temperature grand canonical ensemble study of the minimum electrophilicity principle.

PubMed

Miranda-Quintana, Ramón Alain; Chattaraj, Pratim K; Ayers, Paul W

2017-09-28

We analyze the minimum electrophilicity principle of conceptual density functional theory using the framework of the finite temperature grand canonical ensemble. We provide support for this principle, both for the cases of systems evolving from a non-equilibrium to an equilibrium state and for the change from one equilibrium state to another. In doing so, we clearly delineate the cases where this principle can, or cannot, be used.

Ionic Liquids as Energetic Materials

DTIC Science & Technology

2007-03-01

triazolium halide that can be synthesized from the electrophilic fluorination and quaternization of the amino-substituted triazole. Metathesis with a...silver salt such as silver nitrate forms the nitrate salt. By electrophilic difluoroamination of 1 -alkyl-3-nitro- 1,2,4-triazole, 1,4-dialkyl-3-nitro...nonaromatic salts (1-7) described in Table 1. The presence of small amounts of fluorine in the substituent arm contributes to the thermal stability and has

Biomonitoring Human Albumin Adducts: The Past, the Present, and the Future

PubMed Central

2016-01-01

Serum albumin (Alb) is the most abundant protein in blood plasma. Alb reacts with many carcinogens and/or their electrophilic metabolites. Studies conducted over 20 years ago showed that Alb forms adducts with the human carcinogens aflatoxin B1 and benzene, which were successfully used as biomarkers in molecular epidemiology studies designed to address the role of these chemicals in cancer risk. Alb forms adducts with many therapeutic drugs or their reactive metabolites such as β-lactam antibiotics, acetylsalicylic acid, acetaminophen, nonsteroidal anti-inflammatory drugs, chemotherapeutic agents, and antiretroviral therapy drugs. The identification and characterization of the adduct structures formed with Alb have served to understand the generation of reactive metabolites and to predict idiosyncratic drug reactions and toxicities. The reaction of candidate drugs with Alb is now exploited as part of the battery of screening tools to assess the potential toxicities of drugs. The use of gas chromatography-mass spectrometry, liquid chromatography, or liquid chromatography-mass spectrometry (LC-MS) enabled the identification and quantification of multiple types of Alb xenobiotic adducts in animals and humans during the past three decades. In this perspective, we highlight the history of Alb as a target protein for adduction to environmental and dietary genotoxicants, pesticides, and herbicides, common classes of medicinal drugs, and endogenous electrophiles, and the emerging analytical mass spectrometry technologies to identify Alb-toxicant adducts in humans. PMID:27989119

Global profiling of lysine reactivity and ligandability in the human proteome

NASA Astrophysics Data System (ADS)

Hacker, Stephan M.; Backus, Keriann M.; Lazear, Michael R.; Forli, Stefano; Correia, Bruno E.; Cravatt, Benjamin F.

2017-12-01

Nucleophilic amino acids make important contributions to protein function, including performing key roles in catalysis and serving as sites for post-translational modification. Electrophilic groups that target amino-acid nucleophiles have been used to create covalent ligands and drugs, but have, so far, been mainly limited to cysteine and serine. Here, we report a chemical proteomic platform for the global and quantitative analysis of lysine residues in native biological systems. We have quantified, in total, more than 9,000 lysines in human cell proteomes and have identified several hundred residues with heightened reactivity that are enriched at protein functional sites and can frequently be targeted by electrophilic small molecules. We have also discovered lysine-reactive fragment electrophiles that inhibit enzymes by active site and allosteric mechanisms, as well as disrupt protein-protein interactions in transcriptional regulatory complexes, emphasizing the broad potential and diverse functional consequences of liganding lysine residues throughout the human proteome.

Hydroalumination of Ketenimines and Subsequent Reactions with Heterocumulenes: Synthesis of Unsaturated Amide Derivatives and 1,3-Diimines.

PubMed

Jin, Xing; Willeke, Matthias; Lucchesi, Ralph; Daniliuc, Constantin-Gabriel; Fröhlich, Roland; Wibbeling, Birgit; Uhl, Werner; Würthwein, Ernst-Ulrich

2015-06-19

The series of differently substituted ketenimines 1 was hydroluminated using di-iso-butyl aluminum hydride. For the sterically congested ketenimine 1a, preferred hydroalumination of the C═N-bond was proven by X-ray crystallography (compound 5a). In situ treatment of the hydroaluminated ketenimines 5 with various heterocumulenes like carbodiimides, isocycanates, isothiocyanates and ketenimines as electrophiles and subsequent hydrolytic workup resulted in novel enamine derived amide species in case of N-attack (sterically less hindered ketenimines) under formation of a new C-N-bond or in 1,3-diimines by C-C-bond-formation in case of bulky substituents at the ketenimine-nitrogen atom. Furthermore, domino reactions with more than 1 equiv of the electrophile or by subsequent addition of two different electrophiles are possible and lead to polyfunctional amide derivatives of the biuret type which are otherwise not easily accessible.

Polar Diels-Alder reactions using electrophilic nitrobenzothiophenes. A combined experimental and DFT study

NASA Astrophysics Data System (ADS)

Della Rosa, Claudia D.; Mancini, Pedro M. E.; Kneeteman, Maria N.; Lopez Baena, Anna F.; Suligoy, Melisa A.; Domingo, Luis R.

2015-01-01

The reactions between 2- and 3-nitrobenzothiophenes with three dienes of different nucleophilicity, 1-methoxy-3-trimethylsilyloxy-1,3-butadiene, 1-trimethylsilyloxy-1,3-butadiene and isoprene developed in anhydrous benzene and alternative under microwave irradiation with molecular solvents or in free solvent conditions, respectively, for produce dibenzothiophenes permit to conclude that both nitroheterocycles act as electrophile with the cited dienes. In the cases of the dienes 1-methoxy-3-trimethylsilyloxy-1,3-butadiene and 1-trimethylsilyloxy-1,3-butadiene which posses major nucleophilicity the observed product is the normal cycloaddition one. However when the diene is isoprene the product with both electrophiles follow the hetero Diels-Alder way. These reactions are considered polar cycloaddition reactions and the yields are reasonables. Moreover the polar Diels-Alder reactions of nitrobenzothiophenes with electron rich dienes 1-trimethylsilyloxy-1,3-butadiene have been theoretically studied using DFT methods.

Global profiling of lysine reactivity and ligandability in the human proteome.

PubMed

Hacker, Stephan M; Backus, Keriann M; Lazear, Michael R; Forli, Stefano; Correia, Bruno E; Cravatt, Benjamin F

2017-12-01

Nucleophilic amino acids make important contributions to protein function, including performing key roles in catalysis and serving as sites for post-translational modification. Electrophilic groups that target amino-acid nucleophiles have been used to create covalent ligands and drugs, but have, so far, been mainly limited to cysteine and serine. Here, we report a chemical proteomic platform for the global and quantitative analysis of lysine residues in native biological systems. We have quantified, in total, more than 9,000 lysines in human cell proteomes and have identified several hundred residues with heightened reactivity that are enriched at protein functional sites and can frequently be targeted by electrophilic small molecules. We have also discovered lysine-reactive fragment electrophiles that inhibit enzymes by active site and allosteric mechanisms, as well as disrupt protein-protein interactions in transcriptional regulatory complexes, emphasizing the broad potential and diverse functional consequences of liganding lysine residues throughout the human proteome.

One-pot synthesis of hypervalent iodine reagents for electrophilic trifluoromethylation.

PubMed

Matoušek, Václav; Pietrasiak, Ewa; Schwenk, Rino; Togni, Antonio

2013-07-05

Simplified syntheses suited for large scale preparations of the two hypervalent iodine reagents 1 and 2 for electrophilic trifluoromethylation are reported. In both cases, the stoichiometric oxidants sodium metaperiodate and tert-butyl hypochlorite have been replaced by trichloroisocyanuric acid. Reagent 1 is accessible in a one-pot procedure from 2-iodobenzoic acid in 72% yield. Reagent 2 was prepared via fluoroiodane 11 in a considerably shorter reaction time and with no need of an accurate temperature control.

Re-Orienting Coupling of Organocuprates with Propargyl Electrophiles from SN2' to SN2 with Stereocontrol.

PubMed

Trost, Barry M; Debien, Laurent

2016-01-01

Diorganocuprate(I) reagents derived from lithiated heterocycles and CuCN react with enantioenriched secondary propagryl bromides to give the corresponding propargylated heterocycles. While propargyl electrophiles typically undergo S N 2' displacement, this transformation represents the first example of the reaction of hard carbanions with propargyl eletrophiles in an S N 2 fashion and occurs with excellent levels of stereoinversion. The new method was applied to the formal synthesis of (+)-frondosin B.

Thiol Reactivity of Curcumin and Its Oxidation Products.

PubMed

Luis, Paula B; Boeglin, William E; Schneider, Claus

2018-04-16

The polypharmacological effects of the turmeric compound curcumin may be partly mediated by covalent adduction to cellular protein. Covalent binding to small molecule and protein thiols is thought to occur through a Michael-type addition at the enone moiety of the heptadienedione chain connecting the two methoxyphenol rings of curcumin. Here we show that curcumin forms the predicted thiol-Michael adducts with three model thiols, glutathione, N-acetylcysteine, and β-mercaptoethanol. More abundant, however, are respective thiol adducts of the dioxygenated spiroepoxide intermediate of curcumin autoxidation. Two electrophilic sites at the quinone-like ring of the spiroepoxide are identified. Addition of β-mercaptoethanol at the 5'-position of the ring gives a 1,7-dihydroxycyclopentadione-5' thioether, and addition at the 1'-position results in cleavage of the aromatic ring from the molecule, forming methoxyphenol-thioether and a tentatively identified cyclopentadione aldehyde. The curcuminoids demethoxy- and bisdemethoxycurcumin do not form all of the possible thioether adducts, corresponding with their increased stability toward autoxidation. RAW264.7 macrophage-like cells activated with phorbol ester form curcumin-glutathionyl and the 1,7-dihydroxycyclopentadione-5'-glutathionyl adducts. These studies indicate that the enone of the parent compound is not the only functional electrophile in curcumin, and that its oxidation products provide additional electrophilic sites. This suggests that protein binding by curcumin may involve oxidative activation into reactive quinone methide and spiroepoxide electrophiles.

Generation and esterification of electrophilic fatty acid nitroalkenes in triacylglycerides

PubMed Central

Fazzari, Marco; Khoo, Nicholas; Woodcock, Steven R.; Li, Lihua; Freeman, Bruce A.; Schopfer, Francisco J.

2015-01-01

Electrophilic fatty acid nitroalkenes (NO2-FA) are products of nitric oxide and nitrite-mediated unsaturated fatty acid nitration. These electrophilic products induce pleiotropic signaling actions that modulate metabolic and inflammatory responses in cell and animal models. The metabolism of NO2-FA includes reduction of the vinyl nitro moiety by prostaglandin reductase-1, mitochondrial β–oxidation and Michael addition with low molecular weight nucleophilic amino acids. Complex lipid reactions of fatty acid nitroalkenes are not well defined. Herein we report the detection and characterization of NO2-FA-containing triacylglycerides (NO2-FA-TAG) via mass spectrometry-based methods. In this regard, unsaturated fatty acids of dietary triacylglycerides are targets for nitration reactions during gastric acidification, where NO2-FA-TAG can be detected in rat plasma after oral administration of nitro-oleic acid (NO2-OA). Furthermore, the characterization and profiling of these species, including the generation of beta oxidation and dehydrogenation products, could be detected in NO2-OA supplemented adipocytes. These data revealed that NO2-FA-TAG, formed by either the direct nitration of esterified unsaturated fatty acids or the incorporation of nitrated free fatty acids into triacylglycerides, contribute to the systemic distribution of these reactive electrophilic mediators and may serve as a depot for subsequent mobilization by lipases to in turn impact adipocyte homeostasis and tissue signaling events. PMID:26066303

Dose response relationship in anti-stress gene regulatory networks.

PubMed

Zhang, Qiang; Andersen, Melvin E

2007-03-02

To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products) in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear) depends on changes in the specific values of local response coefficients (gains) distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear, and depending on the level of local gains, presence of gain-changing events, and degree of feedforward gene activation, this region can appear as superlinear, sublinear, or even J-shaped. The general dose response transition proposed here was further examined in a complex anti-electrophilic stress pathway, which involves multiple genes, enzymes, and metabolic reactions. This work would help biologists and especially toxicologists to better assess and predict the cellular impact brought about by biological stressors.

Redox homeostasis: The Golden Mean of healthy living.

PubMed

Ursini, Fulvio; Maiorino, Matilde; Forman, Henry Jay

2016-08-01

The notion that electrophiles serve as messengers in cell signaling is now widely accepted. Nonetheless, major issues restrain acceptance of redox homeostasis and redox signaling as components of maintenance of a normal physiological steady state. The first is that redox signaling requires sudden switching on of oxidant production and bypassing of antioxidant mechanisms rather than a continuous process that, like other signaling mechanisms, can be smoothly turned up or down. The second is the misperception that reactions in redox signaling involve "reactive oxygen species" rather than reaction of specific electrophiles with specific protein thiolates. The third is that hormesis provides protection against oxidants by increasing cellular defense or repair mechanisms rather than by specifically addressing the offset of redox homeostasis. Instead, we propose that both oxidant and antioxidant signaling are main features of redox homeostasis. As the redox shift is rapidly reversed by feedback reactions, homeostasis is maintained by continuous signaling for production and elimination of electrophiles and nucleophiles. Redox homeostasis, which is the maintenance of nucleophilic tone, accounts for a healthy physiological steady state. Electrophiles and nucleophiles are not intrinsically harmful or protective, and redox homeostasis is an essential feature of both the response to challenges and subsequent feedback. While the balance between oxidants and nucleophiles is preserved in redox homeostasis, oxidative stress provokes the establishment of a new radically altered redox steady state. The popular belief that scavenging free radicals by antioxidants has a beneficial effect is wishful thinking. We propose, instead, that continuous feedback preserves nucleophilic tone and that this is supported by redox active nutritional phytochemicals. These nonessential compounds, by activating Nrf2, mimic the effect of endogenously produced electrophiles (parahormesis). In summary, while hormesis, although globally protective, results in setting up of a new phenotype, parahormesis contributes to health by favoring maintenance of homeostasis. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Diastereocontrolled Electrophilic Fluorinations of 2-Deoxyribonolactone: Syntheses of All Corresponding 2-Deoxy-2-fluoro-lactones and 2’-Deoxy-2’-fluoro-NAD+s

PubMed Central

Cen, Yana; Sauve, Anthony A.

2009-01-01

Methods to construct 2’-deoxy-2’-fluoro-nucleosides have undergone limited improvement in the last twenty years in spite of substantially increased value of these compounds as pharmaceuticals and as tools for studying biological processes. We herein describe a consolidated approach to synthesize precursors to these commercially and scientifically valuable compounds via diastereocontrolled fluorination of the readily available precursor 2-deoxy-d-ribonolactone. With employment of appropriate sterically bulky silyl protecting groups at 3 and 5 positions, controlled electrophilic fluorination of the Li-ribonolactone enolate by N-fluorodibenezenesulfonamide yielded the corresponding 2-deoxy-2-fluoro-arabino-lactone in high isolated yield (72 %). The protected 2-deoxy-2, 2-difluoro-ribonolactone was obtained similarly in high yield from a second round of electrophilic fluorination (2 steps, 51% from protected ribonolactone starting material). Accomplishment of the difficult ribo-fluorination of the lactone was achieved by the directive effects of a diastereoselectively installed α-trimethylsilyl group. Electrophilic fluorination of a protected 2-deoxy-2-trimethylsilyl-arabino-lactone via enolate generation provided the protected 2-deoxy-2-fluoro-ribo-lactone as the exclusive fluorinated product. The reaction also yielded the starting material, the desilylated protected 2-deoxy-ribonolactone, which was recycled to provide a 38% chemical yield of the fluorinated product (versus initial protected ribonolactone) after consecutive silylation and fluorination cycles. Using our fluorinated sugar precursors we prepared the 2’-fluoro-arabino-, 2’-fluoro-ribo- and 2’,2’-difluoro-nicotinamide adenine dinucleotides (NAD+) of potential biological interest. These syntheses provide the most consolidated and efficient methods for production of sugar precursors of 2’-deoxy-2’-fluoronucleosides and have the advantage of utilizing an air-stable electrophilic fluorinating agent. The fluorinated NAD+s are anticipated to be useful for studying a variety of cellular metabolic and signaling processes. PMID:19958035

Covalent Adducts Between Thioredoxin Reductase and Endogenous Electrophiles in Human Breast Cancer

DTIC Science & Technology

2005-09-01

previously that treatment of colon cancer cells with electrophilic cyclopentenone PGs such as those in Figure 1 caused conformational derangement of the...Culture - RKO colon cancer cells (gift of M. Agarose in I ml of PBS with 0.4% Tween 20. The Meuth, Institute for Cancer Studies, University of samples...derangement of p53. To test this hypothesis This result, originally observed in colon cancer directly, we used a siRNA-resistant TrxR1 cells, is

Synthesis of S-linked trisaccharide glycal of derhodinosylurdamycin A: Discovery of alkyl thiocyanate as an efficient electrophile for stereoselective sulfenylation of 2-deoxy glycosyl lithium.

PubMed

Acharya, Padam P; Baryal, Kedar N; Reno, Cristin E; Zhu, Jianglong

2017-08-07

Stereoselective synthesis of S-linked trisaccharide glycal of angucycline antitumor antibiotic derhodinosylurdamycin A is described. The synthesis has been accomplished employing our previously reported umpolung S-glycosylation strategy - stereoselective sulfenylation of 2-deoxy glycosyl lithium. It was found that sugar-derived thiocyanate was a better electrophile than corresponding asymmetric disulfide in this type of stereoselective sulfenylation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Applications of the Conceptual Density Functional Theory Indices to Organic Chemistry Reactivity.

PubMed

Domingo, Luis R; Ríos-Gutiérrez, Mar; Pérez, Patricia

2016-06-09

Theoretical reactivity indices based on the conceptual Density Functional Theory (DFT) have become a powerful tool for the semiquantitative study of organic reactivity. A large number of reactivity indices have been proposed in the literature. Herein, global quantities like the electronic chemical potential μ, the electrophilicity ω and the nucleophilicity N indices, and local condensed indices like the electrophilic P k + and nucleophilic P k - Parr functions, as the most relevant indices for the study of organic reactivity, are discussed.

Rational Inhibitors of DNA Base Excision Repair Enzymes: New Tools for Elucidating the Role of BER in Cancer Chemotherapy. Addendum

DTIC Science & Technology

2006-11-01

30. Drohat, A. C., Jagadeesh, J., Ferguson, E., and Stivers, J. T. (1999) The role of electrophilic and base catalysis in the mechanism of Escherichia...based on a duplex previously used in rapid kinetic studies of base flipping by UDG (Figure 2) (5). The 2′ fluorinated deoxyuridine substrate analogue...Boca Raton, FL. 32. Drohat, A. C., Jagadeesh, J., Ferguson, E., and Stivers, J. T. (1999) Role of electrophilic and general base catalysis in the

Reaction of Chlorosulfonyl Isocyanate (CSI) with Fluorosubstituted Alkenes: Evidence of a Concerted Pathway for Reaction of CSI with Fluorosubstituted Alkenes (Preprint)

DTIC Science & Technology

2010-06-01

ABSTRACT Concerted reactions are indicated for the electrophilic addition of chlorosulfonyl isocyanate with monofluoroalkenes. A vinyl fluorine atom on...SO2Cl R F O ‡ N SO2Cl F R O Abstract: Concerted reactions are indicated for the electrophilic addition of chlorosulfonyl isocyanate with...monofluoroalkenes. A vinyl fluorine atom on an alkene raises the energy of a step-wise transition state more than the energy of the competing concerted

Correlation of Calculated Halonium Ion Structures with Experimental Product Distributions from Terminal Alkenes: The Effect of Electron-Withdrawing Fluorine Substituents on the Structure and Charge Localization of Halonium Ions (PREPRINT)

DTIC Science & Technology

2006-04-03

2) Substituting a vinyl hydrogen with a fluorine presents an interesting situation for electrophilic reactions. The π-bond is less...reactive toward electrophiles due to the electron-withdrawing effect of the vinyl fluorine . Therefore, carbocations or radical cations are destabilized...NUMBER Distributions from Terminal Alkenes: The Effect of Electron-Withdrawing Fluorine Substituents on the Structure and Charge Localization of

Organocatalytic C-H bond arylation of aldehydes to bis-heteroaryl ketones.

PubMed

Toh, Qiao Yan; McNally, Andrew; Vera, Silvia; Erdmann, Nico; Gaunt, Matthew J

2013-03-13

An organocatalytic aldehyde C-H bond arylation process for the synthesis of complex heteroaryl ketones has been developed. By exploiting the inherent electrophilicity of diaryliodonium salts, we have found that a commercial N-heterocyclic carbene catalyst promotes the union of heteroaryl aldehydes and these heteroaromatic electrophile equivalents in good yields. This straightforward catalytic protocol offers access to ketones bearing a diverse array of arene and heteroarene substituents that can subsequently be converted into molecules displaying structural motifs commonly found in medicinal agents.

Synthesis of Sequence-Specific DNA-Protein Conjugates via a Reductive Amination Strategy

PubMed Central

Wickramaratne, Susith; Mukherjee, Shivam; Villalta, Peter W.; Schärer, Orlando D.; Tretyakova, Natalia

2013-01-01

DNA-protein cross-links (DPCs) are ubiquitous, structurally diverse DNA lesions formed upon exposure to bis-electrophiles, transition metals, UV light, and reactive oxygen species. Because of their super-bulky, helix distorting nature, DPCs interfere with DNA replication, transcription, and repair, potentially contributing to mutagenesis and carcinogenesis. However, the biological implications of DPC lesions have not been fully elucidated due to the difficulty of generating site-specific DNA substrates representative of DPC lesions formed in vivo. In the present study, a novel approach involving post-synthetic reductive amination has been developed to prepare a range of hydrolytically stable lesions structurally mimicking the DPCs produced between the N7 position of guanine in DNA and basic lysine or arginine side chains of proteins and peptides. PMID:23885807

Peroxide Activation for Electrophilic Reactivity by the Binuclear Non-heme Iron Enzyme AurF

DOE PAGES

Park, Kiyoung; Li, Ning; Kwak, Yeonju; ...

2017-05-01

Binuclear non-heme iron enzymes activate O 2 for diverse chemistries that include oxygenation of organic substrates and hydrogen atom abstraction. This process often involves the formation of peroxo-bridged biferric intermediates, only some of which can perform electrophilic reactions. To elucidate the geometric and electronic structural requirements to activate peroxo reactivity, the active peroxo intermediate in 4-aminobenzoate N-oxygenase (AurF) has been characterized spectroscopically and computationally. A magnetic circular dichroism study of reduced AurF shows that its electronic and geometric structures are poised to react rapidly with O 2. Nuclear resonance vibrational spectroscopic definition of the peroxo intermediate formed in this reactionmore » shows that the active intermediate has a protonated peroxo bridge. Density functional theory computations on the structure established here show that the protonation activates peroxide for electrophilic/single-electron-transfer reactivity. As a result, this activation of peroxide by protonation is likely also relevant to the reactive peroxo intermediates in other binuclear non-heme iron enzymes.« less

In-crystal reaction cycle of a toluene-bound diiron hydroxylase

NASA Astrophysics Data System (ADS)

Acheson, Justin F.; Bailey, Lucas J.; Brunold, Thomas C.; Fox, Brian G.

2017-03-01

Electrophilic aromatic substitution is one of the most important and recognizable classes of organic chemical transformation. Enzymes create the strong electrophiles that are needed for these highly energetic reactions by using O2, electrons, and metals or other cofactors. Although the nature of the oxidants that carry out electrophilic aromatic substitution has been deduced from many approaches, it has been difficult to determine their structures. Here we show the structure of a diiron hydroxylase intermediate formed during a reaction with toluene. Density functional theory geometry optimizations of an active site model reveal that the intermediate is an arylperoxo Fe2+/Fe3+ species with delocalized aryl radical character. The structure suggests that a carboxylate ligand of the diiron centre may trigger homolytic cleavage of the O-O bond by transferring a proton from a metal-bound water. Our work provides the spatial and electronic constraints needed to propose a comprehensive mechanism for diiron enzyme arene hydroxylation that accounts for many prior experimental results.

Cu/Mn bimetallic catalysis enables carbonylative Suzuki–Miyaura coupling with unactivated alkyl electrophiles† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc01170a Click here for additional data file.

PubMed Central

Pye, Dominic R.; Cheng, Li-Jie

2017-01-01

A bimetallic system consisting of Cu-carbene and Mn-carbonyl co-catalysts was employed for carbonylative C–C coupling of arylboronic esters with alkyl halides, allowing for the convergent synthesis of ketones. The system operates under mild conditions and exhibits complementary reactivity to Pd catalysis. The method is compatible with a wide range of arylboronic ester nucleophiles and proceeds smoothly for both primary and secondary alkyl iodide electrophiles. Preliminary mechanistic experiments corroborate a hypothetical catalytic mechanism consisting of co-dependent cycles wherein the Cu-carbene co-catalyst engages in transmetallation to generate an organocopper nucleophile, while the Mn-carbonyl co-catalyst activates the alkyl halide electrophile by single-electron transfer and then undergoes reversible carbonylation to generate an acylmanganese electrophile. The two cycles then intersect with a heterobimetallic, product-releasing C–C coupling step. PMID:28966784

Diverse Reactions of Thiophenes, Selenophenes, and Tellurophenes with Strongly Oxidizing I(III) PhI(L)2 Reagents.

PubMed

Egalahewa, Sathsara; Albayer, Mohammad; Aprile, Antonino; Dutton, Jason L

2017-02-06

We report the outcomes of the reactions of aromatic group 16 thiophene, selenophene, and tellurophene rings with the I(III) oxidants PhI(OAc)(OTf) and [PhI(Pyr) 2 ][OTf] 2 (Pyr = pyridine). In all reactions, oxidative processes take place, with generation of PhI as the reduction product. However, with the exception of tellurophene with PhI(OAc)(OTf), +4 oxidation state complexes are not observed, but rather a variety of other processes occur. In general, where a C-H unit is available on the 5-membered ring, an electrophilic aromatic substitution reaction of either -IPh or pyridine onto the ring occurs. When all positions are blocked, reactions with PhI(OAc)(OTf) give acetic and triflic anhydride as the identifiable oxidative byproducts, while [PhI(Pyr) 2 ][OTf] 2 gives pyridine electrophilic aromatic substitution onto the peripheral rings. Qualitative mechanistic studies indicate that the presence of the oxidizable heteroatom is required for pyridine to act as an electrophile in a substantial manner.

A general approach to intermolecular carbonylation of arene C-H bonds to ketones through catalytic aroyl triflate formation

NASA Astrophysics Data System (ADS)

Garrison Kinney, R.; Tjutrins, Jevgenijs; Torres, Gerardo M.; Liu, Nina Jiabao; Kulkarni, Omkar; Arndtsen, Bruce A.

2018-02-01

The development of metal-catalysed methods to functionalize inert C-H bonds has become a dominant research theme in the past decade as an approach to efficient synthesis. However, the incorporation of carbon monoxide into such reactions to form valuable ketones has to date proved a challenge, despite its potential as a straightforward and green alternative to Friedel-Crafts reactions. Here we describe a new approach to palladium-catalysed C-H bond functionalization in which carbon monoxide is used to drive the generation of high-energy electrophiles. This offers a method to couple the useful features of metal-catalysed C-H functionalization (stable and available reagents) and electrophilic acylations (broad scope and selectivity), and synthesize ketones simply from aryl iodides, CO and arenes. Notably, the reaction proceeds in an intermolecular fashion, without directing groups and at very low palladium-catalyst loadings. Mechanistic studies show that the reaction proceeds through the catalytic build-up of potent aroyl triflate electrophiles.

Substoichiometric hydroxynonenylation of a single protein recapitulates whole-cell-stimulated antioxidant response.

PubMed

Parvez, Saba; Fu, Yuan; Li, Jiayang; Long, Marcus J C; Lin, Hong-Yu; Lee, Dustin K; Hu, Gene S; Aye, Yimon

2015-01-14

Lipid-derived electrophiles (LDEs) that can directly modify proteins have emerged as important small-molecule cues in cellular decision-making. However, because these diffusible LDEs can modify many targets [e.g., >700 cysteines are modified by the well-known LDE 4-hydroxynonenal (HNE)], establishing the functional consequences of LDE modification on individual targets remains devilishly difficult. Whether LDE modifications on a single protein are biologically sufficient to activate discrete redox signaling response downstream also remains untested. Herein, using T-REX (targetable reactive electrophiles and oxidants), an approach aimed at selectively flipping a single redox switch in cells at a precise time, we show that a modest level (∼34%) of HNEylation on a single target is sufficient to elicit the pharmaceutically important antioxidant response element (ARE) activation, and the resultant strength of ARE induction recapitulates that observed from whole-cell electrophilic perturbation. These data provide the first evidence that single-target LDE modifications are important individual events in mammalian physiology.

Peroxide Activation for Electrophilic Reactivity by the Binuclear Non-heme Iron Enzyme AurF

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Kiyoung; Li, Ning; Kwak, Yeonju

Binuclear non-heme iron enzymes activate O 2 for diverse chemistries that include oxygenation of organic substrates and hydrogen atom abstraction. This process often involves the formation of peroxo-bridged biferric intermediates, only some of which can perform electrophilic reactions. To elucidate the geometric and electronic structural requirements to activate peroxo reactivity, the active peroxo intermediate in 4-aminobenzoate N-oxygenase (AurF) has been characterized spectroscopically and computationally. A magnetic circular dichroism study of reduced AurF shows that its electronic and geometric structures are poised to react rapidly with O 2. Nuclear resonance vibrational spectroscopic definition of the peroxo intermediate formed in this reactionmore » shows that the active intermediate has a protonated peroxo bridge. Density functional theory computations on the structure established here show that the protonation activates peroxide for electrophilic/single-electron-transfer reactivity. As a result, this activation of peroxide by protonation is likely also relevant to the reactive peroxo intermediates in other binuclear non-heme iron enzymes.« less

Subclass-specific labeling of protein-reactive natural products with customized nucleophilic probes.

PubMed

Rudolf, Georg C; Koch, Maximilian F; Mandl, Franziska A M; Sieber, Stephan A

2015-02-23

Natural products represent a rich source of bioactive compounds that constitute a large fraction of approved drugs. Among those are molecules with electrophilic scaffolds, such as Michael acceptors, β-lactams, and epoxides that irreversibly inhibit essential enzymes based on their catalytic mechanism. In the search for novel bioactive molecules, current methods are challenged by the frequent rediscovery of known chemical entities. Herein small nucleophilic probes that attack electrophilic natural products and enhance their detection by HPLC-UV and HPLC-MS are introduced. A screen of diverse probe designs revealed one compound with a desired selectivity for epoxide- and maleimide-based antibiotics. Correspondingly, the natural products showdomycin and phosphomycin could be selectively targeted in extracts of their natural producing organism, in which the probe-modified molecules exhibited superior retention and MS detection relative to their unmodified counterparts. This method may thus help to discover small, electrophilic molecules that might otherwise easily elude detection in complex samples. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Electrophilic and free radical nitration of benzene and toluene with various nitrating agents*

PubMed Central

Olah, George A.; Lin, Henry C.; Olah, Judith A.; Narang, Subhash C.

1978-01-01

Electrophilic nitration of toluene and benzene was studied under various conditions with several nitrating systems. It was found that high orthopara regioselectivity is prevalent in all reactions and is independent of the reactivity of the nitrating agent. The methyl group of toluene is predominantly ortho-para directing under all reaction conditions. Steric factors are considered to be important but not the sole reason for the variation in the ortho/para ratio. The results reinforce our earlier views that, in electrophilic aromatic nitrations with reactive nitrating agents, substrate and positional selectivities are determined in two separate steps. The first step involves a π-aromatic-NO2+ ion complex or encounter pair, whereas the subsequent step is of arenium ion nature (separate for the ortho, meta, and para positions). The former determines substrate selectivity, whereas the latter determines regioselectivity. Thermal free radical nitration of benzene and toluene with tetranitromethane in sharp contrast gave nearly statistical product distributions. PMID:16592503

Electrophilic tuning of the chemoprotective natural product sulforaphane

PubMed Central

Ahn, Young-Hoon; Hwang, Yousang; Liu, Hua; Wang, Xiu Jun; Zhang, Ying; Stephenson, Katherine K.; Boronina, Tatiana N.; Cole, Robert N.; Dinkova-Kostova, Albena T.; Talalay, Paul; Cole, Philip A.

2010-01-01

Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane], a naturally occurring isothiocyanate derived from cruciferous vegetables, is a highly potent inducer of phase 2 cytoprotective enzymes and can protect against electrophiles including carcinogens, oxidative stress, and inflammation. The mechanism of action of sulforaphane is believed to involve modifications of critical cysteine residues of Keap1, which lead to stabilization of Nrf2 to activate the antioxidant response element of phase 2 enzymes. However, the dithiocarbamate functional group formed by a reversible reaction between isothiocyanate of sulforaphane and sulfhydryl nucleophiles of Keap1 is kinetically labile, and such modification in intact cells has not yet been demonstrated. Here we designed sulforaphane analogs with replacement of the reactive isothiocyanate by the more gentle electrophilic sulfoxythiocarbamate group that also selectively targets cysteine residues in proteins but forms stable thiocarbamate adducts. Twenty-four sulfoxythiocarbamate analogs were synthesized that retain the structural features important for high potency in sulforaphane analogs: the sulfoxide or keto group and its appropriate distance to electrophilic functional group. Evaluation in various cell lines including hepatoma cells, retinal pigment epithelial cells, and keratinocytes as well as in mouse skin shows that these analogs maintain high potency and efficacy for phase 2 enzyme induction as well as the inhibitory effect on lipopolysaccharide-induced nitric oxide formation like sulforaphane. We further show in living cells that a sulfoxythiocarbamate analog can label Keap1 on several key cysteine residues as well as other cellular proteins offering new insights into the mechanism of chemoprotection. PMID:20439747

Electrophilic tuning of the chemoprotective natural product sulforaphane.

PubMed

Ahn, Young-Hoon; Hwang, Yousang; Liu, Hua; Wang, Xiu Jun; Zhang, Ying; Stephenson, Katherine K; Boronina, Tatiana N; Cole, Robert N; Dinkova-Kostova, Albena T; Talalay, Paul; Cole, Philip A

2010-05-25

Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane], a naturally occurring isothiocyanate derived from cruciferous vegetables, is a highly potent inducer of phase 2 cytoprotective enzymes and can protect against electrophiles including carcinogens, oxidative stress, and inflammation. The mechanism of action of sulforaphane is believed to involve modifications of critical cysteine residues of Keap1, which lead to stabilization of Nrf2 to activate the antioxidant response element of phase 2 enzymes. However, the dithiocarbamate functional group formed by a reversible reaction between isothiocyanate of sulforaphane and sulfhydryl nucleophiles of Keap1 is kinetically labile, and such modification in intact cells has not yet been demonstrated. Here we designed sulforaphane analogs with replacement of the reactive isothiocyanate by the more gentle electrophilic sulfoxythiocarbamate group that also selectively targets cysteine residues in proteins but forms stable thiocarbamate adducts. Twenty-four sulfoxythiocarbamate analogs were synthesized that retain the structural features important for high potency in sulforaphane analogs: the sulfoxide or keto group and its appropriate distance to electrophilic functional group. Evaluation in various cell lines including hepatoma cells, retinal pigment epithelial cells, and keratinocytes as well as in mouse skin shows that these analogs maintain high potency and efficacy for phase 2 enzyme induction as well as the inhibitory effect on lipopolysaccharide-induced nitric oxide formation like sulforaphane. We further show in living cells that a sulfoxythiocarbamate analog can label Keap1 on several key cysteine residues as well as other cellular proteins offering new insights into the mechanism of chemoprotection.

Covalent Allosteric Inactivation of Protein Tyrosine Phosphatase 1B (PTP1B) by an Inhibitor-Electrophile Conjugate.

PubMed

Punthasee, Puminan; Laciak, Adrian R; Cummings, Andrea H; Ruddraraju, Kasi Viswanatharaju; Lewis, Sarah M; Hillebrand, Roman; Singh, Harkewal; Tanner, John J; Gates, Kent S

2017-04-11

Protein tyrosine phosphatase 1B (PTP1B) is a validated drug target, but it has proven difficult to develop medicinally useful, reversible inhibitors of this enzyme. Here we explored covalent strategies for the inactivation of PTP1B using a conjugate composed of an active site-directed 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxide inhibitor connected via a short linker to an electrophilic α-bromoacetamide moiety. Inhibitor-electrophile conjugate 5a caused time-dependent loss of PTP1B activity consistent with a covalent inactivation mechanism. The inactivation occurred with a second-order rate constant of (1.7 ± 0.3) × 10 2 M -1 min -1 . Mass spectrometric analysis of the inactivated enzyme indicated that the primary site of modification was C121, a residue distant from the active site. Previous work provided evidence that covalent modification of the allosteric residue C121 can cause inactivation of PTP1B [Hansen, S. K., Cancilla, M. T., Shiau, T. P., Kung, J., Chen, T., and Erlanson, D. A. (2005) Biochemistry 44, 7704-7712]. Overall, our results are consistent with an unusual enzyme inactivation process in which noncovalent binding of the inhibitor-electrophile conjugate to the active site of PTP1B protects the nucleophilic catalytic C215 residue from covalent modification, thus allowing inactivation of the enzyme via selective modification of allosteric residue C121.

Phosphazenes with Olefinic Side Groups: Proton Abstraction Reactions of Fluoroalkoxy Derivatives.

DTIC Science & Technology

1982-06-24

OPh) (OC(Li)=CF2) 13 and [NP(OC(Li)CF2)2]3 1 respectively. These species are stable in solution at -78*C, but react with electrophiles such as 2...an -OCH2CF3 side group to generate an -OC(M)-CF2 unit. Subsequent treatment with an electrophile was designed to yield an -OC(R)-CF2 side group...resonances for the fluorine atoms in 2 and 5 appeared as multiplets due to the slight differences in chemical shift between the cis and trans

Electrophilic nitro-fatty acids suppress allergic contact dermatitis in mice.

PubMed

Mathers, A R; Carey, C D; Killeen, M E; Diaz-Perez, J A; Salvatore, S R; Schopfer, F J; Freeman, B A; Falo, L D

2017-04-01

Reactions between nitric oxide (NO), nitrite (NO2-), and unsaturated fatty acids give rise to electrophilic nitro-fatty acids (NO 2 -FAs), such as nitro oleic acid (OA-NO 2 ) and nitro linoleic acid (LNO 2 ). Endogenous electrophilic fatty acids (EFAs) mediate anti-inflammatory responses by modulating metabolic and inflammatory signal transduction reactions. Hence, there is considerable interest in employing NO 2 -FAs and other EFAs for the prevention and treatment of inflammatory disorders. Thus, we sought to determine whether OA-NO 2 , an exemplary nitro-fatty acid, has the capacity to inhibit cutaneous inflammation. We evaluated the effect of OA-NO 2 on allergic contact dermatitis (ACD) using an established model of contact hypersensitivity in C57Bl/6 mice utilizing 2,4-dinitrofluorobenzene as the hapten. We found that subcutaneous (SC) OA-NO 2 injections administered 18 h prior to sensitization and elicitation suppresses ACD in both preventative and therapeutic models. In vivo SC OA-NO 2 significantly inhibits pathways that lead to inflammatory cell infiltration and the production of inflammatory cytokines in the skin. Moreover, OA-NO 2 is capable of enhancing regulatory T-cell activity. Thus, OA-NO 2 treatment results in anti-inflammatory effects capable of inhibiting ACD by inducing immunosuppressive responses. Overall, these results support the development of OA-NO 2 as a promising therapeutic for ACD and provides new insights into the role of electrophilic fatty acids in the control of cutaneous immune responses potentially relevant to a broad range of allergic and inflammatory skin diseases. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Theoretical characterization on the size-dependent electron and hole trapping activity of chloride-passivated CdSe nanoclusters

NASA Astrophysics Data System (ADS)

Cui, Yingqi; Cui, Xianhui; Zhang, Li; Xie, Yujuan; Yang, Mingli

2018-04-01

Ligand passivation is often used to suppress the surface trap states of semiconductor quantum dots (QDs) for their continuous photoluminescence output. The suppression process is related to the electrophilic/nucleophilic activity of surface atoms that varies with the structure and size of QD and the electron donating/accepting nature of ligand. Based on first-principles-based descriptors and cluster models, the electrophilic/nucleophilic activities of bare and chloride-coated CdSe clusters were studied to reveal the suppression mechanism of Cl-passivated QDs and compared to experimental observations. The surface atoms of bare clusters have higher activity than inner atoms and their activity decreases with cluster size. In the ligand-coated clusters, the Cd atom remains as the electrophilic site, while the nucleophilic site of Se atoms is replaced by Cl atoms. The activities of Cd and Cl atoms in the coated clusters are, however, remarkably weaker than those in bare clusters. Cluster size, dangling atoms, ligand coverage, electronegativity of ligand atoms, and solvent (water) were found to have considerable influence on the activity of surface atoms. The suppression of surface trap states in Cl-passivated QDs was attributed to the reduction of electrophilic/nucleophilic activity of Cd/Se/Cl atoms. Both saturation to under-coordinated surface atoms and proper selection for the electron donating/accepting strength of ligands are crucial for eliminating the charge carrier traps. Our calculations predicted a similar suppressing effect of chloride ligands with experiments and provided a simple but effective approach to assess the charge carrier trapping behaviors of semiconductor QDs.

Copper-Catalysed Aminoboration of Vinylarenes with Hydroxylamine Esters-A Computational Mechanistic Study.

PubMed

Tobisch, Sven

2017-12-14

An in-depth computational probe of the copper-mediated formal aminoboration of β-alkylstyrenes with bis(pinacolato)diboron B 2 pin 2 and an archetype hydroxylamine ester by a dppbz-ligated {P^P}Cu I boryl catalyst (dppbz≡{P^P}≡1,2-bis(diphenylphosphino)benzene) is presented. This first comprehensive computational study of the copper-mediated formal aminoboration utilising an electrophilic strategy has identified the most accessible pathway for productive catalysis. The mechanistic picture derived from smooth energy profiles acquired by employing a reliable computational protocol applied to a realistic catalyst model conforms to all available experimental data. The high degree of regio- and stereoselectivity achieved in syn-borylcupration and Umpolung electrophilic amination is instrumental to the exclusive generation of the (syn)-β-aminoalkylborane product. On the one hand, syn-borylcupration furnishes exclusively β-borylalkylcopper nucleophile upon boryl addition onto the vinylarene β-carbon. Its subsequent approach by the hydroxylamine electrophile to deliver the product with the release of {P^P}Cu I benzoate favours a stepwise stereoretentive S N 2-type oxidative addition/N-C bond-forming reductive elimination sequence. The copper benzoate species represents the catalyst resting state, and its transformation into the catalytically active borylcopper species upon salt metathesis with Li(OtBu) base and transmetallation with B 2 pin 2 is turnover limiting. Electronically modified β-alkylstyrenes featuring a para-CF 3 substituted phenyl ring render the borylcupration faster, and more electron-rich hydroxylamine agents decelerate the electrophilic amination. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Quinone-Catalyzed Selective Oxidation of Organic Molecules

PubMed Central

Wendlandt, Alison E.

2016-01-01

Lead In Quinones are common stoichiometric reagents in organic chemistry. High potential para-quinones, such as DDQ and chloranil, are widely used and typically promote hydride abstraction. In recent years, many catalytic applications of these methods have been achieved by using transition metals, electrochemistry or O2 to regenerate the oxidized quinone in situ. Complementary studies have led to the development of a different class of quinones that resemble the ortho-quinone cofactors in Copper Amine Oxidases and mediate efficient and selective aerobic and/or electrochemical dehydrogenation of amines. The latter reactions typically proceed via electrophilic transamination and/or addition-elimination reaction mechanisms, rather than hydride abstraction pathways. The collective observations show that the quinone structure has a significant influence on the reaction mechanism and have important implications for the development of new quinone reagents and quinone-catalyzed transformations. PMID:26530485

Role of Lipid Peroxidation-Derived α, β-Unsaturated Aldehydes in Vascular Dysfunction

PubMed Central

Lee, Seung Eun; Park, Yong Seek

2013-01-01

Vascular diseases are the most prominent cause of death, and inflammation and vascular dysfunction are key initiators of the pathophysiology of vascular disease. Lipid peroxidation products, such as acrolein and other α, β-unsaturated aldehydes, have been implicated as mediators of inflammation and vascular dysfunction. α, β-Unsaturated aldehydes are toxic because of their high reactivity with nucleophiles and their ability to form protein and DNA adducts without prior metabolic activation. This strong reactivity leads to electrophilic stress that disrupts normal cellular function. Furthermore, α, β-unsaturated aldehydes are reported to cause endothelial dysfunction by induction of oxidative stress, redox-sensitive mechanisms, and inflammatory changes such as induction of cyclooxygenase-2 and cytokines. This review provides an overview of the effects of lipid peroxidation products, α, β-unsaturated aldehydes, on inflammation and vascular dysfunction. PMID:23819013

Electrophilic Triterpenoid Enones: A Comparative Thiol-Trapping and Bioactivity Study.

PubMed

Del Prete, Danilo; Taglialatela-Scafati, Orazio; Minassi, Alberto; Sirignano, Carmina; Cruz, Cristina; Bellido, Maria L; Muñoz, Eduardo; Appendino, Giovanni

2017-08-25

Bardoxolone methyl (1) is the quintessential member of triterpenoid cyanoacrylates, an emerging class of bioactive compounds capable of transient covalent binding to thiols. The mechanistic basis for this unusual "pulsed reactivity" profile and the mode of its biological translation are unknown. To provide clues on these issues, a series of Δ 1 -dehydrooleanolates bearing an electron-withdrawing group at C-2 (7a-m) were prepared from oleanolic acid (3a) and comparatively investigated in terms of reactivity with thiols and bioactivity against a series of electrophile-sensitive transcription factors (Nrf2, NF-κB, STAT3). The emerging picture suggests that the triterpenoid scaffold sharply decreases the reactivity of the enone system by steric encumbrance and that only strongly electrophilic and sterically undemanding substituents such as a cyanide or a carboxylate group can re-establish Michael reactivity, albeit in a transient way for the cyanide group. In general, a substantial dissection between the thiol-trapping ability and the modulation of biological end-points sensitive to thiol alkylation was observed, highlighting the role of shape complementarity for the activity of triterpenoid thia-Michael acceptors.

Hydrogen-bond-driven electrophilic activation for selectivity control: scope and limitations of fluorous alcohol-promoted selective formation of 1,2-disubstituted benzimidazoles and mechanistic insight for rationale of selectivity.

PubMed

Chebolu, Rajesh; Kommi, Damodara N; Kumar, Dinesh; Bollineni, Narendra; Chakraborti, Asit K

2012-11-16

Hydrogen-bond-driven electrophilic activation for selectivity control during competitive formation of 1,2-disubstituted and 2-substituted benzimidazoles from o-phenylenediamine and aldehydes is reported. The fluorous alcohols trifluoroethanol and hexafluoro-2-propanol efficiently promote the cyclocondensation of o-phenylenediamine with aldehydes to afford selectively the 1,2-disubstituted benzimidazoles at rt in short times. A mechanistic insight is invoked by NMR, mass spectrometry, and chemical studies to rationalize the selectivity. The ability of the fluorous alcohols in promoting the reaction and controlling the selectivity can be envisaged from their better hydrogen bond donor (HBD) abilities compared to that of the other organic solvents as well as of water. Due to the better HBD values, the fluorous alcohols efficiently promote the initial bisimine formation by electrophilic activation of the aldehyde carbonyl. Subsequently the hydrogen-bond-mediated activation of the in situ-formed bisimine triggers the rearrangement via 1,3-hydride shift to form the 1,2-disubstituted benzimidazoles.

A competing, dual mechanism for catalytic direct benzene hydroxylation from combined experimental-DFT studies† †Electronic supplementary information (ESI) available: For experimental catalytic details and mechanistic procedures, including GC and GC-MS traces, additional figures (Fig. S1–S25), computational data including Cartesian coordinates and energies of all stationary points reported in the text. See DOI: 10.1039/c7sc02898a

PubMed Central

Vilella, Laia; Conde, Ana

2017-01-01

A dual mechanism for direct benzene catalytic hydroxylation is described. Experimental studies and DFT calculations have provided a mechanistic explanation for the acid-free, TpxCu-catalyzed hydroxylation of benzene with hydrogen peroxide (Tpx = hydrotrispyrazolylborate ligand). In contrast with other catalytic systems that promote this transformation through Fenton-like pathways, this system operates through a copper-oxyl intermediate that may interact with the arene ring following two different, competitive routes: (a) electrophilic aromatic substitution, with the copper-oxyl species acting as the formal electrophile, and (b) the so-called rebound mechanism, in which the hydrogen is abstracted by the Cu–O moiety prior to the C–O bond formation. Both pathways contribute to the global transformation albeit to different extents, the electrophilic substitution route seeming to be largely favoured. PMID:29619184

Electrophilic dark matter with dark photon: From DAMPE to direct detection

NASA Astrophysics Data System (ADS)

Gu, Pei-Hong; He, Xiao-Gang

2018-03-01

The electron-positron excess reported by the DAMPE collaboration recently may be explained by an electrophilic dark matter (DM). A standard model singlet fermion may play the role of such a DM when it is stabilized by some symmetries, such as a dark U(1)X gauge symmetry, and dominantly annihilates into the electron-positron pairs through the exchange of a scalar mediator. The model, with appropriate Yukawa couplings, can well interpret the DAMPE excess. Naively one expects that in this type of models the DM-nucleon cross section should be small since there is no tree-level DM-quark interactions. We however find that at one-loop level, a testable DM-nucleon cross section can be induced for providing ways to test the electrophilic model. We also find that a U (1) kinetic mixing can generate a sizable DM-nucleon cross section although the U(1)X dark photon only has a negligible contribution to the DM annihilation. Depending on the signs of the mixing parameter, the dark photon can enhance/reduce the one-loop induced DM-nucleon cross section.

Efficacy ranking of triterpenoids as inducers of a cytoprotective enzyme and as inhibitors of a cellular inflammatory response via their electron affinity and their electrophilicity index

PubMed Central

Bensasson, René V.; Zoete, Vincent; Berthier, Gaston; Talalay, Paul; Dinkova-Kostova, Albena T.

2010-01-01

Electron affinity (EA) and electrophilicity index (ω) of 16 synthetic triterpenoids (TP), previously identified as inducers of cytoprotective enzymes and as inhibitors of cellular inflammatory responses, have been calculated by the molecular orbital method. Linear correlations were obtained by plotting the values of EA, as well as those of ω versus (i) the potencies of induction of NAD(P)H quinone reductase (NQO1, EC 1.6.99.2), a cytoprotective enzyme, expressed via the concentration of TP required to double the specific activity of NQO1 (CD value) and (ii) the values of their anti-inflammatory activity expressed via the IC-50 of TP for suppression of upregulation of inducible nitric oxide synthase (iNOS, EC 1.14.13.39), both previously experimentally determined. The observed correlations demonstrate quantitatively for a series of triterpenoids that their electrophilicity is a major factor determining their potency as inducers of the cytoprotective phase 2 response and as inhibitors of inflammatory processes. PMID:20433811

Redox signaling regulated by an electrophilic cyclic nucleotide and reactive cysteine persulfides.

PubMed

Fujii, Shigemoto; Sawa, Tomohiro; Nishida, Motohiro; Ihara, Hideshi; Ida, Tomoaki; Motohashi, Hozumi; Akaike, Takaaki

2016-04-01

Reactive oxygen (oxidant) and free radical species are known to cause nonspecific damage of various biological molecules. The oxidant toxicology is developing an emerging concept of the physiological functions of reactive oxygen species in cell signaling regulation. Redox signaling is precisely modulated by endogenous electrophilic substances that are generated from reactive oxygen species during cellular oxidative stress responses. Among diverse electrophilic molecular species that are endogenously generated, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is a unique second messenger whose formation, signaling, and metabolism in cells was recently clarified. Most important, our current studies revealed that reactive cysteine persulfides that are formed abundantly in cells are critically involved in the metabolism of 8-nitro-cGMP. Modern redox biology involves frontiers of cell research and stem cell research; medical and clinical investigations of infections, cancer, metabolic syndrome, aging, and neurodegenerative diseases; and other fields. 8-Nitro-cGMP-mediated signaling and metabolism in cells may therefore be potential targets for drug development, which may lead to discovery of new therapeutic agents for many diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

The Stille Reaction (Vittorio Farina, Venkat Krishnamurthy, and William J. Scott)

NASA Astrophysics Data System (ADS)

Cochran, John C.

1999-10-01

In 1997, Volume 50 of Organic Reactions was published in a handsome and appropriate gold hard-cover edition. This was only the third volume in this prestigious series that consisted of a single chapter. The treatise, The Stille Reaction, describes a palladium-catalyzed cross-coupling between a carbon ligand on tin and a carbon with electrophilic character. This reaction has been around only since 1977, and the literature is covered here through 1994 with a few references in 1995. It is truly astounding that, in the space of about 17 years, a new reaction could generate enough literature for not only a chapter in Organic Reactions, but a complete volume of 652 pages, 864 literature citations, and more than 4300 specific reaction examples. The editorial board of Organic Reactions has graciously decided to make this extensive review available to a broader audience by authorizing a paperback edition of The Stille Reaction. While the mechanistic details of the Stille reaction are generally understood, there are many fine points that must be tuned to each case. For instance, about 15 different solvents have been used, ranging in polarity from benzene to water; at least ten different ligands for the palladium atom are available and they range from hard to soft; CuI, Ag2CO3, and LiCl are sometimes useful cocatalysts but sometimes have no effect, and in some cases LiCl is inhibitory; vinyl triflates couple with alkenyl-, alkynyl- and allylstannanes but not with arylstannanes; reaction temperatures vary from room temperature to refluxing DMF. An important consideration is that most stannanes are reasonably air and moisture stable and do not react with most common functional groups. Thus, it is not necessary to build protection-deprotection sequences into the synthetic scheme. The extensive reaction examples are arranged in 33 tables that show, for each reaction, the structures of the electrophile, the stannane, and the product and specify the catalyst, cocatalyst, solvent temperature, and yield. The tables are sequenced by the structure of the electrophiles, which are listed in order of increasing carbon count for the group that is transferred. For the same electrophile, different stannanes are listed by the increasing carbon count of the group transferred from tin. For example, the three tables with the most examples are titled "Direct Cross-Coupling of Alkenyl Electrophiles," "Direct Cross-Coupling of Aryl Electrophiles", and "Direct Cross-Coupling of Miscellaneous Heterocyclic Electrophiles". They include 661, 1043, and 339 examples, respectively. The narrative section of the book begins with an overview of the mechanism, regiochemistry, and stereochemistry of the Stille reaction. This is followed by discussions of the scope and limitations of both the electrophilic species and the stannane. The Stille reaction can also involve the incorporation of a carbonyl in the coupling sequence. The carbonyl results from inclusion of carbon monoxide in the reaction medium. This variation of the reaction is also discussed. The narrative continues with discussion of Hech-Stille tandem sequences, side reactions, and comparisons with other cross-coupling reactions. It concludes with a very useful section on experimental considerations and nine examples of procedures from the literature. The book also includes a useful index (covering the narrative section), which has been added to the original Organic Reactions edition. Finally, it should be noted that a careful inspection of the thousands of structures in the table did not turn up one typographical error. In a 1993 research paper (J. Org. Chem. 1993, 58, 5434) the lead author, Vittorio Farina, writes that "A survey of applications of transition metal-mediated cross-coupling reactions for the year 1992 shows that the Stille coupling accounts for over 50% of all cross-couplings reported." It seems that, given the magnitude of this review, the significance of this reaction has continued to grow. Every synthetic organic chemist should have easy access to the massive amount of information contained in this book.

Dramatic Influence of Ionic Liquid and Ultrasound Irradiation on the Electrophilic Sulfinylation of Aromatic Compounds by Sulfinic Esters.

PubMed

Nguyen, Ngoc-Lan Thi; Vo, Hong-Thom; Duus, Fritz; Luu, Thi Xuan Thi

2017-09-04

The sulfinylation reaction of aromatic and hetero-aromatic compounds with sulfinic esters as electrophiles has been investigated in different ionic liquids and by means of different Lewis acid salts in order to get moderate to good yields of asymmetrical sulfoxides. Mixtures of 1-butyl-3-methylimidazolium chloride and aluminum chloride were found to be the most efficient and recyclable reaction framework. Ultrasound sonication appeared to be the most useful and green activation method to afford the sulfoxides in yields better than or equivalent to those obtained under the longer-lasting conventional stirring conditions.

Silyl Radical Activation of Alkyl Halides in Metallaphotoredox Catalysis: A Unique Pathway for Cross-Electrophile Coupling.

PubMed

Zhang, Patricia; Le, Chi Chip; MacMillan, David W C

2016-07-06

A strategy for cross-electrophile coupling has been developed via the merger of photoredox and transition metal catalysis. In this report, we demonstrate the use of commercially available tris(trimethylsilyl)silane with metallaphotoredox catalysis to efficiently couple alkyl bromides with aryl or heteroaryl bromides in excellent yields. We hypothesize that a photocatalytically generated silyl radical species can perform halogen-atom abstraction to activate alkyl halides as nucleophilic cross-coupling partners. This protocol allows the use of mild yet robust conditions to construct Csp(3)-Csp(2) bonds generically via a unique cross-coupling pathway.

Synthesis of benzil-o-carboxylate derivatives and isocoumarins through neighboring ester-participating bromocyclizations of o-alkynylbenzoates.

PubMed

Yuan, Si-Tian; Zhou, Hongwei; Zhang, Lianpeng; Liu, Jin-Biao; Qiu, Guanyinsheng

2017-06-07

Bromide mediated neighboring ester-participating bromocyclizations of o-alkynylbenzoates are described here for the synthesis of benzil-o-carboxylates. 4-bromoisocoumarins are also synthesized when phenyl o-alkynylbenzoate is used as the substrate. Mechanistic studies suggest that the whole process is composed of an electrophilic bromocyclization and a dibromohydration-based ring-opening, and the neighboring ester group participates in the bromocyclization. Interestingly, the two oxygen atoms of the keto carbonyls in benzil-o-carboxylates are both derived from water. The electrophilic bromo source is in situ generated from the oxidation of bromide.

Investigating mitochondrial dysfunction in human lung cells exposed to redox-active PM components.

PubMed

Lavrich, Katelyn S; Corteselli, Elizabeth M; Wages, Phillip A; Bromberg, Philip A; Simmons, Steven O; Gibbs-Flournoy, Eugene A; Samet, James M

2018-03-01

Exposure to ambient particulate matter (PM) causes cardiopulmonary morbidity and mortality through mechanisms that involve oxidative stress. 1,2-naphthoquinone (1,2-NQ) is a ubiquitous component of PM and a potent redox-active electrophile. We previously reported that 1,2-NQ increases mitochondrial H 2 O 2 production through an unidentified mechanism. We sought to characterize the effects of 1,2-NQ exposure on mitochondrial respiration as a source of H 2 O 2 in human airway epithelial cells. We measured the effects of acute exposure to 1,2-NQ on oxygen consumption rate (OCR) in the human bronchial epithelial cell line BEAS-2B and mitochondrial preparations using extracellular flux analysis. Complex-specific assays and NADPH depletion by glucose deprivation distinguished between mitochondrial and non-mitochondrial oxygen utilization. 1,2-NQ exposure of BEAS cells caused a rapid, marked dose-dependent increase in OCR that was independent of mitochondrial respiration, exceeded the OCR observed after mitochondrial uncoupling, and remained sensitive to NADPH depletion, implicating extra-mitochondrial redox cycling processes. Similar effects were observed with the environmentally relevant redox-cycling quinones 1,4-naphthoquinone and 9,10-phenanthrenequinone, but not with quinones that do not redox cycle, such as 1,4-benzoquinone. In mitochondrial preparations, 1,2-NQ caused a decrease in Complex I-linked substrate oxidation, suggesting impairment of pyruvate utilization or transport, a novel mechanism of mitochondrial inhibition by an environmental exposure. This study also highlights the methodological utility and challenges in the use of extracellular flux analysis to elucidate the mechanisms of action of redox-active electrophiles present in ambient air. Published by Elsevier Inc.

The Reaction of Hydrogen Sulfide with Disulfides: Formation of a Stable Trisulfide and Implications to Biological Systems.

PubMed

Bianco, Christopher L; Akaike, Takaaki; Ida, Tomoaki; Nagy, Peter; Bogdandi, Virag; Toscano, John P; Kumagai, Yoshito; Henderson, Catherine F; Goddu, Robert N; Lin, Joseph; Fukuto, Jon M

2018-05-29

The signaling associated with hydrogen sulfide (H 2 S) remains to be established and recent studies have alluded to the possibility that H 2 S-derived species play important roles. Of particular interest are hydropersulfides (RSSH) and related polysulfides (RSS n R, n>1). This work elucidates the fundamental chemical relationship between these sulfur species as well as examine their biological effects. Using standard analytical techniques ( 1 H-NMR and mass spectrometry), the equilibrium reactions between H 2 S, disulfides (RSSR), RSSH, dialkyltrisulfides (RSSSR) and thiols (RSH) were examined. Their ability to protect cells from electrophilic and/or oxidative stress was also examined using cell culture. H 2 S, RSSR, RSSH, RSSSR and RSH are all in a dynamic equilibrium. In a biological system, these species can exist simultaneously and thus it is difficult to discern which species is (are) the biological effector (s). Treatment of cells with the dialkyl trisulfide cysteine trisulfide (Cys-SSS-Cys) results in high intracellular levels of hydropersulfides and protection from electrophilic stress. In aqueous systems, the reaction between H 2 S and RSSR results in the formation of equilbria whereby H 2 S, RSH, RSSR, RSSH and RSSSR are present. In a biological system, any of these species can be responsible for the observed biological activity. These equilibrium species can also be generated via the reaction of RSH with RSSSR. Due to these equilibria, Cys-SSS-Cys can be a method for generating any of the other species. Importantly, HEK293T cells treated with Cys-SSS-Cys results in increased levels of hydropersulfides, allowing examination of the biological effects of RSSH. This article is protected by copyright. All rights reserved.

Where does the electron go? The nature of ortho/para and meta group directing in electrophilic aromatic substitution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Shubin, E-mail: shubin@email.unc.edu

Electrophilic aromatic substitution as one of the most fundamental chemical processes is affected by atoms or groups already attached to the aromatic ring. The groups that promote substitution at the ortho/para or meta positions are, respectively, called ortho/para and meta directing groups, which are often characterized by their capability to donate electrons to or withdraw electrons from the ring. Though resonance and inductive effects have been employed in textbooks to explain this phenomenon, no satisfactory quantitative interpretation is available in the literature. Here, based on the theoretical framework we recently established in density functional reactivity theory (DFRT), where electrophilicity andmore » nucleophilicity are simultaneously quantified by the Hirshfeld charge, the nature of ortho/para and meta group directing is systematically investigated for a total of 85 systems. We find that regioselectivity of electrophilic attacks is determined by the Hirshfeld charge distribution on the aromatic ring. Ortho/para directing groups have most negative charges on the ortho/para positions, while meta directing groups often possess the largest negative charge on the meta position. Our results do not support that ortho/para directing groups are electron donors and meta directing groups are electron acceptors. Most neutral species we studied here are electron withdrawal in nature. Anionic systems are always electron donors. There are also electron donors serving as meta directing groups. We predicted ortho/para and meta group directing behaviors for a list of groups whose regioselectivity is previously unknown. In addition, strong linear correlations between the Hirshfeld charge and the highest occupied molecular orbital have been observed, providing the first link between the frontier molecular orbital theory and DFRT.« less

Replacing Conventional Carbon Nucleophiles with Electrophiles: Nickel-Catalyzed Reductive Alkylation of Aryl Bromides and Chlorides

PubMed Central

2012-01-01

A general method is presented for the synthesis of alkylated arenes by the chemoselective combination of two electrophilic carbons. Under the optimized conditions, a variety of aryl and vinyl bromides are reductively coupled with alkyl bromides in high yields. Under similar conditions, activated aryl chlorides can also be coupled with bromoalkanes. The protocols are highly functional-group tolerant (−OH, −NHTs, −OAc, −OTs, −OTf, −COMe, −NHBoc, −NHCbz, −CN, −SO2Me), and the reactions are assembled on the benchtop with no special precautions to exclude air or moisture. The reaction displays different chemoselectivity than conventional cross-coupling reactions, such as the Suzuki–Miyaura, Stille, and Hiyama–Denmark reactions. Substrates bearing both an electrophilic and nucleophilic carbon result in selective coupling at the electrophilic carbon (R–X) and no reaction at the nucleophilic carbon (R–[M]) for organoboron (−Bpin), organotin (−SnMe3), and organosilicon (−SiMe2OH) containing organic halides (X–R–[M]). A Hammett study showed a linear correlation of σ and σ(−) parameters with the relative rate of reaction of substituted aryl bromides with bromoalkanes. The small ρ values for these correlations (1.2–1.7) indicate that oxidative addition of the bromoarene is not the turnover-frequency determining step. The rate of reaction has a positive dependence on the concentration of alkyl bromide and catalyst, no dependence upon the amount of zinc (reducing agent), and an inverse dependence upon aryl halide concentration. These results and studies with an organic reductant (TDAE) argue against the intermediacy of organozinc reagents. PMID:22463689

Iron-Catalyzed C-O Bond Activation: Opportunity for Sustainable Catalysis.

PubMed

Bisz, Elwira; Szostak, Michal

2017-10-23

Oxygen-based electrophiles have emerged as some of the most valuable cross-coupling partners in organic synthesis due to several major strategic and environmental benefits, such as abundance and potential to avoid toxic halide waste. In this context, iron-catalyzed C-O activation/cross-coupling holds particular promise to achieve sustainable catalytic protocols due to its natural abundance, inherent low toxicity, and excellent economic and ecological profile. Recently, tremendous progress has been achieved in the development of new methods for functional-group-tolerant iron-catalyzed cross-coupling reactions by selective C-O cleavage. These methods establish highly attractive alternatives to traditional cross-coupling reactions by using halides as electrophilic partners. In particular, new easily accessible oxygen-based electrophiles have emerged as substrates in iron-catalyzed cross-coupling reactions, which significantly broaden the scope of this catalysis platform. New mechanistic manifolds involving iron catalysis have been established; thus opening up vistas for the development of a wide range of unprecedented reactions. The synthetic potential of this sustainable mode of reactivity has been highlighted by the development of new strategies in the construction of complex motifs, including in target synthesis. The most recent advances in sustainable iron-catalyzed cross-coupling of C-O-based electrophiles are reviewed, with a focus on both mechanistic aspects and synthetic utility. It should be noted that this catalytic manifold provides access to motifs that are often not easily available by other methods, such as the assembly of stereodefined dienes or C(sp 2 )-C(sp 3 ) cross-couplings, thus emphasizing the synthetic importance of this mode of reactivity. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Sizable NSI from the SU(2) L scalar doublet-singlet mixing and the implications in DUNE

DOE PAGES

Forero, David V.; Huang, Wei -Chih

2017-03-03

Here, we propose a novel and simple mechanism where sizable effects of non-standard interactions (NSI) in neutrino propagation are induced from the mixing between an electrophilic second Higgs doublet and a charged singlet. The mixing arises from a dimensionful coupling of the scalar doublet and singlet to the standard model Higgs boson. In light of the small mass, the light mass eigenstate from the doublet-singlet mixing can generate much larger NSI than those induced by the heavy eigenstate. We show that a sizable NSI ε eτ (~0.3) can be attained without being excluded by a variety of experimental constraints. Furthermore,more » we demonstrate that NSI can mimic effects of the Dirac CP phase in the neutrino mixing matrix but they can potentially be disentangled by future long-baseline neutrino experiments, such as the Deep Underground Neutrino Experiment (DUNE).« less

Structural dissection of Shewanella oneidensis old yellow enzyme 4 bound to a Meisenheimer complex and (nitro)phenolic ligands.

PubMed

Elegheert, Jonathan; Brigé, Ann; Van Beeumen, Jozef; Savvides, Savvas N

2017-10-01

Shewanella oneidensis, a Gram-negative γ-proteobacterium with an extensive redox capacity, possesses four old yellow enzyme (OYE) homologs. Of these, Shewanella yellow enzyme 4 (SYE4) is implicated in resistance to oxidative stress. Here, we present a series of high-resolution crystal structures for SYE4 in the oxidized and reduced states, and in complex with phenolic ligands and the nitro-aromatic explosive picric acid. The structures unmask new features, including the identification of a binding platform for long-chain hydrophobic molecules. Furthermore, we present the first structural observation of a hydride-Meisenheimer complex of picric acid with a flavoenzyme. Overall, our study exposes the binding promiscuity of SYE4 toward a variety of electrophilic substrates and is consistent with a general detoxification function for SYE4. © 2017 Federation of European Biochemical Societies.

Sizable NSI from the SU(2) L scalar doublet-singlet mixing and the implications in DUNE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Forero, David V.; Huang, Wei -Chih

Here, we propose a novel and simple mechanism where sizable effects of non-standard interactions (NSI) in neutrino propagation are induced from the mixing between an electrophilic second Higgs doublet and a charged singlet. The mixing arises from a dimensionful coupling of the scalar doublet and singlet to the standard model Higgs boson. In light of the small mass, the light mass eigenstate from the doublet-singlet mixing can generate much larger NSI than those induced by the heavy eigenstate. We show that a sizable NSI ε eτ (~0.3) can be attained without being excluded by a variety of experimental constraints. Furthermore,more » we demonstrate that NSI can mimic effects of the Dirac CP phase in the neutrino mixing matrix but they can potentially be disentangled by future long-baseline neutrino experiments, such as the Deep Underground Neutrino Experiment (DUNE).« less

A combination of directing groups and chiral anion phase-transfer catalysis for enantioselective fluorination of alkenes

PubMed Central

Wu, Jeffrey; Wang, Yi-Ming; Drljevic, Amela; Rauniyar, Vivek; Phipps, Robert J.; Toste, F. Dean

2013-01-01

We report a catalytic enantioselective electrophilic fluorination of alkenes to form tertiary and quaternary C(sp3)-F bonds and generate β-amino- and β-aryl-allylic fluorides. The reaction takes advantage of the ability of chiral phosphate anions to serve as solid–liquid phase transfer catalysts and hydrogen bond with directing groups on the substrate. A variety of heterocyclic, carbocyclic, and acyclic alkenes react with good to excellent yields and high enantioselectivities. Further, we demonstrate a one-pot, tandem dihalogenation–cyclization reaction, using the same catalytic system twice in series, with an analogous electrophilic brominating reagent in the second step. PMID:23922394

Centrohexaindane: six benzene rings mutually fixed in three dimensions - solid-state structure and six-fold nitration.

PubMed

Kuck, Dietmar; Linke, Jens; Teichmann, Lisa Christin; Barth, Dieter; Tellenbröker, Jörg; Gestmann, Detlef; Neumann, Beate; Stammler, Hans-Georg; Bögge, Hartmut

2016-04-28

The solid-state molecular structure of centrohexaindane (), a unique hydrocarbon comprising six benzene rings clamped to each other in three dimensions around a neopentane core, and the molecular packing in crystals of ·CHCl3 are reported. The molecular Td-symmetry and the Cartesian orientation of the six indane wings of in the solid state have been confirmed. The course and limitation of electrophilic aromatic substitution of are demonstrated for the case of nitration. Based on nitration experiments of a lower congener of , tribenzotriquinacene , the six-fold nitrofunctionalisation of has been achieved in excellent yield, giving four constitutional isomers, two nonsymmetrical ( and ) and two C3-symmetrical ones ( and ), all of which contain one single nitro group in each of the six benzene rings. The relative yields of the four isomers (∼3 : 1 : 1 : 3) point to a random electrophilic attack of the electrophiles at the twelve formally equivalent outer positions of the aromatic periphery of , suggesting electronic independence of its six aromatic π-electron systems. In turn, the pronounced conformational rigidity of the centrohexacyclic framework of enables the unequivocal structural identification of the isomeric hexanitrocentrohexaindanes by (1)H NMR spectroscopy.

Donation and back-donation analyzed through a charge transfer model based on density functional theory.

PubMed

Orozco-Valencia, Ulises; Gázquez, José L; Vela, Alberto

2017-07-01

The net charge transfer process that occurs between two species, A and B, interacting with each other, may be decomposed into two processes: one in which A receives charge from B, which can be identified as the electrophilic channel for A or the nucleophilic channel for B, and a second in which A donates charge to B, which can be identified as the nucleophilic channel for A or the electrophilic channel for B. By determining the amount of charge associated with both processes through the minimization of the interaction energy associated with each case, the expressions for the amount of charge involved in each case can be expressed in terms of the directional chemical potentials and the hardnesses of the interacting species. The correlation between the charges obtained for the interaction between phosphine ligands of the type PRR'R'' and Ni, and the A 1 carbonyl stretching frequency provides support for their interpretation as measures of the electrophilicity and nucleophilicity of a chemical species, and, at the same time, allows one to describe the donation and back-donation processes in terms of the density functional theory of chemical reactivity.

Redox Signaling Regulated by Cysteine Persulfide and Protein Polysulfidation.

PubMed

Kasamatsu, Shingo; Nishimura, Akira; Morita, Masanobu; Matsunaga, Tetsuro; Abdul Hamid, Hisyam; Akaike, Takaaki

2016-12-15

For decades, reactive persulfide species including cysteine persulfide (CysSSH) have been known to exist endogenously in organisms. However, the physiological significance of endogenous persulfides remains poorly understood. That cystathionine β-synthase and cystathionine γ-lyase produced CysSSH from cystine was recently demonstrated. An endogenous sulfur transfer system involving CysSSH evidently generates glutathione persulfide (GSSH) that exists at concentrations greater than 100 μM in vivo. Because reactive persulfide species such as CysSSH and GSSH have higher nucleophilicity than parental cysteine (Cys) and glutathione do, these reactive species exhibit strong scavenging activities against oxidants, e.g., hydrogen peroxide, and electrophiles, which contributes to redox signaling regulation. Also, several papers indicated that various proteins and enzymes have Cys polysulfides including CysSSH at their specific Cys residues, which is called protein polysulfidation. Apart from the redox signaling regulatory mechanism, another plausible function of protein polysulfidation is providing protection for protein thiol residues against irreversible chemical modification caused by oxidants and electrophiles. Elucidation of the redox signaling regulatory mechanism of reactive persulfide species including small thiol molecules and thiol-containing proteins should lead to the development of new therapeutic strategies and drug discoveries for oxidative and electrophilic stress-related diseases.

Nrf2 the rescue: effects of the antioxidative/electrophilic response on the liver.

PubMed

Klaassen, Curtis D; Reisman, Scott A

2010-04-01

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that positively regulates the basal and inducible expression of a large battery of cytoprotective genes. These gene products include proteins that catalyze reduction reactions (NAD(P)H:quinone oxidoreductase 1, Nqo1), conjugation reactions (glutathione-S-transferases, Gsts and UDP-glucuronosyltransferases, Ugts), as well as the efflux of potentially toxic xenobiotics and xenobiotic conjugates (multidrug resistance-associated proteins, Mrps). The significance of Nrf2 in the liver has been established, as livers of Nrf2-null mice are more susceptible to various oxidative/electrophilic stress-induced pathologies than wild-type mice. In contrast, both pharmacological and genetic models of hepatic Nrf2 activation are protective against oxidative/electrophilic stress. Furthermore, because certain Nrf2-target genes in the liver could affect the distribution, metabolism, and excretion of xenobiotics, the effects of Nrf2 on the kinetics of drugs and other xenobiotics should also be considered, with a special emphasis on metabolism and excretion. Therefore, this review highlights the research that has contributed to the understanding of the importance of Nrf2 in toxicodynamics and toxicokinetics, especially that which pertains to the liver. 2010 Elsevier Inc. All rights reserved.

Electrophilic Pt(II) Complexes: Precision Instruments for the Initiation of Transformations Mediated by the Cation–Olefin Reaction

PubMed Central

2015-01-01

A discontinuity exists between the importance of the cation–olefin reaction as the principal C–C bond forming reaction in terpene biosynthesis and the synthetic tools for mimicking this reaction under catalyst control; that is, having the product identity, stereochemistry, and functionality under the control of a catalyst. The main reason for this deficiency is that the cation–olefin reaction starts with a reactive intermediate (a carbocation) that reacts exothermically with an alkene to reform the reactive intermediate; not to mention that reactive intermediates can also react in nonproductive fashions. In this Account, we detail our efforts to realize catalyst control over this most fundamental of reactions and thereby access steroid like compounds. Our story is organized around our progress in each component of the cascade reaction: the metal controlled electrophilic initiation, the propagation and termination of the cyclization (the cyclase phase), and the turnover deplatinating events. Electrophilic Pt(II) complexes efficiently initiate the cation–olefin reaction by first coordinating to the alkene with selection rules that favor less substituted alkenes over more substituted alkenes. In complex substrates with multiple alkenes, this preference ensures that the least substituted alkene is always the better ligand for the Pt(II) initiator, and consequently the site at which all electrophilic chemistry is initiated. This control element is invariant. With a suitably electron deficient ligand set, the catalyst then activates the coordinated alkene to intramolecular addition by a second alkene, which initiates the cation–olefin reaction cascade and generates an organometallic Pt(II)-alkyl. Deplatination by a range of mechanisms (β-H elimination, single electron oxidation, two-electron oxidation, etc.) provides an additional level of control that ultimately enables A-ring functionalizations that are orthogonal to the cyclase cascade. We particularly focus on reactions that combine an initiated cyclization reaction with a turnover defining β-hydride elimination, fluorination, and oxygenation. These latter demetalation schemes lead to new compounds functionalized at the C3 carbon of the A-ring (steroid numbering convention) and thus provide access to interesting potentially bioactive targets. Progress toward efficient and diverse polycyclization reactions has been achieved by investing in both synthetic challenges and fundamental organometallic reactivity. In addition to an interest in the entrance and exit of the metal catalyst from this reaction scheme, we have been intrigued by the role of neighboring group participation in the cyclase phase. Computational studies have served to provide nuance and clarity on several key aspects, including the role (and consequences) of neighboring group participation in cation generation and stabilization. For example, these calculations have demonstrated that traversing carbonium ion transition states significantly impacts the kinetics of competitive 6-endo and 5-exo A-ring forming reactions. The resulting nonclassical transition states then become subject to a portion of the strain energy inherent to bicyclic structures, with the net result being that the 6-endo pathway becomes kinetically favored for alkene nucleophiles, in contrast to heteroatom nucleophiles which progress through classical transition states and preferentially follow 5-exo pathways. These vignettes articulate our approach to achieving the desired catalyst control. PMID:24845777

Carbon-hydrogen to carbon-phosphorus transformations.

PubMed

Montchamp, Jean-Luc

2015-01-01

Literature published between 2008 and 2013 concerning the functionalization of carbon-hydrogen into carbon-phosphorus bonds is surveyed. The chapter is organized by reaction mechanism. The majority of methods still proceed via deprotonation of C-H into C-M (M=Li, Na, etc.) followed by reaction with a phosphorus electrophile P-X, where X is usually chlorine. A few examples of electrophilic aromatic substitution and related processes have also been reported, although this approach has not yet been developed significantly. Over the past 5 years a rapidly growing family of reactions includes transition metal "C-H activation" and formally related radical-based processes has been developed. The latter processes offer exciting prospects for the synthesis of organophosphorus compounds.

Amination of electrophilic aromatic compounds by vicarious nucleophilic substitution

DOEpatents

Mitchell, Alexander R.; Pagoria, Philip F.; Schmidt, Robert D.

2000-01-01

The present invention relates to a process to aminate electrophilic aromatic compounds by vicarious nucleophilic substitution of hydrogen using quaternary hydrazinium salts. The use of trialkylhydrazinium halide, e.g., trimethylhydrazinium iodide, as well as hydroxylamine, alkoxylamines, and 4-amino-1,2,4-triazole to produce aminated aromatic structures, such as 1,3-diamino-2,4,6-trinitrobenzene (DATB), 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) and 3,5-diamino-2,4,6-trinitrotoluene (DATNT), is described. DATB and TATB are useful insensitive high explosives. TATB is also used for the preparation of benzenehexamine, a starting material for the synthesis of novel materials (optical imaging devices, liquid crystals, ferromagnetic compounds).

New Horizons in C-F Activation by Main Group Electrophiles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ozerov, Oleg V.

2016-02-13

This technical report describes progress on the DOE sponsored project "New Horizons in C-F Activation by Main Group Electrophiles" during the period of 09/15/2010 – 08/31/2015. The main goal of this project was to develop improved catalysts for conversion of carbon-fluorine bonds in potentially harmful compounds. The approach involved combining of a highly reactive positively charged main-group compound with a highly unreactive negatively charged species (anions) as a way to access potent catalysts for carbon-fluorine bond activation. This report details progress made in improving synthetic pathways to a variety of new anions with improved properties and analysis of their potentialmore » in catalysis.« less

Chemoselective covalent coupling of oligonucleotide probes to self-assembled monolayers.

PubMed

Devaraj, Neal K; Miller, Gregory P; Ebina, Wataru; Kakaradov, Boyko; Collman, James P; Kool, Eric T; Chidsey, Christopher E D

2005-06-22

A chemoselective route to routinely and rapidly attach oligonucleotide probes to well-defined surfaces is presented. Cu(I) tris(benzyltriazolylmethyl)amine-catalyzed coupling of terminal acetylenes to azides on a self-assembled monolayer is used instead of traditional nucleophilic-electrophilic coupling reactions. The reaction proceeds well even in the presence of purposely introduced nucleophilic and electrophilic impurities. The density of oligonucleotide probes can be controlled by controlling the amount of azide functionality. Although most of our work was done on gold surfaces, this technique should be readily applicable to any surface on which an azide-containing monolayer can be assembled as we have preliminarily demonstrated by derivatizing azidotrimethoxysilane-modified glass slides with fluorescein-containing oligonucleotides.

Pyrimidine Nucleosides with a Reactive (β-Chlorovinyl)sulfone or (β-Keto)sulfone Group at the C5 Position, Their Reactions with Nucleophiles and Electrophiles, and Their Polymerase-Catalyzed Incorporation into DNA

PubMed Central

2018-01-01

Transition-metal-catalyzed chlorosulfonylation of 5-ethynylpyrimidine nucleosides provided (E)-5-(β-chlorovinyl)sulfones A, which undergo nucleophilic substitution with amines or thiols affording B. The treatment of vinyl sulfones A with ammonia followed by acid-catalyzed hydrolysis of the intermediary β-sulfonylvinylamines gave 5-(β-keto)sulfones C. The latter reacts with electrophiles, yielding α-carbon-alkylated or -sulfanylated analogues D. The 5′-triphosphates of A and C were incorporated into double-stranded DNA, using open and one-nucleotide gap substrates, by human or Escherichia coli DNA-polymerase-catalyzed reactions. PMID:29732453

Effect of adsorbate electrophilicity and spiky uneven surfaces on single gold nanourchin-based localized surface plasmon resonance sensors

NASA Astrophysics Data System (ADS)

Kim, Geun Wan; Ha, Ji Won

2018-04-01

We present single particle studies on gold nanourchins (AuNUs) for their use as localized surface plasmon resonance (LSPR) biosensors under dark-field (DF) microscopy. First, the LSPR wavelength of single AuNUs was red-shifted as thiol molecules were attached onto the surface. AuNUs with sharp tips showed higher sensitivity for detecting thiol molecules than gold nanospheres (AuNSs) of similar size. Second, the degree of red shift was affected by the electrophilicity of adsorbate molecules on the nanoparticle surface. Last, real-time monitoring of molecular binding events on single AuNUs was achieved with introducing 1 μM of 4-aminothiophenol.

DFT calculations on molecular structure, spectral analysis, multiple interactions, reactivity, NLO property and molecular docking study of flavanol-2,4-dinitrophenylhydrazone

NASA Astrophysics Data System (ADS)

Singh, Ravindra Kumar; Singh, Ashok Kumar

2017-02-01

A new flavanol-2,4-dinitrophenylhydrazone (FDNP) was synthesized and its structure was confirmed by FT-IR, FT-Raman, 1H NMR, mass spectrometry and elemental analysis. All quantum chemical calculations were carried out at level of density functional theory (DFT) with B3LYP functional using 6-311++ G (d,p) basis atomic set. UV-Vis absorption spectra for the singlet-singlet transition computed for fully optimized ground state geometry using Time-Dependent-Density Functional Theory (TD-DFT) with CAM-B3LYP functional was found to be in consistent with that of experimental findings. Analysis of vibrational (FT-IR and FT-Raman) spectrum and their assignments has been done by computing Potential Energy Distribution (PED) using Gar2ped. HOMO-LUMO analysis was performed and reactivity descriptors were calculated. Calculated global electrophilicity index (ω = 7.986 eV) shows molecule to be a strong electrophile. 1H NMR chemical shift calculated with the help of gauge-including atomic orbital (GIAO) approach shows agreement with experimental data. Various intramolecular interactions were analysed by AIM approach. DFT computed total first static hyperpolarizability (β0 = 189.03 × 10-30 esu) indicates that title molecule can be used as attractive future NLO material. Solvent induced effects on the NLO properties studied by using self-consistent reaction field (SCRF) method shows that β0 value increases with increase in solvent polarity. To study the thermal behaviour of title molecule, thermodynamic properties such as heat capacity, entropy and enthalpy change at various temperatures have been calculated and reported. Molecular docking results suggests title molecule to be a potential kinase inhibitor and might be used in future for designing of new anticancer drug.

Density functional theory and surface reactivity study of bimetallic AgnYm (n+m = 10) clusters

NASA Astrophysics Data System (ADS)

Hussain, Riaz; Hussain, Abdullah Ijaz; Chatha, Shahzad Ali Shahid; Hussain, Riaz; Hanif, Usman; Ayub, Khurshid

2018-06-01

Density functional theory calculations have been performed on pure silver (Agn), yttrium (Ym) and bimetallic silver yttrium clusters AgnYm (n + m = 2-10) for reactivity descriptors in order to realize sites for nucleophilic and electrophilic attack. The reactivity descriptors of the clusters, studied as a function of cluster size and shape, reveal the presence of different type of reactive sites in a cluster. The size and shape of the pure silver, yttrium and bimetallic silver yttrium cluster (n = 2-10) strongly influences the number and position of active sites for an electrophilic and/or nucleophilic attack. The trends of reactivities through reactivity descriptors are confirmed through comparison with experimental data for CO binding with silver clusters. Moreover, the adsorption of CO on bimetallic silver yttrium clusters is also evaluated. The trends of binding energies support the reactivity descriptors values. Doping of pure cluster with the other element also influence the hardness, softness and chemical reactivity of the clusters. The softness increases as we increase the number of silver atoms in the cluster, whereas the hardness decreases. The chemical reactivity increases with silver doping whereas it decreases by increasing yttrium concentration. Silver atoms are nucleophilic in small clusters but changed to electrophilic in large clusters.

A fluorescence high throughput screening method for the detection of reactive electrophiles as potential skin sensitizers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Avonto, Cristina; Chittiboyina, Amar G.; Rua, Diego

2015-12-01

Skin sensitization is an important toxicological end-point in the risk assessment of chemical allergens. Because of the complexity of the biological mechanisms associated with skin sensitization, integrated approaches combining different chemical, biological and in silico methods are recommended to replace conventional animal tests. Chemical methods are intended to characterize the potential of a sensitizer to induce earlier molecular initiating events. The presence of an electrophilic mechanistic domain is considered one of the essential chemical features to covalently bind to the biological target and induce further haptenation processes. Current in chemico assays rely on the quantification of unreacted model nucleophiles aftermore » incubation with the candidate sensitizer. In the current study, a new fluorescence-based method, ‘HTS-DCYA assay’, is proposed. The assay aims at the identification of reactive electrophiles based on their chemical reactivity toward a model fluorescent thiol. The reaction workflow enabled the development of a High Throughput Screening (HTS) method to directly quantify the reaction adducts. The reaction conditions have been optimized to minimize solubility issues, oxidative side reactions and increase the throughput of the assay while minimizing the reaction time, which are common issues with existing methods. Thirty-six chemicals previously classified with LLNA, DPRA or KeratinoSens™ were tested as a proof of concept. Preliminary results gave an estimated 82% accuracy, 78% sensitivity, 90% specificity, comparable to other in chemico methods such as Cys-DPRA. In addition to validated chemicals, six natural products were analyzed and a prediction of their sensitization potential is presented for the first time. - Highlights: • A novel fluorescence-based method to detect electrophilic sensitizers is proposed. • A model fluorescent thiol was used to directly quantify the reaction products. • A discussion of the reaction workflow and critical parameters is presented. • The method could provide a useful tool to complement existing chemical assays.« less

Electrochemical oxidation and protein adduct formation of aniline: a liquid chromatography/mass spectrometry study.

PubMed

Melles, Daniel; Vielhaber, Torsten; Baumann, Anne; Zazzeroni, Raniero; Karst, Uwe

2012-04-01

Historically, skin sensitization tests are typically based on in vivo animal tests. However, for substances used in cosmetic products, these tests have to be replaced according to the European Commission regulation no. 1223/2009. Modification of skin proteins by electrophilic chemicals is a key process associated with the induction of skin sensitization. The present study investigates the capabilities of a purely instrumental setup to determine the potential of commonly used non-electrophilic chemicals to cause skin sensitization by the generation of electrophilic species from the parent compound. In this work, the electrophiles were generated by the electrochemical oxidation of aniline, a basic industrial chemical which may also be released from azo dyes in cosmetics. The compound is a known sensitizer and was oxidized in an electrochemical thin-layer cell which was coupled online to electrospray ionization-mass spectrometry. The electrochemical oxidation was performed on a boron-doped diamond working electrode, which is able to generate hydroxyl radicals in aqueous solutions at high potentials. Without any pretreatment, the oxidation products were identified by electrospray ionization/time-of-flight mass spectrometry (ESI-ToF-MS) using their exact masses. A mass voltammogram was generated by plotting the obtained mass spectra against the applied potential. Oligomerization states with up to six monomeric units in different redox states of aniline were observed using this setup. This approach was extended to generate adducts between the oxidation products of aniline and the tripeptide glutathione. Two adducts were identified with this trapping experiment. Protein modification was carried out subsequently: Aniline was oxidized at a constant potential and was allowed to react with β-lactoglobulin A (β-LGA) or human serum albumin (HSA), respectively. The generated adducts were analyzed by liquid chromatography coupled to ESI-ToF-MS. For both β-LGA and HSA, aniline adducts were successfully generated and identified.

Quantifying reactivity for electrophilic aromatic substitution reactions with Hirshfeld charge.

PubMed

Liu, Shubin

2015-03-26

An electrophilic aromatic substitution is a process where one atom or group on an aromatic ring is replaced by an incoming electrophile. The reactivity and regioselectivity of this category of reactions is significantly impacted by the group that is already attached to the aromatic ring. Groups promoting substitution at the ortho/para and meta position are called ortho/para and meta directing groups, respectively. Earlier, we have shown that regioselectivity of the electrophilic aromatic substitution is dictated by the nucleophilicity of the substituted aromatic ring, which is proportional to the Hirshfeld charge on the regioselective site. Ortho/para directing groups have the largest negative charge values at the ortho/para positions, whereas meta directing groups often have the largest negative charge value at the meta position. The electron donation or acceptance feature of a substitution group is irrelevant to the regioselectivity. In this contribution, we extend our previous study by quantifying the reactivity for this kind of reactions. To that end, we examine the transition-state structure and activation energy of an identity reaction for a series of monosubstituted-benzene molecules reacting with hydrogen fluoride using BF3 as the catalyst in the gas phase. A total of 18 substitution groups will be considered, nine of which are ortho/para directing and the other nine groups meta directing. From this study, we found that the barrier height of these reactions strongly correlates with the Hirshfeld charge on the regioselective site for both ortho/para and meta directing groups, with the correlation coefficient R(2) both better than 0.96. We also discovered a less accurate correlation between the barrier height and HOMO energy. These results reconfirm the validity and effectiveness of employing the Hirshfeld charge as a reliable descriptor of both reactivity and regioselectivity for this vastly important category of chemical transformations.

Action mechanism of tyrosinase on meta- and para-hydroxylated monophenols.

PubMed

Fenoll, L G; Rodríguez-López, J N; Varón, R; García-Ruiz, P A; García-Cánovas, F; Tudela, J

2000-04-01

The relationship between the structure and activity of meta- and para-hydroxylated monophenols was studied during their tyrosinase-catalysed hydroxylation and the rate-limiting steps of the reaction mechanism were identified. The para-hydroxylated substrates permit us to study the effect of a substituent (R) in the carbon-1 position (C-1) of the benzene ring on the nucleophilic attack step, while the meta group permits a similar study of the effect on the electrophilic attack step. Substrates with a -OCH3 group on C-1, as p-hydroxyanisol (4HA) and m-hydroxyanisol (3HA), or with a -CH2OH group, as p-hydroxybenzylalcohol (4HBA) and m-hydroxybenzylalcohol (3HBA), were used because the effect of the substituent (R) size was assumed to be similar. However, the electron-donating effect of the -OCH3 group means that the carbon-4 position (C-4) is favoured for nucleophilic attack (para-hydroxylated substrates) or for electrophilic attack (meta-hydroxylated substrates). The electron-attracting effect of the -CH2OH group has the opposite effect, hindering nucleophilic (para) or electrophilic (meta) attack of C-4. The experimental data point to differences between the maximum steady-state rate (V(M)Max) of the different substrates, the value of this parameter depends on the nucleophilic and electrophilic attack. However, differences are greatest in the Michaelis constants (K(M)m), with the meta-hydroxylated substrates having very large values. The catalytic efficiency k(M)cat/K(M)m is much greater for thepara-hydroxylated substrates although it varies greatly between one substrate and the other. However, it varies much less in the meta-hydroxylated substrates since this parameter describes the power of the nucleophilic attack, which is weaker in the meta OH. The large increase in the K(M)m of the meta-hydroxylated substrates might suggest that the phenolic OH takes part in substrate binding. Since this is a weaker nucleophil than the para-hydroxylated substrates, the binding constant decreases, leading to an increase in K(M)m. The catalytic efficiency of tyrosinase on a monophenol (para or meta) is directly related to the nucleophilic power of the oxygen of the phenolic OH. The oxidation step is not limiting since if this were the case, the para and meta substrates would have the same V(M)max. The small difference between the absolute values of V(M)max suggests that the rate constants of the nucleophilic and electrophilic attacks are on the same order of magnitude.

Oxidases and Peroxidases in Cardiovascular and Lung Disease: New Concepts in Reactive Oxygen Species Signaling

PubMed Central

Ghouleh, Imad Al; Khoo, Nicholas K.H.; Knaus, Ulla G.; Griendling, Kathy K.; Touyz, Rhian M.; Thannickal, Victor J.; Barchowsky, Aaron; Nauseef, William M.; Kelley, Eric E.; Bauer, Phillip M.; Darley-Usmar, Victor; Shiva, Sruti; Cifuentes-Pagano, Eugenia; Freeman, Bruce A.; Gladwin, Mark T.; Pagano, Patrick J.

2011-01-01

Reactive oxygen species (ROS) are involved in numerous physiological and pathophysiological responses. Increasing evidence implicates ROS as signaling molecules involved in the propagation of cellular pathways. The NADPH oxidase (Nox) family of enzymes is a major source of ROS in the cell and has been related to the progression of many diseases and even in environmental toxicity. The complexity of this family’s effects on cellular processes stems from the fact that there are 7 members, each with unique tissue distribution, cellular localization and expression. Nox proteins also differ in activation mechanisms and the major ROS detected as their product. To add to this complexity, mounting evidence suggests that other cellular oxidases or their products may be involved in Nox regulation. The overall redox and metabolic status of the cell, specifically the mitochondria, also has implications on ROS signaling. Signaling of such molecules as electrophillic fatty acids has impact on many redox sensitive pathologies, and thus, as anti-inflammatory molecules, contributes to the complexity of ROS regulation. The following review is based on the proceedings of a recent international Oxidase Signaling Symposium at the University of Pittsburgh’s Vascular Medicine Institute and Department of Pharmacology and Chemical Biology, and encompasses further interaction and discussion among the presenters. PMID:21722728

Magnesium-based energy storage systems and methods having improved electrolytes

DOEpatents

Liu, Tianbiao; Li, Guosheng; Liu, Jun; Shao, Yuyan

2016-12-20

Electrolytes for Mg-based energy storage devices can be formed from non-nucleophilic Mg.sup.2+ sources to provide outstanding electrochemical performance and improved electrophilic susceptibility compared to electrolytes employing nucleophilic sources. The instant electrolytes are characterized by high oxidation stability (up to 3.4 V vs Mg), improved electrophile compatibility and electrochemical reversibility (up to 100% coulombic efficiency). Synthesis of the Mg.sup.2+ electrolytes utilizes inexpensive and safe magnesium dihalides as non-nucleophilic Mg.sup.2+ sources in combination with Lewis acids, MR.sub.aX.sub.3-a (for 3.gtoreq.a.gtoreq.1). Furthermore, addition of free-halide-anion donors can improve the coulombic efficiency of Mg electrolytes from nucleophilic or non-nucleophilic Mg.sup.2+ sources.

Fragmentation pathways of O-alkyl methylphosphonothionocyanidates in the gas phase: toward unambiguous structural characterization of chemicals in the Chemical Weapons Convention framework.

PubMed

Saeidian, Hamid; Babri, Mehran; Ashrafi, Davood; Sarabadani, Mansour; Naseri, Mohammad Taghi

2013-08-01

The electron-impact (EI) mass spectra of a series of O-alkyl methylphosphonothionocyanidates were studied for Chemical Weapons Convention (CWC) purposes. General EI fragmentation pathways were constructed and discussed, and collision-induced dissociation studies of the major EI ions were performed to confirm proposed fragment structures by analyzing fragment ions of deuterated analogs and by use of density functional theory (DFT) calculations. Thiono-thiolo rearrangement, McLafferty-type rearrangement, and a previously unknown intramolecular electrophilic aromatic substitution reaction were observed and confirmed. The study also focused on differentiation of isomeric compounds. Retention indices for all compounds, and an electrophilicity index for several compounds, are reported and interpreted.

Mild Aromatic Palladium-Catalyzed Protodecarboxylation: Kinetic Assessment of the Decarboxylative Palladation and the Protodepalladation Steps

PubMed Central

Dickstein, Joshua S.; Curto, John M.; Gutierrez, Osvaldo; Mulrooney, Carol A.; Kozlowski, Marisa C.

2013-01-01

Mechanism studies of a mild palladium catalyzed decarboxylation of aromatic carboxylic acids are described. In particular, reaction orders and activation parameters for the two stages of the transformation were determined. These studies guided development of a catalytic system capable of turnover. Further evidence reinforces that the second stage, protonation of the aryl palladium intermediate, is the rate-determining step of the reaction. The first step, decarboxylative palladation is proposed to occur through an intramolecular electrophilic palladation pathway, which is supported by computational and mechansim studies. In contrast to the reverse reaction (C-H insertion), the data support an electrophilic aromatic substitution mechanism involving a stepwise intramolecular protonation sequence for the protodepalladation portion of the reaction. PMID:23590518

Inversion of Configuration at the Phosphorus Nucleophile in the Diastereoselective and Enantioselective Synthesis of P-Stereogenic syn-Phosphiranes from Chiral Epoxides.

PubMed

Muldoon, Jake A; Varga, Balázs R; Deegan, Meaghan M; Chapp, Timothy W; Eördögh, Ádám M; Hughes, Russell P; Glueck, David S; Moore, Curtis E; Rheingold, Arnold L

2018-04-23

Nucleophilic substitution results in inversion of configuration at the electrophilic carbon center (S N 2) or racemization (S N 1). The stereochemistry of the nucleophile is rarely considered, but phosphines, which have a high barrier to pyramidal inversion, attack electrophiles with retention of configuration at P. Surprisingly, cyclization of bifunctional secondary phosphine alkyl tosylates proceeded under mild conditions with inversion of configuration at the nucleophile to yield P-stereogenic syn-phosphiranes. DFT studies suggested that the novel stereochemistry results from acid-promoted tosylate dissociation to yield an intermediate phosphenium-bridged cation, which undergoes syn-selective cyclization. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Enantioconvergent Cross-Couplings of Racemic Alkylmetal Reagents with Unactivated Secondary Alkyl Electrophiles: Catalytic Asymmetric Negishi α-Alkylations of N-Boc-pyrrolidine

PubMed Central

Cordier, Christopher J.; Lundgren, Rylan J.; Fu, Gregory C.

2013-01-01

Although enantioconvergent alkyl-alkyl couplings of racemic electrophiles have been developed, there have been no reports of the corresponding reactions of racemic nucleophiles. Herein, we describe Negishi cross-couplings of racemic α-zincated N-Boc-pyrrolidine with unactivated secondary halides, thus providing a one-pot, catalytic asymmetric method for the synthesis of a range of 2-alkylpyrrolidines (an important family of target molecules) from N-Boc-pyrrolidine, a commercially available precursor. Preliminary mechanistic studies indicate that two of the most straightforward mechanisms for enantioconvergence (a dynamic kinetic resolution of the organometallic coupling partner and a simple β-hydride elimination/β-migratory insertion pathway) are unlikely to be operative. PMID:23869442

Synthesis of 3-iodoindoles by the Pd/Cu-catalyzed coupling of N,N-dialkyl-2-iodoanilines and terminal acetylenes, followed by electrophilic cyclization.

PubMed

Yue, Dawei; Yao, Tuanli; Larock, Richard C

2006-01-06

[reaction: see text] 3-Iodoindoles have been prepared in excellent yields by coupling terminal acetylenes with N,N-dialkyl-o-iodoanilines in the presence of a Pd/Cu catalyst, followed by an electrophilic cyclization of the resulting N,N-dialkyl-o-(1-alkynyl)anilines using I2 in CH2Cl2. Aryl-, vinylic-, alkyl-, and silyl-substituted terminal acetylenes undergo this process to produce excellent yields of 3-iodoindoles. The reactivity of the carbon-nitrogen bond cleavage during cyclization follows the following order: Me > n-Bu, Me > Ph, and cyclohexyl > Me. Subsequent palladium-catalyzed Sonogashira, Suzuki, and Heck reactions of the resulting 3-iodoindoles proceed smoothly in good yields.

Chiral 2-Aminobenzimidazole as Bifunctional Catalyst in the Asymmetric Electrophilic Amination of Unprotected 3-Substituted Oxindoles.

PubMed

Benavent, Llorenç; Baeza, Alejandro; Freckleton, Megan

2018-06-06

The use of readily available chiral trans -cyclohexanediamine-benzimidazole derivatives as bifunctional organocatalysts in the asymmetric electrophilic amination of unprotected 3-substituted oxindoles is presented. Different organocatalysts were evaluated; the most successful one contained a dimethylamino moiety ( 5 ). With this catalyst under optimized conditions, different oxindoles containing a wide variety of substituents at the 3-position were aminated in good yields and with good to excellent enantioselectivities using di- tert -butylazodicarboxylate as the aminating agent. The procedure proved to be also efficient for the amination of 3-substituted benzofuranones, although with moderate results. A bifunctional role of the catalyst, acting as Brønsted base and hydrogen bond donor, is proposed according to the experimental results observed.

Lewis Acid-Assisted Photoinduced Intermolecular Coupling between Acylsilanes and Aldehydes: A Formal Cross Benzoin-Type Condensation.

PubMed

Ishida, Kento; Tobita, Fumiya; Kusama, Hiroyuki

2018-01-12

Intermolecular carbon-carbon bond-forming reaction between readily available acylsilanes and aldehydes was achieved under photoirradiation conditions with assistance of a catalytic amount of Lewis acid. Nucleophilic addition of photochemically generated siloxycarbenes to aldehydes followed by 1,4-silyl migration afforded synthetically useful α-siloxyketones. Electrophilic activation of aldehydes by Lewis acid is highly important to realize this reaction efficiently, otherwise the yield of the desired coupling products were significantly decreased. Noteworthy is that a formal cross benzoin-type reaction using acylsilanes was achieved under Lewis acidic conditions. This is the first example of Lewis acid-catalyzed reaction of photochemically generated siloxycarbenes with electrophiles. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

GSTP1 Polymorphisms and their Association with Glutathione Transferase and Peroxidase Activities in Patients with Motor Neuron Disease.

PubMed

Gajewska, Beata; Kaźmierczak, Beata; Kuźma-Kozakiewicz, Magdalena; Jamrozik, Zygmunt; Barańczyk-Kuźma, Anna

2015-01-01

Glutathione S-transferase pi (GSTP1) is a crucial enzyme in detoxification of electrophilic compounds and organic peroxides. Together with Se-dependent glutathione peroxidase (Se-GSHPx) it protects cells against oxidative stress which may be a primary factor implicated in motor neuron disease (MND) pathogenesis. We investigated GSTP1 polymorphisms and their relationship with GST and Se-GSTPx activities in a cohort of Polish patients with MND. Results were correlated with clinical phenotypes. The frequency of genetic variants for GSTP1 exon 5 (I105V) and exon 6 (A114V) was studied in 104 patients and 100 healthy controls using real-time polymerase chain reaction. GST transferase activity was determined in serum with 1-chloro-2,4-dinitrobenzene, its peroxidase activity with cumene hydroperoxide, and Se-GSHPx activity with hydrogen peroxide. There were no differences in the prevalence of GSTP1 polymorphism I105V and A114V between MND and controls, however the occurrence of CT variant in codon 114 was associated with a higher risk for MND. GSTP1 polymorphisms were less frequent in classic ALS than in progressive bulbar palsy. In classic ALS C* (heterozygous I /V and A /V) all studied activities were significantly lower than in classic ALS A* (homozygous I /I and A/A). GST peroxidase activity and Se-GSHPx activity were lower in classic ALS C* than in control C*, but in classic ALS A* Se-GSHPx activity was significantly higher than in control A*. It can be concluded that the presence of GSTP1 A114V but not I105V variant increases the risk of MND, and combined GSTP1 polymorphisms in codon 105 and 114 may result in lower protection of MND patients against the toxicity of electrophilic compounds, organic and inorganic hydroperoxides.

Bonding reactivity descriptor from conceptual density functional theory and its applications to elucidate bonding formation

NASA Astrophysics Data System (ADS)

Zhou, Pan-Pan; Liu, Shubin; Ayers, Paul W.; Zhang, Rui-Qin

2017-10-01

Condensed-to-atom Fukui functions which reflect the atomic reactivity like the tendency susceptible to either nucleophilic or electrophilic attack demonstrate the bonding trend of an atom in a molecule. Accordingly, Fukui functions based concepts, that is, bonding reactivity descriptors which reveal the bonding properties of molecules in the reaction were put forward and then applied to pericyclic and cluster reactions to confirm their effectiveness and reliability. In terms of the results from the bonding descriptors, a covalent bond can readily be predicted between two atoms with large Fukui functions (i.e., one governs nucleophilic attack while the other one governs electrophilic attack, or both of them govern radical attacks) for pericyclic reactions. For SinOm clusters' reactions, the clusters with a low O atom ratio readily form a bond between two Si atoms with big values of their Fukui functions in which they respectively govern nucleophilic and electrophilic attacks or both govern radical attacks. Also, our results from bonding descriptors show that Si—Si bonds can be formed via the radical mechanism between two Si atoms, and formations of Si—O and O—O bonds are possible when the O content is high. These results conform with experimental findings and can help experimentalists design appropriate clusters to synthesize Si nanowires with high yields. The approach established in this work could be generalized and applied to study reactivity properties for other systems.

Characterization and quantification of endogenous fatty acid nitroalkene metabolites in human urine[S

PubMed Central

Salvatore, Sonia R.; Vitturi, Dario A.; Baker, Paul R. S.; Bonacci, Gustavo; Koenitzer, Jeffrey R.; Woodcock, Steven R.; Freeman, Bruce A.; Schopfer, Francisco J.

2013-01-01

The oxidation and nitration of unsaturated fatty acids transforms cell membrane and lipoprotein constituents into mediators that regulate signal transduction. The formation of 9-NO2-octadeca-9,11-dienoic acid and 12-NO2-octadeca-9,11-dienoic acid stems from peroxynitrite- and myeloperoxidase-derived nitrogen dioxide reactions as well as secondary to nitrite disproportionation under the acidic conditions of digestion. Broad anti-inflammatory and tissue-protective responses are mediated by nitro-fatty acids. It is now shown that electrophilic fatty acid nitroalkenes are present in the urine of healthy human volunteers (9.9 ± 4.0 pmol/mg creatinine); along with electrophilic 16- and 14-carbon nitroalkenyl β-oxidation metabolites. High resolution mass determinations and coelution with isotopically-labeled metabolites support renal excretion of cysteine-nitroalkene conjugates. These products of Michael addition are in equilibrium with the free nitroalkene pool in urine and are displaced by thiol reaction with mercury chloride. This reaction increases the level of free nitroalkene fraction >10-fold and displays a KD of 7.5 × 10−6 M. In aggregate, the data indicates that formation of Michael adducts by electrophilic fatty acids is favored under biological conditions and that reversal of these addition reactions is critical for detecting both parent nitroalkenes and their metabolites. The measurement of this class of mediators can constitute a sensitive noninvasive index of metabolic and inflammatory status. PMID:23620137

Transition-state charge transfer reveals electrophilic, ambiphilic, and nucleophilic carbon-hydrogen bond activation.

PubMed

Ess, Daniel H; Nielsen, Robert J; Goddard, William A; Periana, Roy A

2009-08-26

Absolutely localized molecular orbital energy decomposition analysis of C-H activation transition states (TSs), including Pt, Au, Ir, Ru, W, Sc, and Re metal centers, shows an electrophilic, ambiphilic, and nucleophilic charge transfer (CT) continuum irrespective of the bonding paradigm (oxidative addition, sigma-bond metathesis, oxidative hydrogen migration, 1,2-substitution). Pt(II) insertion and Au(III) substitution TSs are highly electrophilic and dominated by C-H bond to metal/ligand orbital stabilization, while Ir-X and Ru-X (X = R, NH(2), OR, or BOR(2)) substitution TSs are ambiphilic in nature. In this ambiphilic activation regime, an increase in one direction of CT typically leads to a decrease in the reverse direction. Comparison of Tp(CO)Ru-OH and Tp(CO)Ru-NH(2) complexes showed no evidence for the classic d(pi)-p(pi) repulsion model. Complexes such as and Cp(CO)(2)W-B(OR)(2), (PNP)Ir(I), Cp(2)ScMe, and (acac-kappaO,kappaO)(2)Re(III)-OH were found to mediate nucleophilic C-H activation, where the CT is dominated by the metal/ligand orbital to C-H antibonding orbital interaction. This CT continuum ultimately affects the metal-alkyl intermediate polarization and possible functionalization reactions. This analysis will impact the design of new activation reactions and stimulate the discovery of more nucleophilic activation complexes.

Palladium-catalysed electrophilic aromatic C-H fluorination

NASA Astrophysics Data System (ADS)

Yamamoto, Kumiko; Li, Jiakun; Garber, Jeffrey A. O.; Rolfes, Julian D.; Boursalian, Gregory B.; Borghs, Jannik C.; Genicot, Christophe; Jacq, Jérôme; van Gastel, Maurice; Neese, Frank; Ritter, Tobias

2018-02-01

Aryl fluorides are widely used in the pharmaceutical and agrochemical industries, and recent advances have enabled their synthesis through the conversion of various functional groups. However, there is a lack of general methods for direct aromatic carbon-hydrogen (C-H) fluorination. Conventional methods require the use of either strong fluorinating reagents, which are often unselective and difficult to handle, such as elemental fluorine, or less reactive reagents that attack only the most activated arenes, which reduces the substrate scope. A method for the direct fluorination of aromatic C-H bonds could facilitate access to fluorinated derivatives of functional molecules that would otherwise be difficult to produce. For example, drug candidates with improved properties, such as increased metabolic stability or better blood-brain-barrier penetration, may become available. Here we describe an approach to catalysis and the resulting development of an undirected, palladium-catalysed method for aromatic C-H fluorination using mild electrophilic fluorinating reagents. The reaction involves a mode of catalysis that is unusual in aromatic C-H functionalization because no organometallic intermediate is formed; instead, a reactive transition-metal-fluoride electrophile is generated catalytically for the fluorination of arenes that do not otherwise react with mild fluorinating reagents. The scope and functional-group tolerance of this reaction could provide access to functional fluorinated molecules in pharmaceutical and agrochemical development that would otherwise not be readily accessible.

Subcellular localization and cytoplasmic complex status of endogenous Keap1.

PubMed

Watai, Yoriko; Kobayashi, Akira; Nagase, Hiroko; Mizukami, Mio; McEvoy, Justina; Singer, Jeffrey D; Itoh, Ken; Yamamoto, Masayuki

2007-10-01

Keap1 acts as a sensor for oxidative/electrophilic stress, an adaptor for Cullin-3-based ubiquitin ligase, and a regulator of Nrf2 activity through the interaction with Nrf2 Neh2 domain. However, the mechanism(s) of Nrf2 migration into the nucleus in response to stress remains largely unknown due to the lack of a reliable antibody for the detection of endogenous Keap1 molecule. Here, we report the generation of a new monoclonal antibody for the detection of endogenous Keap1 molecules. Immunocytochemical analysis of mouse embryonic fibroblasts with the antibody revealed that under normal, unstressed condition, Keap1 is localized primarily in the cytoplasm with minimal amount in the nucleus and endoplasmic reticulum. This subcellular localization profile of Keap1 appears unchanged after treatment of cells with diethyl maleate, an electrophile, and/or Leptomycin B, a nuclear export inhibitor. Subcellular fractionation analysis of mouse liver cells showed similar results. No substantial change in the subcellular distribution profile could be observed in cells isolated from butylated hydroxyanisole-treated mice. Analyses of sucrose density gradient centrifugation of mouse liver cells indicated that Keap1 appears to form multiprotein complexes in the cytoplasm. These results demonstrate that endogenous Keap1 remains mostly in the cytoplasm, and electrophiles promote nuclear accumulation of Nrf2 without altering the subcellular localization of Keap1.

Oxidation of DJ-1 Induced by 6-Hydroxydopamine Decreasing Intracellular Glutathione

PubMed Central

Miyama, Akiko; Saito, Yoshiro; Yamanaka, Kazunori; Hayashi, Kojiro; Hamakubo, Takao; Noguchi, Noriko

2011-01-01

DJ-1, the causative gene of a familial form of Parkinson's disease (PD), has been reported to undergo preferential oxidation of the cysteine residue at position 106 (Cys-106) under oxidative stress; however, details of the molecular mechanisms are not well known. In the present study, mechanisms of DJ-1 oxidation induced by 6-hydroxydopamine (6-OHDA) were investigated by using SH-SY5Y cells. The treatment of these cells with 6-OHDA caused an obvious acidic spot sift of DJ-1 due to its oxidation. However, when catalase, which is an hydrogen peroxide (H2O2)-removing enzyme, was added during the treatment, it failed to prevent the oxidation induced by 6-OHDA, suggesting that electrophilic p-quinone formed from 6-OHDA, but not H2O2, was responsible for the DJ-1 oxidation. Benzoquinone, another electrophilic p-quinone, also induced DJ-1 oxidation. The intracellular glutathione (GSH) levels were significantly decreased by 6-OHDA, irrespective of the presence or absence of catalase. The inhibition of GSH synthesis by buthionine sulfoximine resulted in a decrease in GSH levels and enhancement of DJ-1 oxidation. The pretreatment of cells with N-acetyl-cysteine prevented the loss of intracellular GSH and subsequently DJ-1 oxidation induced by 6-OHDA. Collectively, these results suggest that electrophilic p-quinone formed from 6-OHDA induces DJ-1 oxidation by decreasing intracellular GSH. PMID:22132160

Syntheses and Functionalizations of Porphyrin Macrocycles

PubMed Central

Vicente, Maria da G.H.; Smith, Kevin M.

2014-01-01

Porphyrin macrocycles have been the subject of intense study in the last century because they are widely distributed in nature, usually as metal complexes of either iron or magnesium. As such, they serve as the prosthetic groups in a wide variety of primary metabolites, such as hemoglobins, myoglobins, cytochromes, catalases, peroxidases, chlorophylls, and bacteriochlorophylls; these compounds have multiple applications in materials science, biology and medicine. This article describes current methodology for preparation of simple, symmetrical model porphyrins, as well as more complex protocols for preparation of unsymmetrically substituted porphyrin macrocycles similar to those found in nature. The basic chemical reactivity of porphyrins and metalloporphyrin is also described, including electrophilic and nucleophilic reactions, oxidations, reductions, and metal-mediated cross-coupling reactions. Using the synthetic approaches and reactivity profiles presented, eventually almost any substituted porphyrin system can be prepared for applications in a variety of areas, including in catalysis, electron transport, model biological systems and therapeutics. PMID:25484638

A Mechanistic Investigation of the Gold(III)-Catalyzed Hydrofurylation of C-C Multiple Bonds.

PubMed

Hossein Bagi, Amin; Khaledi, Yousef; Ghari, Hossein; Arndt, Sebastian; Hashmi, A Stephen K; Yates, Brian F; Ariafard, Alireza

2016-11-09

The gold-catalyzed direct functionalization of aromatic C-H bonds has attracted interest for constructing organic compounds which have application in pharmaceuticals, agrochemicals, and other important fields. In the literature, two major mechanisms have been proposed for these catalytic reactions: inner-sphere syn-addition and outer-sphere anti-addition (Friedel-Crafts-type mechanism). In this article, the AuCl 3 -catalyzed hydrofurylation of allenyl ketone, vinyl ketone, ketone, and alcohol substrates is investigated with the aid of density functional theory calculations, and it is found that the corresponding functionalizations are best rationalized in terms of a novel mechanism called "concerted electrophilic ipso-substitution" (CEIS) in which the gold(III)-furyl σ-bond produced by furan auration acts as a nucleophile and attacks the protonated substrate via an outer-sphere mechanism. This unprecedented mechanism needs to be considered as an alternative plausible pathway for gold(III)-catalyzed arene functionalization reactions in future studies.

Vibrational Spectroscopy of Fluoroformate, FCO2-, Trapped in Helium Nanodroplets.

PubMed

Thomas, Daniel A; Mucha, Eike; Gewinner, Sandy; Schöllkopf, Wieland; Meijer, Gerard; von Helden, Gert

2018-05-03

Fluoroformate, also known as carbonofluoridate, is an intriguing molecule readily formed by the reductive derivatization of carbon dioxide. In spite of its well-known stability, a detailed structural characterization of the isolated anion has yet to be reported. Presented in this work is the vibrational spectrum of fluoroformate obtained by infrared action spectroscopy of ions trapped in helium nanodroplets, the first application of this technique to a molecular anion. The experimental method yields narrow spectral lines, providing experimental constraints on the structure that can be accurately reproduced using high-level ab initio methods. In addition, two notable Fermi resonances between a fundamental and combination band are observed. The electrostatic potential map of fluoroformate reveals substantial charge density on fluorine as well as on the oxygen atoms, suggesting multiple sites for interaction with hydrogen bond donors and electrophiles, which may in turn lead to intriguing solvation structures and reaction pathways.

A Potent and Site-Selective Agonist of TRPA1.

PubMed

Takaya, Junichiro; Mio, Kazuhiro; Shiraishi, Takuya; Kurokawa, Tatsuki; Otsuka, Shinya; Mori, Yasuo; Uesugi, Motonari

2015-12-23

TRPA1 is a member of the transient receptor potential (TRP) cation channel family that is expressed primarily on sensory neurons. This chemosensor is activated through covalent modification of multiple cysteine residues with a wide range of reactive compounds including allyl isothiocyanate (AITC), a spicy component of wasabi. The present study reports on potent and selective agonists of TRPA1, discovered through screening 1657 electrophilic molecules. In an effort to validate the mode of action of hit molecules, we noted a new TRPA1-selective agonist, JT010 (molecule 1), which opens the TRPA1 channel by covalently and site-selectively binding to Cys621 (EC50 = 0.65 nM). The results suggest that a single modification of Cys621 is sufficient to open the TRPA1 channel. The TRPA1-selective probe described herein might be useful for further mechanistic studies of TRPA1 activation.

Lithium prevents acrolein-induced neurotoxicity in HT22 mouse hippocampal cells.

PubMed

Huang, Yingjuan; Qin, Jian; Chen, Meihui; Chao, Xiaojuan; Chen, Ziwei; Ramassamy, Charles; Pi, Rongbiao; Jin, Minghua

2014-04-01

Acrolein is a highly electrophilic alpha, beta-unsaturated aldehyde to which humans are exposed in many situations and has been implicated in neurodegenerative diseases, such as Alzheimer's disease. Lithium is demonstrated to have neuroprotective and neurotrophic effects in brain ischemia, trauma, neurodegenerative disorders, and psychiatric disorders. Previously we have found that acrolein induced neuronal death in HT22 mouse hippocampal cells. In this study, the effects of lithium on the acrolein-induced neurotoxicity in HT22 cells as well as its mechanism(s) were investigated. We found that lithium protected HT22 cells against acrolein-induced damage by the attenuation of reactive oxygen species and the enhancement of the glutathione level. Lithium also attenuated the mitochondrial dysfunction caused by acrolein. Furthermore, lithium significantly increased the level of phospho-glycogen synthase kinase-3 beta (GSK-3β), the non-activated GSK-3β. Taken together, our findings suggest that lithium is a protective agent for acrolein-related neurotoxicity.

Transcriptional regulation of nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase in murine hepatoma cells by 6-(methylsufinyl)hexyl isothiocyanate, an active principle of wasabi (Eutrema wasabi Maxim).

PubMed

Hou, D X; Fukuda, M; Fujii, M; Fuke, Y

2000-12-20

Wasabi is a very popular pungent spice in Japan. This study examined the ability of 6-(methylsufinyl)hexyl isothiocyanate (6-MITC), an active principle of wasabi, to induce the cellular expression of nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase (QR) in Hepa 1c1c7 cells. The cells were treated with various concentrations of 6-MITC, and were then assessed for cell growth, QR activity and QR mRNA expression. The induction of QR activity and QR mRNA expression was time- and dose-responsive over a narrow range of 0.1-5 microM, with declining induction at higher concentrations due to cell toxicity. Furthermore, transfection studies demonstrated that the induction of transcription of the QR gene by 6-MITC involved an antioxidant/electrophile-responsive element (ARE/EpRE) activation. Our results suggest a novel mechanism by which dietary wasabi 6-MITC may be implicated in cancer chemoprevention.

Experimental and theoretical analysis of a rare nitrato bridged 3d-4f complex containing LaZn2 core synthesized from a Zn(II) metalloligand

NASA Astrophysics Data System (ADS)

Sreejith, S. S.; Mohan, Nithya; Kurup, M. R. Prathapachandra

2018-02-01

A trinulcear Zn2La Schiff base complex was synthesized using slow-solvent evaporation technique from a Zn(II) mononuclear metalloligand by 2:1 addition with La(NO3)3 salt. Single crystal XRD analysis revealed a rare nitrato bridged trinuclear entity which is seldom seen in these class of ligand systems. Qualitative and quantitative analysis of intermolecular interactions/short contacts were done using Hirshfeld surface and 2D finger print analysis. The thermally stable, blue luminescent compound exhibits internal heavy atom effect thereby quenching the emission intensity of the ligand. DFT calculations were performed on the compound to analyze frontier orbitals and also ESP plots were used to monitor nucleophilic/electrophilic regions on the compound and its implications on hydrogen bonding. A comparison of the bond orders and atomic charges on the trinuclear compound and the Zn(II) metalloligand precursor was performed to substantiate the formation of the trinuclear product through ligand exchange.

Generation and reactions of oxiranyllithiums by use of a flow microreactor system.

PubMed

Nagaki, Aiichiro; Takizawa, Eiji; Yoshida, Jun-ichi

2010-12-17

A flow microreactor system consisting of micromixers and microtubes provides an effective reactor for the generation and reactions of aryloxiranyllithiums without decomposition by virtue of short residence time and efficient temperature control. The deprotonation of styrene oxides with sBuLi can be conducted by using the flow microreactor system at -78 or -68 °C (whereas much lower temperatures (< -100 °C) are needed for the same reactions conducted under macrobatch conditions). The resulting α-aryloxiranyllithiums were allowed to react with electrophiles in the flow microreactor system at the same temperature. The sequential introduction of various electrophiles onto 2,3-diphenyloxiranes was also achieved by using an integrated flow microreactor, which serves as a powerful system for the stereoselective synthesis of tetrasubstituted epoxides.

Reaction to Halogens and Interhalogens with 4-Halo-1,1,2-trifluorobut-1-enes: Rearrangement of 3-Membered Halonium to 5-Membered Trifluorotetramethylene Halonium Ion Intermediates and Comparison of Open-Chloronium Fluorosubstituted Ions to Flurocarbocations from Protons (Preprint)

DTIC Science & Technology

2008-02-28

were found to be open-ion (A or E), unsymmetrical (B or D), or symmetrical C depending on the halogen electrophile and on the position and number of...Rearranged products 4 (Structures A-E) 1 Z = Cl 2 Z = Br 3 Z = I XY = Cl2, Br2, BrCl ICl, IBr Scheme 1 Y on the fluorine atoms of 5 shield the carbon nucleus...and 3) WITH HALOGEN ELECTROPHILES IN METHYLENE CHLORIDE F F F Z XY CH2Cl2 CF2CFZ Y X CF2CFZ X Y CF2CFY X Z + + M aM Rearranged Run Alkene (Z

NemR Is a Bleach-sensing Transcription Factor*

PubMed Central

Gray, Michael J.; Wholey, Wei-Yun; Parker, Benjamin W.; Kim, Minwook; Jakob, Ursula

2013-01-01

Hypochlorous acid (HOCl), the active component of household bleach, also functions as a powerful antimicrobial during the innate immune response. Despite its widespread use, surprisingly little is known about how cells sense or respond to HOCl. We now demonstrate that Escherichia coli NemR is a redox-regulated transcriptional repressor, which uses the oxidation status of HOCl-sensitive cysteine residues to respond to bleach and related reactive chlorine species. NemR controls bleach-mediated expression of two enzymes required for detoxification of reactive electrophiles: glyoxalase I and N-ethylmaleimide reductase. Both enzymes contribute to bacterial bleach survival. These results provide evidence that bleach resistance relies on the capacity of organisms to specifically sense reactive chlorine species and respond with the up-regulation of enzymes dedicated to detoxification of methylglyoxal and other reactive electrophiles. PMID:23536188

Reaction of bromine and chlorine with phenolic compounds and natural organic matter extracts--Electrophilic aromatic substitution and oxidation.

PubMed

Criquet, Justine; Rodriguez, Eva M; Allard, Sebastien; Wellauer, Sven; Salhi, Elisabeth; Joll, Cynthia A; von Gunten, Urs

2015-11-15

Phenolic compounds are known structural moieties of natural organic matter (NOM), and their reactivity is a key parameter for understanding the reactivity of NOM and the disinfection by-product formation during oxidative water treatment. In this study, species-specific and/or apparent second order rate constants and mechanisms for the reactions of bromine and chlorine have been determined for various phenolic compounds (phenol, resorcinol, catechol, hydroquinone, phloroglucinol, bisphenol A, p-hydroxybenzoic acid, gallic acid, hesperetin and tannic acid) and flavone. The reactivity of bromine with phenolic compounds is very high, with apparent second order rate constants at pH 7 in the range of 10(4) to 10(7) M(-1) s(-1). The highest value was recorded for the reaction between HOBr and the fully deprotonated resorcinol (k = 2.1 × 10(9) M(-1) s(-1)). The reactivity of phenolic compounds is enhanced by the activating character of the phenolic substituents, e.g. further hydroxyl groups. With the data set from this study, the ratio between the species-specific rate constants for the reactions of chlorine versus bromine with phenolic compounds was confirmed to be about 3000. Phenolic compounds react with bromine or chlorine either by oxidation (electron transfer, ET) or electrophilic aromatic substitution (EAS) processes. The dominant process mainly depends on the relative position of the hydroxyl substituents and the possibility of quinone formation. While phenol, p-hydroxybenzoic acid and bisphenol A undergo EAS, hydroquinone, catechol, gallic acid and tannic acid, with hydroxyl substituents in ortho or para positions, react with bromine by ET leading to quantitative formation of the corresponding quinones. Some compounds (e.g. phloroglucinol) show both partial oxidation and partial electrophilic aromatic substitution and the ratio observed for the pathways depends on the pH. For the reaction of six NOM extracts with bromine, electrophilic aromatic substitution accounted for only 20% of the reaction, and for one NOM extract (Pony Lake fulvic acid) it accounted for <10%. This shows that for natural organic matter samples, oxidation (ET) is far more important than bromine incorporation (EAS). Copyright © 2015 Elsevier Ltd. All rights reserved.

Versatile telluracycle synthesis via the sequential electrophilic telluration of C(sp2)–Zn and C(sp2)–H bonds† †Electronic supplementary information (ESI) available. CCDC 1523262–1523264. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7sc01162h Click here for additional data file. Click here for additional data file.

PubMed Central

Wu, Bin; Melvina; Wu, Xiangyang; Lee Yeow, Edwin Kok

2017-01-01

We report herein a new approach for the synthesis of tellurium-bridged aromatic compounds based on the sequential electrophilic telluration of C(sp2)–Zn and C(sp2)–H bonds with tellurium(iv) chlorides. A combination of transition metal-catalyzed (migratory) arylmetalation of alkynes and sequential telluration allows for the expedient construction of a library of functionalized benzo[b]tellurophenes. Furthermore, a variety of heteroarene-fused benzotellurophenes and other novel tellurium-embedded polycyclic aromatics can be readily synthesized from the corresponding 2-iodoheterobiaryls. PMID:28970880

Electrophilic properties of common MALDI matrix molecules

NASA Astrophysics Data System (ADS)

Lippa, T. P.; Eustis, S. N.; Wang, D.; Bowen, K. H.

2007-11-01

The negative ion photoelectron spectra of the following MALDI matrix molecules have been measured: 3-carboxypyridine (nicotinic acid), 2,5-dihydroxybenzoic acid (DHB), 3,5-dimethoxy-4-hydroxycinnamic acid (sinapinic acid), 2,6-dihydroxyacetophenone (DHAP), 3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid (ferulic acid), 3-hydroxy-2-pyridinecarboxylic acid (3HPA), and 2,6-pyridinedicarboxylic acid (dipicolinic acid). Adiabatic electron affinities and vertical detachment energies were extracted from these spectra and reported. In addition, electron affinities were calculated for DHAP, ferulic acid, dipicolinic acid and sinapinic acid. Photoelectron spectra were also measured for the dimer anions of DHB and nicotinic acid and for the fragment anion in which alpha-cyano-cinnamic acid had lost a CO2 unit. Together, these results augment the database of presently available electrophilic data on common matrix molecules along with some of their dimers and fragments.

Experimental and theoretical study using DFT method for the competitive adsorption of two cationic dyes from wastewaters

NASA Astrophysics Data System (ADS)

Regti, Abdelmajid; Ayouchia, Hicham Ben El; Laamari, My Rachid; Stiriba, Salah Eddine; Anane, Hafid; Haddad, Mohammadine El

2016-12-01

The adsorption of cationic dyes, Basic Yellow (BY28) and Methylene Blue (MB) on a new activated carbon from medlar species were studied in both single and binary system. Some experimental parameters, namely, pH, amount of adsorbent and contact time are studied. Quantum chemical results indicate that the adsorption efficiency was directly related to the dye electrophilicity power. Some theorical parameters were calculated and proved that MB is more electrophilic than BY28, than greatest interaction with surface sites. Kinetic study showed that the adsorption follows the pseudo-second-order model and Freundlich was the best model to describe the phenomenon in the single and binary system. According to the local reactivity results using Parr functions, the sulphur and nitrogen atoms will be the main adsorption sites.

A Molecular Electron Density Theory Study of the Chemical Reactivity of Cis- and Trans-Resveratrol.

PubMed

Frau, Juan; Muñoz, Francisco; Glossman-Mitnik, Daniel

2016-12-01

The chemical reactivity of resveratrol isomers with the potential to play a role as inhibitors of the nonenzymatic glycation of amino acids and proteins, both acting as antioxidants and as chelating agents for metallic ions such as Cu, Al and Fe, have been studied by resorting to the latest family of Minnesota density functionals. The chemical reactivity descriptors have been calculated through Molecular Electron Density Theory encompassing Conceptual DFT. The active sites for nucleophilic and electrophilic attacks have been chosen by relating them to the Fukui function indices, the dual descriptor f ( 2 ) ( r ) and the electrophilic and nucleophilic Parr functions. The validity of "Koopmans' theorem in DFT" has been assessed by means of a comparison between the descriptors calculated through vertical energy values and those arising from the HOMO and LUMO values.

Conceptual DFT Descriptors of Amino Acids with Potential Corrosion Inhibition Properties Calculated with the Latest Minnesota Density Functionals.

PubMed

Frau, Juan; Glossman-Mitnik, Daniel

2017-01-01

Amino acids and peptides have the potential to perform as corrosion inhibitors. The chemical reactivity descriptors that arise from Conceptual DFT for the twenty natural amino acids have been calculated by using the latest Minnesota family of density functionals. In order to verify the validity of the calculation of the descriptors directly from the HOMO and LUMO, a comparison has been performed with those obtained through ΔSCF results. Moreover, the active sites for nucleophilic and electrophilic attacks have been identified through Fukui function indices, the dual descriptor Δf( r ) and the electrophilic and nucleophilic Parr functions. The results could be of interest as a starting point for the study of large peptides where the calculation of the radical cation and anion of each system may be computationally harder and costly.

Putting corannulene in its place. Reactivity studies comparing corannulene with other aromatic hydrocarbons.

PubMed

George, Stephen R D; Frith, Thomas D H; Thomas, Donald S; Harper, Jason B

2015-09-14

A series of aromatic hydrocarbons were investigated so as to compare the reactivity of corannulene with planar aromatic hydrocarbons. Corannulene was found to be more reactive than benzene, naphthalene and triphenylene to Friedel-Crafts acylation whilst electrophilic aromatic bromination was also used to confirm that triphenylene was less reactive than corannulene and that pyrene, perylene and acenaphthene were more so. The stabilisation of a neighbouring carbocation by the various aromatic systems was investigated through consideration of the rates of methanolysis of a series of benzylic alcohols. The reactivity series was found to parallel that observed for the electrophilic aromatic substitutions and both series are supported by computational studies. As such, a reactivity scale was devised that showed that corannulene was less reactive than would be expected for an aromatic planar species of similar pi electron count.

The versatility of boron in biological target engagement

NASA Astrophysics Data System (ADS)

Diaz, Diego B.; Yudin, Andrei K.

2017-08-01

Boron-containing molecules have been extensively used for the purposes of chemical sensing, biological probe development and drug discovery. Due to boron's empty p orbital, it can coordinate to heteroatoms such as oxygen and nitrogen. This reversible covalent mode of interaction has led to the use of boron as bait for nucleophilic residues in disease-associated proteins, culminating in the approval of new therapeutics that work by covalent mechanisms. Our analysis of a wide range of covalent inhibitors with electrophilic groups suggests that boron is a unique electrophile in its chameleonic ability to engage protein targets. Here we review boron's interactions with a range of protein side-chain residues and reveal that boron's properties are nuanced and arise from its uncommon coordination preferences. These mechanistic and structural insights should serve as a guide for the development of selective boron-based bioactive molecules.

Carbene-catalysed reductive coupling of nitrobenzyl bromides and activated ketones or imines via single-electron-transfer process

NASA Astrophysics Data System (ADS)

Li, Bao-Sheng; Wang, Yuhuang; Proctor, Rupert S. J.; Zhang, Yuexia; Webster, Richard D.; Yang, Song; Song, Baoan; Chi, Yonggui Robin

2016-09-01

Benzyl bromides and related molecules are among the most common substrates in organic synthesis. They are typically used as electrophiles in nucleophilic substitution reactions. These molecules can also be activated via single-electron-transfer (SET) process for radical reactions. Representative recent progress includes α-carbon benzylation of ketones and aldehydes via photoredox catalysis. Here we disclose the generation of (nitro)benzyl radicals via N-heterocyclic carbene (NHC) catalysis under reductive conditions. The radical intermediates generated via NHC catalysis undergo formal 1,2-addition with ketones to eventually afford tertiary alcohol products. The overall process constitutes a formal polarity-inversion of benzyl bromide, allowing a direct coupling of two initially electrophilic carbons. Our study provides a new carbene-catalysed reaction mode that should enable unconventional transformation of (nitro)benzyl bromides under mild organocatalytic conditions.

Thiol reactivity and its impact on the ciliate toxicity of α,β-unsaturated aldehydes, ketones, and esters.

PubMed

Böhme, Alexander; Thaens, Diana; Schramm, Franziska; Paschke, Albrecht; Schüürmann, Gerrit

2010-12-20

A recently introduced chemoassay has been used to determine second-order rate constants of the electrophile-nucleophile reaction of 15 α,β-unsaturated aldehydes with glutathione. The respective kGSH values vary for more than 3 orders of magnitude, and are within the range determined previously for 31 α,β-unsaturated ketones and esters. Structure-reactivity analyses yield distinct relationships between kGSH and structural features of the compounds. Moreover, increasing kGSH increases the aldehyde toxicity toward ciliates in terms of 48 h-EC50 values (effective concentration yielding 50% growth inhibition of Tetrahymena pyriformis within 48 h). A respective log-log regression equation including both kGSH and the octanol/water partition coefficient, Kow, yields a squared correlation coefficient of 0.96. Comparative analysis with corresponding data for 15 ketones and 16 esters reveals systematic differences between the three compound classes with regard to the individual contributions of hydrophobicity and electrophilic reactivity to aquatic toxicity. The former is particularly pronounced for aldehydes, while the ester toxicity is largely governed by reactivity, with ketones showing an intermediate pattern that is more similar to the one of esters than of aldehydes. It follows that within the Michael acceptor domain of α,β-unsaturated carbonyls, a distinction between aldehydes and nonaldehydic derivatives appears necessary when employing electrophilic reactivity as a component for the quantitative prediction of their reactive toxicity toward aquatic organisms.

Rhodium mediated bond activation: from synthesis to catalysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ho, Hung-An

Recently, our lab has developed monoanionic tridentate ligand, To R, showing the corresponding coordination chemistry and catalyst reactivity of magnesium, zirconium, zinc and iridium complexes. This thesis details synthetic chemistry, structural study and catalytic reactivity of the To R-supported rhodium compounds. Tl[To R] has been proved to be a superior ligand transfer agent for synthesizing rhodium complexes. The salt metathesis route of Tl[To M] with [Rh(μ-Cl)(CO)] 2 and [Rh(μ- Cl)(COE)] 2 gives To MRh(CO) 2 (2.2) and To MRhH(β 3-C 8H 13) (3.1) respectively while Tl[To M] with [Rh(μ-Cl)(CO)] 2 affords To PRh(CO) 2 (2.3). 2.2 reacts with both strongmore » and weak electrophiles, resulting in the oxazoline N-attacked and the metal center-attacked compounds correspondingly. Using one of the metal center-attacked electrophiles, 2.3 was demonstrated to give high diastereoselectivity. Parallel to COE allylic C-H activation complex 3.1, the propene and allylbenzene allylic C-H activation products have also been synthesized. The subsequent functionalization attempts have been examined by treating with Brønsted acids, Lewis acids, electrophiles, nucleophiles, 1,3-dipolar reagents and reagents containing multiple bonds able to be inserted. Various related complexes have been obtained under these conditions, in which one of the azide insertion compounds reductively eliminates to give an allylic functionalization product stoichiometrically. 3.1 reacts with various primary alcohols to give the decarbonylation dihydride complex To MRh(H) 2CO (4.1). 4.1 shows catalytic reactivity for primary alcohol decarbonylation under a photolytic condition. Meanwhile, 2.2 has been found to be more reactive than 4.1 for catalytic alcohol decarbonylation under the same condition. Various complexes and primary alcohols have been investigated as well. The proposed mechanism is based on the stochiometric reactions of the possible metal and organic intermediates. Primary amines, hypothesized to undergo a similar reaction pathway, have been verified to give dehydrogenative coupling product, imines. In the end, the well-developed neutral tridentate Tpm coordinates to the rhodium bis(ethylene) dimer in the presence of TlPF 6 to give the cationic complex, [TpmRh(C 2H 4) 2][PF 6] (5.1). 5.1 serves as the first example of explicit determination of the solid state hapticity, evidenced by X-ray structure, among all the cationic Tpm RM(C 2H 4) 2 + (Tpm R = Tpm, Tpm*, M = Rh, Ir) derivatives. The substitution chemistry of this compound has been studied by treating with soft and hard donors. The trimethylphosphine-sbustituted complex activates molecular hydrogen to give the dihydride compound.« less

Bacillithiol, a New Player in Bacterial Redox Homeostasis

PubMed Central

2011-01-01

Abstract Bacillithiol (BSH), the α-anomeric glycoside of l-cysteinyl-d-glucosamine with l-malic acid, plays a dominant role in the cytosolic thiol redox chemistry of the low guanine and cytosine (GC) Gram-positive bacteria (phylum Firmicutes). BSH is functionally analogous to glutathione (GSH) but differs sufficiently in chemical structure that cells have evolved a distinct set of enzymes that use BSH as cofactor. BSH was discovered in Bacillus subtilis as a mixed disulfide with the redox-sensing repressor OhrR and in B. anthracis by biochemical analysis of pools of labeled thiols. The structure of BSH was determined after purification from Deinococcus radiodurans. Similarities in structure between BSH and mycothiol (MSH) facilitated the identification of biosynthetic genes for BSH in the model organism B. subtilis. Phylogenomic analyses have identified several candidate BSH-using or associated proteins, including a BSH reductase, glutaredoxin-like thiol-dependent oxidoreductases (bacilliredoxins), and a BSH-S-transferase (FosB) involved in resistance to the epoxide antibiotic fosfomycin. Preliminary results implicate BSH in cellular processes to maintain cytosolic redox balance and for adaptation to reactive oxygen, nitrogen, and electrophilic species. BSH also is predicted to chelate metals avidly, in part due to the appended malate moiety, although the implications of BSH for metal ion homeostasis have yet to be explored in detail. Antioxid. Redox Signal. 15, 123–133. PMID:20712413

The Preparation of Lucigenin.

ERIC Educational Resources Information Center

Amiet, R. G.

1982-01-01

Outlines and discusses procedures for the preparation of lucigenin, a powerfully chemiluminescent compound. Major techniques (requiring three 4-hour sessions) involving nucleophilic and electrophilic aromatic substitution, nucleophilic aliphatic substitution, reductive coupling, and oxidation reactions include steam distillation, decolorization…

‘Umpolung’ Reactivity in Semiaqueous Amide and Peptide Synthesis

PubMed Central

Shen, Bo; Makley, Dawn M.; Johnston, Jeffrey N.

2010-01-01

The amide functional group is one of Nature’s key functional and structural elements, most notably within peptides. Amides are also key intermediates in the preparation of a diverse range of therapeutic small molecules. Its construction using available methods focuses principally upon dehydrative approaches, although oxidative and radical-based methods are representative alternatives. During the carbon-nitrogen bond forming step in most every example, the carbon and nitrogen bear electrophilic and nucleophilic character, respectively. Here we show that activation of amines and nitroalkanes with an electrophilic iodine source in wet THF can lead directly to amide products. Preliminary observations support a mechanistic construct in which reactant polarity is reversed (umpolung) during C-N bond formation relative to traditional approaches. The use of nitroalkanes as acyl anion equivalents provides a conceptually innovative approach to amide and peptide synthesis, and one that might ultimately provide for efficient peptide synthesis that is fully reliant on enantioselective methods. PMID:20577205

Electrophilicity: the "dark-side" of indole chemistry.

PubMed

Bandini, Marco

2013-08-28

Indole is by far one of the most popular heterocyclic scaffolds in nature. The intriguing and challenging molecular architectures of polycyclic, naturally occurring indolyl compounds constitute a continuous stimulus for development in organic synthesis. The field had a formidable boom across the new millennium when catalysis started revolutionizing the chemistry of indole, providing always more convincing and sustainable solutions to the selective "decoration" of this pharmacophore. A common guideline of these approaches relies on the intrinsic overexpression of electron density of the indole core. Despite less diffusion, the "dark-side" of indole reactivity, electrophilicity, has been also elegantly documented with direct applications towards the realization of specific interatomic connections that would be difficult to obtain by means of conventional indole reactivity. The present Perspective article summarizes the major findings that brought the research area from the pioneering findings of the 60s to the state of the art.

Carbene-catalysed reductive coupling of nitrobenzyl bromides and activated ketones or imines via single-electron-transfer process

PubMed Central

Li, Bao-Sheng; Wang, Yuhuang; Proctor, Rupert S. J.; Zhang, Yuexia; Webster, Richard D.; Yang, Song; Song, Baoan; Chi, Yonggui Robin

2016-01-01

Benzyl bromides and related molecules are among the most common substrates in organic synthesis. They are typically used as electrophiles in nucleophilic substitution reactions. These molecules can also be activated via single-electron-transfer (SET) process for radical reactions. Representative recent progress includes α-carbon benzylation of ketones and aldehydes via photoredox catalysis. Here we disclose the generation of (nitro)benzyl radicals via N-heterocyclic carbene (NHC) catalysis under reductive conditions. The radical intermediates generated via NHC catalysis undergo formal 1,2-addition with ketones to eventually afford tertiary alcohol products. The overall process constitutes a formal polarity-inversion of benzyl bromide, allowing a direct coupling of two initially electrophilic carbons. Our study provides a new carbene-catalysed reaction mode that should enable unconventional transformation of (nitro)benzyl bromides under mild organocatalytic conditions. PMID:27671606

Metal-Dependent Amyloid β-Degrading Catalytic Antibody Construct

PubMed Central

Nishiyama, Yasuhiro; Taguchi, Hiroaki; Hara, Mariko; Planque, Stephanie A.; Mitsuda, Yukie; Paul, Sudhir

2015-01-01

Catalytic antibodies (catabodies) that degrade target antigens rapidly are rare. We describe the metal-dependence of catabody construct 2E6, an engineered heterodimer of immunoglobulin light chain variable domains that hydrolyzes amyloid β peptides (Aβ) specifically. In addition to the electrophilic phosphonate inhibitor of serine proteases, the metal chelators ethylenediaminetetraacetic acid (EDTA) and 1,10-phenanthroline completely inhibited the hydrolysis of Aβ by catabody 2E6. Formation of catabody-electrophilic phosphonate inhibitor adducts was unaffected by EDTA, suggesting that the metal exerts a favorable effect on a catalytic step after the initial catabody nucleophilic attack on Aβ. The EDTA inactivated catabody failed to disaggregate fibrillar Aβ, indicating the functional importance of the Aβ hydrolytic activity. Treating the EDTA-inactivated catabody with Zn2+ or Co2+ restored the Aβ hydrolytic activity, and Zn2+-induced catabody conformational transitions were evident by fluorescence emission spectroscopy. The studies reveal the absolute catabody dependence on a metal cofactor. PMID:24698848

Main-group compounds selectively oxidize mixtures of methane, ethane, and propane to alcohol esters.

PubMed

Hashiguchi, Brian G; Konnick, Michael M; Bischof, Steven M; Gustafson, Samantha J; Devarajan, Deepa; Gunsalus, Niles; Ess, Daniel H; Periana, Roy A

2014-03-14

Much of the recent research on homogeneous alkane oxidation has focused on the use of transition metal catalysts. Here, we report that the electrophilic main-group cations thallium(III) and lead(IV) stoichiometrically oxidize methane, ethane, and propane, separately or as a one-pot mixture, to corresponding alcohol esters in trifluoroacetic acid solvent. Esters of methanol, ethanol, ethylene glycol, isopropanol, and propylene glycol are obtained with greater than 95% selectivity in concentrations up to 1.48 molar within 3 hours at 180°C. Experiment and theory support a mechanism involving electrophilic carbon-hydrogen bond activation to generate metal alkyl intermediates. We posit that the comparatively high reactivity of these d(10) main-group cations relative to transition metals stems from facile alkane coordination at vacant sites, enabled by the overall lability of the ligand sphere and the absence of ligand field stabilization energies in systems with filled d-orbitals.

Cobalt co-catalysis for cross-electrophile coupling: diarylmethanes from benzyl mesylates and aryl halides† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c4sc03106g Click here for additional data file.

PubMed Central

Ackerman, Laura K. G.; Anka-Lufford, Lukiana L.; Naodovic, Marina

2015-01-01

The nickel-catalyzed cross-coupling of aryl halides with alkyl radicals derived from alkyl halides has recently been extended to couplings with carbon radicals generated by a co-catalyst. In this study, a new co-catalyst, cobalt phthalocyanine (Co(Pc)), is introduced and demonstrated to be effective for coupling substrates not prone to homolysis. This is because Co(Pc) reacts with electrophiles by an SN2 mechanism instead of by the electron-transfer or halogen abstraction mechanisms previously explored. Studies demonstrating the orthogonal reactivity of (bpy)Ni and Co(Pc), applying this selectivity to the coupling of benzyl mesylates with aryl halides, and the adaptation of these conditions to the less reactive benzyl phosphate ester and an enantioconvergent reaction are presented. PMID:25685312

15-Hydroxygermacranolides as Sources of Structural Diversity: Synthesis of Sesquiterpene Lactones by Cyclization and Rearrangement Reactions. Experimental and DFT Study.

PubMed

Álvarez-Calero, José María; Ruiz, Enrique; López-Pérez, José Luis; Jaraíz, Martín; Rubio, José E; Jorge, Zacarías D; Suárez, Margarita; Massanet, Guillermo M

2018-05-18

A study on the electrophile-induced rearrangement of two 15-hydroxygermacranolides, salonitenolide and artemisiifolin, was carried out. These compounds underwent electrophilic intramolecular cyclizations or acid-mediated rearrangements to give sesquiterpene lactones with different skeletons such as eudesmanolides, guaianolides, amorphanolides, or other germacranolides. The cyclization that gives guaianolides can be considered a biomimetic route to this type of sesquiterpene lactones. The use of acetone as a solvent changes the reactivity of the two starting germacranolides to the acid catalysts, with a 4,15-diol acetonide being the main product obtained. The δ-amorphenolide obtained by intramolecular cyclization of this acetonide is a valuable intermediate for accessing the antimalarials artemisinin and its derivatives. Mechanistic proposals for the transformations are raised, and to provide support them, quantum chemical calculations [DFT B3LYP/6-31+G(d,p) level] were undertaken.

Conceptual DFT Descriptors of Amino Acids with Potential Corrosion Inhibition Properties Calculated with the Latest Minnesota Density Functionals

PubMed Central

Frau, Juan; Glossman-Mitnik, Daniel

2017-01-01

Amino acids and peptides have the potential to perform as corrosion inhibitors. The chemical reactivity descriptors that arise from Conceptual DFT for the twenty natural amino acids have been calculated by using the latest Minnesota family of density functionals. In order to verify the validity of the calculation of the descriptors directly from the HOMO and LUMO, a comparison has been performed with those obtained through ΔSCF results. Moreover, the active sites for nucleophilic and electrophilic attacks have been identified through Fukui function indices, the dual descriptor Δf(r) and the electrophilic and nucleophilic Parr functions. The results could be of interest as a starting point for the study of large peptides where the calculation of the radical cation and anion of each system may be computationally harder and costly. PMID:28361050

Arynes, diaryliodonium salts and azine N-oxides in transition metal-free electrophilic N-arylation

NASA Astrophysics Data System (ADS)

Bugaenko, D. I.; Karchava, A. V.; Yurovskaya, M. A.

2018-03-01

The main approach to the synthesis of aromatic and heteroaromatic amines is based on palladium- and copper-catalyzed N-arylation reactions. Although these methods are highly efficient and provide extensive opportunities for the synthesis of (het)arylamines with various structures and properties, they have some limitations related to the catalysts used and reaction conditions. This review addresses alternative approaches to N-(het)arylation that have been extensively developed in the past decade and are based on the use of arynes, diaryliodonium salts and azine N-oxides as electrophilic (het)arylating agents. Because of mild reaction conditions and no need for catalysts and strong bases, these N-(het)arylation methods are attractive for various synthetic applications and open up new possibilities for the preparation of valuable organic compounds inaccessible via traditional catalytic methods. The attention is focussed on publications of the last decade. The bibliography includes 112 references.

Covalent inhibitors: an opportunity for rational target selectivity.

PubMed

Lagoutte, Roman; Patouret, Remi; Winssinger, Nicolas

2017-08-01

There is a resurging interest in compounds that engage their target through covalent interactions. Cysteine's thiol is endowed with enhanced reactivity, making it the nucleophile of choice for covalent engagement with a ligand aligning an electrophilic trap with a cysteine residue in a target of interest. The paucity of cysteine in the proteome coupled to the fact that closely related proteins do not necessarily share a given cysteine residue enable a level of unprecedented rational target selectivity. The recent demonstration that a lysine's amine can also be engaged covalently with a mild electrophile extends the potential of covalent inhibitors. The growing database of protein structures facilitates the discovery of covalent inhibitors while the advent of proteomic technologies enables a finer resolution in the selectivity of covalently engaged proteins. Here, we discuss recent examples of discovery and design of covalent inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen and Amine Nucleophiles by Using Electrophilic Iodine.

PubMed

Li, Jing; Lear, Martin J; Kwon, Eunsang; Hayashi, Yujiro

2016-04-11

Recently, we developed a direct method to oxidatively convert primary nitroalkanes into amides that entailed mixing an iodonium source with an amine, base, and oxygen. Herein, we systematically investigated the mechanism and likely intermediates of such methods. We conclude that an amine-iodonium complex first forms through N-halogen bonding. This complex reacts with aci-nitronates to give both α-iodo- and α,α-diiodonitroalkanes, which can act as alternative sources of electrophilic iodine and also generate an extra equimolar amount of I(+) under O2. In particular, evidence supports α,α-diiodonitroalkane intermediates reacting with molecular oxygen to form a peroxy adduct; alternatively, these tetrahedral intermediates rearrange anaerobically to form a cleavable nitrite ester. In either case, activated esters are proposed to form that eventually reacts with nucleophilic amines in a traditional fashion. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Catalyst-Free Amination of Functional Organolithium Reagents by Flow Chemistry.

PubMed

Kim, Heejin; Yonekura, Yuya; Yoshida, Jun-Ichi

2018-04-03

Reported is the electrophilic amination of functional organolithium intermediates with well-designed aminating reagents under mild reaction conditions using flow microreactors. The aminating reagents were optimized to achieve efficient C-N bond formation without using any catalyst. The electrophilic amination reactions of functionalized aryllithiums were successfully conducted under mild reaction conditions, within 1 minute, by using flow microreactors. The aminating reagent was also prepared by the flow method. Based on stopped-flow NMR analysis, the reaction time for the preparation of the aminating reagent was quickly optimized without the necessity of work-up. Integrated one-flow synthesis consisting of the generation of an aryllithium, the preparation of an aminating reagent, and their combined reaction was successfully achieved to give the desired amine within 5 minutes of total reaction time. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Michael acceptor containing drugs are a novel class of 5-lipoxygenase inhibitor targeting the surface cysteines C416 and C418.

PubMed

Maucher, Isabelle V; Rühl, Michael; Kretschmer, Simon B M; Hofmann, Bettina; Kühn, Benjamin; Fettel, Jasmin; Vogel, Anja; Flügel, Karsten T; Manolikakes, Georg; Hellmuth, Nadine; Häfner, Ann-Kathrin; Golghalyani, Vahid; Ball, Ann-Katrin; Piesche, Matthias; Matrone, Carmela; Geisslinger, Gerd; Parnham, Michael J; Karas, Michael; Steinhilber, Dieter; Roos, Jessica; Maier, Thorsten J

2017-02-01

Recently, we published that nitro-fatty acids (NFA) are potent electrophilic molecules which inhibit 5-lipoxygenase (5-LO) by interacting catalytically with cysteine residues next to a substrate entry channel. The electrophilicity is derived from an intramolecular Michael acceptor moiety consisting of an electron-withdrawing group in close proximity to a double bond. The potential of the Michael acceptor moiety to interact with functionally relevant cysteines of proteins potentially renders them effective and sustained enzyme activity modulators. We screened a large library of naturally derived and synthetic electrophilic compounds to investigate whether other types of Michael acceptor containing drugs suppress 5-LO enzyme activity. The activity was measured by assessing the effect on the 5-LO product formation of intact human polymorphonuclear leukocytes. We demonstrated that a number of structurally different compounds were suppressive in the activity assays and showed that Michael acceptors of the quinone and nitro-alkene group produced the strongest inhibition of 5-LO product formation. Reactivity with the catalytically relevant cysteines 416 and 418 was confirmed using mutated recombinant 5-LO and mass spectrometric analysis (MALDI-MS). In the present study, we show for the first time that a number of well-recognized naturally occurring or synthetic anti-inflammatory compounds carrying a Michael acceptor, such as thymoquinone (TQ), the paracetamol metabolite NAPQI, the 5-LO inhibitor AA-861, and bardoxolone methyl (also known as RTA 402 or CDDO-methyl ester) are direct covalent 5-LO enzyme inhibitors that target the catalytically relevant cysteines 416 and 418. Copyright © 2016 Elsevier Inc. All rights reserved.

Prototype Systems Containing Human Cytochrome P450 for High-Throughput Real-Time Detection of DNA Damage by Compounds That Form DNA-Reactive Metabolites.

PubMed

Brito Palma, Bernardo; Fisher, Charles W; Rueff, José; Kranendonk, Michel

2016-05-16

The formation of reactive metabolites through biotransformation is the suspected cause of many adverse drug reactions. Testing for the propensity of a drug to form reactive metabolites has increasingly become an integral part of lead-optimization strategy in drug discovery. DNA reactivity is one undesirable facet of a drug or its metabolites and can lead to increased risk of cancer and reproductive toxicity. Many drugs are metabolized by cytochromes P450 in the liver and other tissues, and these reactions can generate hard electrophiles. These hard electrophilic reactive metabolites may react with DNA and may be detected in standard in vitro genotoxicity assays; however, the majority of these assays fall short due to the use of animal-derived organ extracts that inadequately represent human metabolism. The current study describes the development of bacterial systems that efficiently detect DNA-damaging electrophilic reactive metabolites generated by human P450 biotransformation. These assays use a GFP reporter system that detects DNA damage through induction of the SOS response and a GFP reporter to control for cytotoxicity. Two human CYP1A2-competent prototypes presented here have appropriate characteristics for the detection of DNA-damaging reactive metabolites in a high-throughput manner. The advantages of this approach include a short assay time (120-180 min) with real-time measurement, sensitivity to small amounts of compound, and adaptability to a microplate format. These systems are suitable for high-throughput assays and can serve as prototypes for the development of future enhanced versions.

Halogen bond: a long overlooked interaction.

PubMed

Cavallo, Gabriella; Metrangolo, Pierangelo; Pilati, Tullio; Resnati, Giuseppe; Terraneo, Giancarlo

2015-01-01

Because of their high electronegativity, halogen atoms are typically considered, in most of their derivatives, as sites of high electron density and it is commonly accepted that they can form attractive interactions by functioning as the electron donor site (nucleophilic site). This is the case when they work as hydrogen bond acceptor sites. However, the electron density in covalently bound halogens is anisotropically distributed. There is a region of higher electron density, accounting for the ability of halogens to function as electron donor sites in attractive interactions, and a region of lower electron density where the electrostatic potential is frequently positive (mainly in the heavier halogens). This latter region is responsible for the ability of halogen atoms to function as the electron-acceptor site (electrophilic site) in attractive interactions formed with a variety of lone pair-possessing atoms, anions, and π-systems. This ability is quite general and is shown by a wide diversity of halogenated compounds (e.g., organohalogen derivatives and dihalogens). According to the definition proposed by the International Union of Pure and Applied Chemistry, any attractive interactions wherein the halogen atom is the electrophile is named halogen bond (XB). In this chapter, it is discussed how the practice and the concept of XB developed and a brief history of the interaction is presented. Papers (either from the primary or secondary literature) which have reported major experimental findings in the field or which have given important theoretical contributions for the development of the concept are recollected in order to trace how a unifying and comprehensive categorization emerged encompassing all interactions wherein halogen atoms function as the electrophilic site.

A systematic computational study of electronic effects on hydrogen sensitivity of olefin polymerization catalysts (abstract only).

PubMed

Coussens, Betty B; Budzelaar, Peter H M; Friederichs, Nic

2008-02-13

One of the important product parameters of polyolefins is their molecular weight (distribution). A common way to control this parameter is to add molecular hydrogen during the polymerization, which then acts as a chain transfer agent. The factors governing the hydrogen sensitivity of olefin polymerization catalysts are poorly understood and have attracted little attention from computational chemists. To explore the electronic factors determining hydrogen sensitivity we performed density functional calculations on a wide range of simple model systems including some metallocenes and a few basic models of heterogeneous catalysts. As a quantitative measure for hydrogen sensitivity we used the ratio of (i) the rate constant for chain transfer to hydrogen to (ii) the rate constant for ethene insertion, k(h)/k(p) (see the scheme below), and as a measure of electrophilicity we used the energy of complexation to the probe molecule ammonia. [Formula: see text] For isolated species in the gas phase, complexation energies appear to dominate the chemistry. Ethene complexes more strongly than hydrogen and with increasing electrophilicity of the metal centre this difference grows; the hydrogen sensitivity decreases accordingly. Although many factors (like catalyst dormancy and deactivation issues) complicate the comparison with experiment, this result seems to agree both in broad terms with the experimental lower hydrogen sensitivity of heterogeneous catalysts, and more specifically with the increased hydrogen sensitivity of highly alkylated or fused metallocenes. The opposite conclusion reached by Blom (see Blom et al 2002 Macromol. Chem. Phys. 203 381-7) is due to the use of a very different measure of electrophilicity, rather than to different experimental data.

A fluorescence high throughput screening method for the detection of reactive electrophiles as potential skin sensitizers.

PubMed

Avonto, Cristina; Chittiboyina, Amar G; Rua, Diego; Khan, Ikhlas A

2015-12-01

Skin sensitization is an important toxicological end-point in the risk assessment of chemical allergens. Because of the complexity of the biological mechanisms associated with skin sensitization, integrated approaches combining different chemical, biological and in silico methods are recommended to replace conventional animal tests. Chemical methods are intended to characterize the potential of a sensitizer to induce earlier molecular initiating events. The presence of an electrophilic mechanistic domain is considered one of the essential chemical features to covalently bind to the biological target and induce further haptenation processes. Current in chemico assays rely on the quantification of unreacted model nucleophiles after incubation with the candidate sensitizer. In the current study, a new fluorescence-based method, 'HTS-DCYA assay', is proposed. The assay aims at the identification of reactive electrophiles based on their chemical reactivity toward a model fluorescent thiol. The reaction workflow enabled the development of a High Throughput Screening (HTS) method to directly quantify the reaction adducts. The reaction conditions have been optimized to minimize solubility issues, oxidative side reactions and increase the throughput of the assay while minimizing the reaction time, which are common issues with existing methods. Thirty-six chemicals previously classified with LLNA, DPRA or KeratinoSens™ were tested as a proof of concept. Preliminary results gave an estimated 82% accuracy, 78% sensitivity, 90% specificity, comparable to other in chemico methods such as Cys-DPRA. In addition to validated chemicals, six natural products were analyzed and a prediction of their sensitization potential is presented for the first time. Copyright © 2015 Elsevier Inc. All rights reserved.

How does tunneling contribute to counterintuitive H-abstraction reactivity of nonheme Fe(IV)O oxidants with alkanes?

PubMed

Mandal, Debasish; Ramanan, Rajeev; Usharani, Dandamudi; Janardanan, Deepa; Wang, Binju; Shaik, Sason

2015-01-21

This article addresses the intriguing hydrogen-abstraction (H-abstraction) and oxygen-transfer (O-transfer) reactivity of a series of nonheme [Fe(IV)(O)(TMC)(Lax)](z+) complexes, with a tetramethyl cyclam ligand and a variable axial ligand (Lax), toward three substrates: 1,4-cyclohexadiene, 9,10-dihydroanthracene, and triphenyl phosphine. Experimentally, O-transfer-reactivity follows the relative electrophilicity of the complexes, whereas the corresponding H-abstraction-reactivity generally increases as the axial ligand becomes a better electron donor, hence exhibiting an antielectrophilic trend. Our theoretical results show that the antielectrophilic trend in H-abstraction is affected by tunneling contributions. Room-temperature tunneling increases with increase of the electron donation power of the axial-ligand, and this reverses the natural electrophilic trend, as revealed through calculations without tunneling, and leads to the observed antielectrophilic trend. By contrast, O-transfer-reactivity, not being subject to tunneling, retains an electrophilic-dependent reactivity trend, as revealed experimentally and computationally. Tunneling-corrected kinetic-isotope effect (KIE) calculations matched the experimental KIE values only if all of the H-abstraction reactions proceeded on the quintet state (S = 2) surface. As such, the present results corroborate the initially predicted two-state reactivity (TSR) scenario for these reactions. The increase of tunneling with the electron-releasing power of the axial ligand, and the reversal of the "natural" reactivity pattern, support the "tunneling control" hypothesis (Schreiner et al., ref 19). Should these predictions be corroborated, the entire field of C-H bond activation in bioinorganic chemistry would lay open to reinvestigation.

Chameleonic reactivity of vicinal diazonium salt of acetylenyl-9,10-anthraquinones: synthetic application toward two heterocyclic targets.

PubMed

Stepanov, A A; Gornostaev, L M; Vasilevsky, S F; Arnold, E V; Mamatyuk, V I; Fadeev, D S; Gold, B; Alabugin, I V

2011-11-04

The nature of products in the diazotization of 1-amino-2-acetylenyl-9,10-anthraquinones strongly depends on the nature of substituents at both the alkyne and at the anthraquinone core. Donor substitution (NHAr, OH) at the fourth position stabilizes the diazonium salt at C1, decelerating electrophilic cyclization at the arylethynyl substituent at C2. This effect allows the replacement of the diazonium with azide group and subsequent closure into isoxazole ring with preservation of the alkyne. In contrast, electrophilic 5-exo-dig cyclizations to condensed pyrazoles is observed for the combination of donor substituents at the aryl alkyne moiety and an OAc substituent at C4. The latter process provides a new synthetic route to 3-ethynyl-[1,9-cd]isoxazol-6-ones that are difficult to access otherwise. DFT calculations suggest that donor substituents have only a minor effect on alkyne and diazonium polarization in the reactant but provide specific transition state stabilization by stabilizing the incipient vinyl cation. This analysis provides the first computational data on electrophilic 5-exo-dig cyclization in its parent form and the nucleophile-promoted version. This cyclization is a relatively fast but endothermic process that is rendered thermodynamically feasible by the enol-keto tautomerization with concomitant aromatization in the five-membered heteroaromatic ring. Computations suggest that the importance of nucleophilic assistance in the transition state for a relatively weak nucleophile such as water is minor because the energy gain due to the Lewis base coordination to the carbocationic center is more than compensated for by the unfavorable entropic term for the bimolecular proces.

Selenium-mediated synthesis of biaryls through rearrangement.

PubMed

Shahzad, Sohail A; Vivant, Clotilde; Wirth, Thomas

2010-03-19

A new cyclization of beta-keto ester substituted stilbene derivatives using selenium electrophiles in the presence of Lewis acids is described. Substituted naphthols are obtained through cyclization and subsequent 1,2-rearrangement of aryl groups under very mild reaction conditions.

Hydrolysis of the quinone methide of butylated hydroxytoluene in aqueous solutions.

PubMed

Willcockson, Maren Gulsrud; Toteva, Maria M; Stella, Valentino J

2013-10-01

Butylated hydroxytoluene or BHT is an antioxidant commonly used in pharmaceutical formulations. BHT upon oxidation forms a quinone methide (QM). QM is a highly reactive electrophilic species that can undergo nucleophilic addition. Here, the kinetic reactivity of QM with water at various apparent pH values in a 50% (v/v) water-acetonitrile solution at constant ionic strength of I = 0.5 (NaCl)4 , was studied. The hydrolysis of QM in the presence of added acid, base, sodium chloride, and phosphate buffer resulted in the formation of only one product--the corresponding 3,5-di-tert-butyl-4-hydroxybenzyl alcohol (BA). The rate of BA formation was catalyzed by the addition of acid and base, but not chloride and phosphate species. Nucleophilic excipients, used in the pharmaceutical formulation, or nucleophilic groups on active pharmaceutical ingredient molecule may form adducts with QM, the immediate oxidative product of BHT degradation, thus having implications for drug product impurity profiles. Because of these considerations, BHT should be used with caution in formulations containing drugs or excipients capable of acting as nucleophiles. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Modulation of NRF2 signaling pathway by nuclear receptors: implications for cancer.

PubMed

Namani, Akhileshwar; Li, Yulong; Wang, Xiu Jun; Tang, Xiuwen

2014-09-01

Nuclear factor-erythroid 2 p45-related factor 2 (NRF2, also known as Nfe2l2) plays a critical role in regulating cellular defense against electrophilic and oxidative stress by activating the expression of an array of antioxidant response element-dependent genes. On one hand, NRF2 activators have been used in clinical trials for cancer prevention and the treatment of diseases associated with oxidative stress; on the other hand, constitutive activation of NRF2 in many types of tumors contributes to the survival and growth of cancer cells, as well as resistance to anticancer therapy. In this review, we provide an overview of the NRF2 signaling pathway and discuss its role in carcinogenesis. We also introduce the inhibition of NRF2 by nuclear receptors. Further, we address the biological significance of regulation of the NRF2 signaling pathway by nuclear receptors in health and disease. Finally, we discuss the possible impact of NRF2 inhibition by nuclear receptors on cancer therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

Mechanism of degradation of 2'-deoxycytidine by formamide: implications for chemical DNA sequencing procedures.

PubMed

Saladino, R; Crestini, C; Mincione, E; Costanzo, G; Di Mauro, E; Negri, R

1997-11-01

We describe the reaction of formamide with 2'-deoxycytidine to give pyrimidine ring opening by nucleophilic addition on the electrophilic C(6) and C(4) positions. This information is confirmed by the analysis of the products of formamide attack on 2'-deoxycytidine, 5-methyl-2'-deoxycytidine, and 5-bromo-2'-deoxycytidine, residues when the latter are incorporated into oligonucleotides by DNA polymerase-driven polymerization and solid-phase phosphoramidite procedure. The increased sensitivity of 5-bromo-2'-deoxycytidine relative to that of 2'-deoxycytidine is pivotal for the improvement of the one-lane chemical DNA sequencing procedure based on the base-selective reaction of formamide with DNA. In many DNA sequencing cases it will in fact be possible to incorporate this base analogue into the DNA to be sequenced, thus providing a complete discrimination between its UV absorption signal and that of the thymidine residues. The wide spectrum of different sensitivities to formamide displayed by the 2'-deoxycytidine analogues solves, in the DNA single-lane chemical sequencing procedure, the possible source of errors due to low discrimination between C and T residues.

Intrinsic electrophilic properties of nucleosides: Photoelectron spectroscopy of their parent anions

NASA Astrophysics Data System (ADS)

Stokes, Sarah T.; Li, Xiang; Grubisic, Andrej; Ko, Yeon Jae; Bowen, Kit H.

2007-08-01

The nucleoside parent anions 2'-deoxythymidine-, 2'-deoxycytidine-, 2'-deoxyadenosine-, uridine-, cytidine-, adenosine-, and guanosine- were generated in a novel source, employing a combination of infrared desorption, electron photoemission, and a gas jet expansion. Once mass selected, the anion photoelectron spectrum of each of these was recorded. In the three cases in which comparisons were possible, the vertical detachment energies and likely adiabatic electron affinities extracted from these spectra agreed well with the values calculated both by Richardson et al. [J. Am. Chem. Soc. 126, 4404 (2004)] and by Li et al. [Radiat. Res. 165, 721 (2006)]. Through the combination of our experimental results and their theoretical calculations, several implications emerge. (1) With the possible exception of dG-, the parent anions of nucleosides exist, and they are stable. (2) These nucleoside anions are valence anions, and in most cases the negative charge is closely associated with the nucleobase moiety. (3) The nucleoside parent anions we have generated and studied are the negative ions of canonical, neutral nucleosides, similar to those found in DNA.

Intrinsic electrophilic properties of nucleosides: photoelectron spectroscopy of their parent anions.

PubMed

Stokes, Sarah T; Li, Xiang; Grubisic, Andrej; Ko, Yeon Jae; Bowen, Kit H

2007-08-28

The nucleoside parent anions 2(')-deoxythymidine(-), 2(')-deoxycytidine(-), 2(')-deoxyadenosine(-), uridine(-), cytidine(-), adenosine(-), and guanosine(-) were generated in a novel source, employing a combination of infrared desorption, electron photoemission, and a gas jet expansion. Once mass selected, the anion photoelectron spectrum of each of these was recorded. In the three cases in which comparisons were possible, the vertical detachment energies and likely adiabatic electron affinities extracted from these spectra agreed well with the values calculated both by Richardson et al. [J. Am. Chem. Soc. 126, 4404 (2004)] and by Li et al. [Radiat. Res. 165, 721 (2006)]. Through the combination of our experimental results and their theoretical calculations, several implications emerge. (1) With the possible exception of dG(-), the parent anions of nucleosides exist, and they are stable. (2) These nucleoside anions are valence anions, and in most cases the negative charge is closely associated with the nucleobase moiety. (3) The nucleoside parent anions we have generated and studied are the negative ions of canonical, neutral nucleosides, similar to those found in DNA.

Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol*

PubMed Central

Goedken, Eric R.; Argiriadi, Maria A.; Banach, David L.; Fiamengo, Bryan A.; Foley, Sage E.; Frank, Kristine E.; George, Jonathan S.; Harris, Christopher M.; Hobson, Adrian D.; Ihle, David C.; Marcotte, Douglas; Merta, Philip J.; Michalak, Mark E.; Murdock, Sara E.; Tomlinson, Medha J.; Voss, Jeffrey W.

2015-01-01

The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC50 < 100 nm) inhibit Jak3 activity in cell-based assays. These results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases. PMID:25552479

Late-stage chemoselective functional-group manipulation of bioactive natural products with super-electrophilic silylium ions

NASA Astrophysics Data System (ADS)

Bender, Trandon A.; Payne, Philippa R.; Gagné, Michel R.

2018-01-01

The selective (and controllable) modification of complex molecules with disparate functional groups (for example, natural products) is a long-standing challenge that has been addressed using catalysts tuned to perform singular transformations (for example, C-H hydroxylation). A method whereby reactions with diverse functional groups within a single natural product are feasible depending on which catalyst or reagent is chosen would widen the possible structures one could obtain. Fluoroarylborane catalysts can heterolytically split Si-H bonds to yield an oxophilic silylium (R3Si+) equivalent along with a reducing (H-) equivalent. Together, these reactive intermediates enable the reduction of multiple functional groups. Exogenous phosphine Lewis bases further modify the catalyst speciation and attenuate aggressive silylium ions for the selective modification of complex natural products. Manipulation of the catalyst, silane reagent and the reaction conditions provides experimental control over which site is modified (and how). Applying this catalytic method to complex bioactive compounds (natural products or drugs) provides a powerful tool for studying structure-activity relationships.

Multiple-orifice liquid injection into hypersonic airstreams and applications to ram C-3 flight

NASA Technical Reports Server (NTRS)

Weaver, W. L.

1972-01-01

Experimental data are presented for the oblique injection of water and three electrophilic liquids (fluorocarbon compounds) through multiple-orifice nozzles from a flat plate and the sides of a hemisphere-cone (0.375 scale of RAM C spacecraft) into hypersonic airstreams. The nozzle patterns included single and multiple orifices, single rows of nozzles, and duplicates of the RAM C-III nozzles. The flat-plate tests were made at Mach 8. Total pressure was varied from 3.45 MN/m2 to 10.34 MN/m2, Reynolds number was varied form 9,840,000 per meter to 19,700,000 per meter, and liquid injection pressure was varied from 0.69 MN/m2 to 3.5 MN/m2. The hemisphere-cone tests were made at Mach 7.3. Total pressure was varied from 1.38 MN/m2, to 6.89 MN/m2, Reynolds number was varied from 3,540,000 per meter to 17,700,000 per meter, and liquid-injection pressure was varied from 0.34 MN/m2 to 4.14 MN/m2. Photographs of the tests and plots of liquid-penetration and spray cross-section area are presented. Maximum penetration was found to vary as the square root of the dynamic-pressure ratio and the square root of the total injection nozzle area. Spray cross-section area was linear with maximum penetration. The test results are used to compute injection parameters for the RAM C-3 flight injection experiment.

Discovery of highly potent, selective, covalent inhibitors of JAK3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kempson, James; Ovalle, Damaso; Guo, Junqing

A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.

Green Synthesis of a Fluorescent Natural Product

ERIC Educational Resources Information Center

Young, Douglas M.; Welker, Jacob J. C.; Doxsee, Kenneth M.

2011-01-01

Synthesis of 4-methylumbelliferone via the acid-catalyzed Pechmann condensation introduces students to several types of organic reactions: transesterification, electrophilic aromatic substitution, and alcohol dehydration. Performed with a recyclable, solid catalyst and under solvent-free conditions, the experiment illustrates many of the…

C-H carbonylation: In situ acyl triflates ace it

NASA Astrophysics Data System (ADS)

Lee, Yong Ho; Morandi, Bill

2018-02-01

A simple palladium catalyst has mediated the facile formation of aroyl triflates -- an extremely reactive class of electrophiles. These intermediates, generated in situ, enable the Friedel-Crafts acylation of traditionally unreactive arenes, addressing a significant gap in C-H carbonylation methodology.

Changing the chemical and physical properties of high valent heterobimetallic bis-(μ-oxido) Cu-Ni complexes by ligand effects.

PubMed

Kafentzi, Maria-Chrysanthi; Orio, Maylis; Réglier, Marius; Yao, Shenglai; Kuhlmann, Uwe; Hildebrandt, Peter; Driess, Matthias; Simaan, A Jalila; Ray, Kallol

2016-10-12

Two new heterobimetallic [LNiO 2 Cu(RPY2)] + (RPY2 = N-substituted bis 2-pyridyl(ethylamine) ligands with R = indane, 3a or R = Me, 3b) complexes have been spectroscopically trapped at low temperatures. They were prepared by reacting the mononuclear side-on LNi II superoxo precursor bearing a β-diketiminate ligand (L = [HC-(CMeNC 6 H 3 (iPr) 2 ) 2 ]) with the Cu(i) complexes. In contrast to the oxo groups in known high-valent [M 2 (μ-O) 2 ] n+ (M = Fe, Co, Ni, Cu) cores that display electrophilic reactivities, 3a and 3b display rather nucleophilic oxo cores active in aldehyde deformylation reactions. However, the spectroscopic and reactivity properties of 3a/3b are found to be distinct relative to that of the previously reported [LNiO 2 Cu(MeAN)] + complex containing a more basic (nucleophilic) N,N,N',N',N'-pentamethyl-dipropylenetriamine (MeAN) ligand at the copper centre. The geometry and electronic properties of the copper ligands affect the electron density of the oxygen atoms of the heterodinuclear {Ni(μ-O) 2 } core and 3a/3b undergo slower nucleophilic and faster electrophilic reactions than the previously reported [LNiO 2 Cu(MeAN)] + intermediate. The present study therefore demonstrates the tuning of the electrophilicity/nucleophilicity of the oxygen atoms of the heterobimetallic [Ni(μ-O) 2 Cu] 2+ cores by controlling the electron donation from the ancillary ligands, and underlines the significance of subtle electronic changes in the physical and chemical properties of the biologically relevant heterobimetallic metal-dioxygen intermediates.

Synthesis, spectral and chemical reactivity analysis of 2,4-dinitrophenyl hydrazone having pyrrole moiety

NASA Astrophysics Data System (ADS)

Rawat, Poonam; Singh, R. N.

2015-10-01

In this paper we present combined experimental and theoretical study on a newly synthesized ethyl 2-cyano-3-[5-(2,4-dinitrophenyl)-hydrazonomethyl)-1H-pyrrol-2-yl]-acrylate (ECDHPA). Quantum chemical calculations have been performed using HF/6-31G(d,p), B3LYP/6-31G(d,p) and B3LYP/6-31++G(d,p) levels. The results obtained from quantum chemical calculations matches well with the experimental finding. Molecular electrostatic potential (MEP) surface of N17sbnd H39⋯O42dbnd N37 zone show green color having moderate electrostatic potential indicating hydrogen bonding. For the interactions N17sbnd H34⋯O42 electron density and its Laplacian (∇2ρBCP) are in the range 0.051-0.119 a.u., indicating interaction follows the Koch and Popelier criteria. The observed Nsbnd H (νN17sbnd H34) stretch of sbnd CHdbnd Nsbnd NH sbnd part of molecule at 3262 cm-1 indicate the red shift and the involvement in hydrogen bonding. Natural bond orbital (NBO) investigation shows various intramolecular interactions within molecule. Electrophilic charge transfer (ECT) has been calculated to investigate the relative electrophilic or nucleophilic behavior of reactant molecules involved in chemical reaction. The first hyperpolarizability (β0) value of ECDHPA is calculated as 22.42 × 10-30 esu. The solvent-induced effects on the non-linear optical properties (NLO) were studied using self-consistent reaction field (SCRF) method and observed that the β0 value increases as solvent polarity increases. DFT based electronic descriptors analysis reveals that studied molecule is a strong electrophile and it would undergo to form various heterocyclic compounds.

Sequential one-pot addition of excess aryl-Grignard reagents and electrophiles to O-alkyl thioformates.

PubMed

Murai, Toshiaki; Morikawa, Kenta; Maruyama, Toshifumi

2013-09-23

The sequential addition of aromatic Grignard reagents to O-alkyl thioformates proceeded to completion within 30 s to give aryl benzylic sulfanes in good yields. This reaction may begin with the nucleophilic attack of the Grignard reagent onto the carbon atom of the O-alkyl thioformates, followed by the elimination of ROMgBr to generate aromatic thioaldehydes, which then react with a second molecule of the Grignard reagent at the sulfur atom to form arylsulfanyl benzylic Grignard reagents. To confirm the generation of aromatic thioaldehydes, the reaction between O-alkyl thioformates and phenyl Grignard reagent was carried out in the presence of cyclopentadiene. As a result, hetero-Diels-Alder adducts of the thioaldehyde and the diene were formed. The treatment of a mixture of the thioformate and phenyl Grignard reagent with iodine gave 1,2-bis(phenylsulfanyl)-1,2-diphenyl ethane as a product, which indicated the formation of arylsulfanyl benzylic Grignard reagents in the reaction mixture. When electrophiles were added to the Grignard reagents that were generated in situ, four-component coupling products, that is, O-alkyl thioformates, two molecules of Grignard reagents, and electrophiles, were obtained in moderate-to-good yields. The use of silyl chloride or allylic bromides gave the adducts within 5 min, whereas the reaction with benzylic halides required more than 30 min. The addition to carbonyl compounds was complete within 1 min and the use of lithium bromide as an additive enhanced the yields of the four-component coupling products. Finally, oxiranes and imines also participated in the coupling reaction. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Symmetrically tetrasubstituted [2.2]paracyclophanes: their systematization and regioselective synthesis of several types of bis-bifunctional derivatives by double electrophilic substitution.

PubMed

Vorontsova, Natalia V; Rozenberg, Valeria I; Sergeeva, Elena V; Vorontsov, Evgenii V; Starikova, Zoya A; Lyssenko, Konstantin A; Hopf, Henning

2008-01-01

The possible number of chiral and achiral tetrasubstituted [2.2]paracyclophanes possessing different types of symmetry (C(2), C(i), C(s), C(2v), C(2h)) is evaluated and a unified independent trivial naming descriptor system is introduced. The reactivity and regioselectivity of the electrophilic substitution of the chiral pseudo-meta- and achiral pseudo-para-disubstituted [2.2]paracyclophanes are investigated in an approach suggested to be general for the synthesis of bis-bifunctional [2.2]paracyclophanes. The mono- and diacylation of chiral pseudo-meta-dihydroxy[2.2]paracyclophane 14 with acetylchloride occur ortho-regioselectively to produce tri- 22, 23 and symmetrically 21 tetrasubstituted acyl derivatives. The same reaction with benzoylchloride is neither regio-, nor chemoselective, and gives rise to a mixture of ortho-/para-, mono-/diacylated compounds 27-31. The double acylation of pseudo-meta-dimethoxy[2.2]paracyclophane 18 is completely para-regioselective. Electrophilic substitution of pseudo-meta-bis(methoxycarbonyl)[2.2]paracyclophane 20 regioselectively generates the pseudo-gem-substitution pattern. Formylation of this substrate produces the monocarbonyl derivatives 35 only, whereas the Fe-catalyzed bromination may be directed towards mono- 36 or disubstitution 37 products chemoselectively by varying the reactions conditions. The diacylation and dibromination reactions of the respective achiral diphenol 12 and bis(methoxycarbonyl) 40 derivatives of the pseudo-para-structure retain regioselectivities which are characteristic for their pseudo-meta-regioisomers. Imino ligands 26, 25, and 39, which were obtained from monoacyl- 22 and diacyldihydroxy[2.2]paracyclophanes 21, 38, are tested as chiral ligands in stereoselective Et(2)Zn addition to benzaldehyde producing 1-phenylpropanol with ee values up to 76 %.

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

PubMed

Neu, Heather M; Yang, Tzuhsiung; Baglia, Regina A; Yosca, Timothy H; Green, Michael T; Quesne, Matthew G; de Visser, Sam P; Goldberg, David P

2014-10-01

Addition of anionic donors to the manganese(V)-oxo corrolazine complex Mn(V)(O)(TBP8Cz) has a dramatic influence on oxygen-atom transfer (OAT) reactivity with thioether substrates. The six-coordinate anionic [Mn(V)(O)(TBP8Cz)(X)](-) complexes (X = F(-), N3(-), OCN(-)) exhibit a ∼5 cm(-1) downshift of the Mn-O vibrational mode relative to the parent Mn(V)(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 Mn(V)(O)(TBP8Cz) complex. A Hammett study was performed with p-X-C6H4SCH3 derivatives and [Mn(V)(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 [Mn(V)(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 Mn(V)(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 Mn(V)(O) porphyrinoid complexes.

Redox biotransformation and delivery of anthracycline anticancer antibiotics: How interpretable structure-activity relationships of lethality using electrophilicity and the London formula for dispersion interaction work.

PubMed

Pang, Siu-Kwong

2017-03-30

Quantum chemical methods and molecular mechanics approaches face a lot of challenges in drug metabolism study because of their either insufficient accuracy or huge computational cost, or lack of clear molecular level pictures for building computational models. Low-cost QSAR methods can often be carried out even though molecular level pictures are not well defined; however, they show difficulty in identifying the mechanisms of drug metabolism and delineating the effects of chemical structures on drug toxicity because a certain amount of molecular descriptors are difficult to be interpreted. In order to make a breakthrough, it was proposed that mechanistically interpretable molecular descriptors were used to correlate with biological activity to establish structure-activity plots. The mechanistically interpretable molecular descriptors used in this study include electrophilicity and the mathematical function in the London formula for dispersion interaction, and they were calculated using quantum chemical methods. The biological activity is the lethality of anthracycline anticancer antibiotics denoted as log LD50, which were obtained by intraperitoneal injection into mice. The results reveal that the plots for electrophilicity, which can be interpreted as redox reactivity of anthracyclines, can describe oxidative degradation for detoxification and reductive bioactivation for toxicity induction. The plots for the dispersion interaction function, which represent the attraction between anthracyclines and biomolecules, can describe efflux from and influx into target cells of toxicity. The plots can also identify three structural scaffolds of anthracyclines that have different metabolic pathways, resulting in their different toxicity behavior. This structure-dependent toxicity behavior revealed in the plots can provide perspectives on design of anthracycline anticancer antibiotics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

1-CHLOROMETHYLPYRENE; A SKIN SENSITIZER AND GENOTOXIN

EPA Science Inventory

1-Chloromethylpyrene has been evaluated as a model mutagen and toxin related to the ultimate electrophiles derived from BaP and 1-Nitropyren. t was mutagenic to salmonella 6100 picograms/plate) and exceptionally reactive to DNA when assessed by the postlabeling assay. MP was inac...

Bromination of Phenol

ERIC Educational Resources Information Center

Talbot, Christopher

2013-01-01

This "Science note" examines the bromination of phenol, a reaction that is commonly taught at A-level and IB (International Baccalaureate) as an example of electrophilic substitution. Phenol undergoes bromination with bromine or bromine water at room temperature. A white precipitate of 2,4,6-tribromophenol is rapidly formed. This…

Characterization and Neutralization of Recovered Lewisite Munitions

DTIC Science & Technology

2006-12-01

chlorine being rated as 1.0.51 Oxidative Species Relative Oxidizing Strength* Fluorine 2.23 Hydroxyl Radical 2.06 Atomic Oxygen 1.78 Hydrogen...containing carbon-carbon double bonds, aldehyde groups or hydroxyl groups. As an electrophile , the permnanganate ion is strongly attracted to the electrons

A Conceptual Framework for Predicting the Toxicity of Reactive Chemicals: Modeling Soft Electrophilicity

EPA Science Inventory

Although the literature is replete with QSAR models developed for many toxic effects caused by reversible chemical interactions, the development of QSARs for the toxic effects of reactive chemicals lacks a consistent approach. While limitations exit, an appropriate starting-point...

Effects of Acute Exposure to an Environmental Electrophile on Human Platelet Bioenergetics

EPA Science Inventory

Exposure to air pollution is a global public health problem associated with cardiovascular morbidity and mortality. Exposure to particulate matter (PM) has been reported to activate circulating platelets in vulnerable populations (patients with type 2 diabetes or coronary heart d...

Relationships among alcoholic liver disease, antioxidants, and antioxidant enzymes

PubMed Central

Han, Kyu-Ho; Hashimoto, Naoto; Fukushima, Michihiro

2016-01-01

Excessive consumption of alcoholic beverages is a serious cause of liver disease worldwide. The metabolism of ethanol generates reactive oxygen species, which play a significant role in the deterioration of alcoholic liver disease (ALD). Antioxidant phytochemicals, such as polyphenols, regulate the expression of ALD-associated proteins and peptides, namely, catalase, superoxide dismutase, glutathione, glutathione peroxidase, and glutathione reductase. These plant antioxidants have electrophilic activity and may induce antioxidant enzymes via the Kelch-like ECH-associated protein 1-NF-E2-related factor-2 pathway and antioxidant responsive elements. Furthermore, these antioxidants are reported to alleviate cell injury caused by oxidants or inflammatory cytokines. These phenomena are likely induced via the regulation of mitogen-activating protein kinase (MAPK) pathways by plant antioxidants, similar to preconditioning in ischemia-reperfusion models. Although the relationship between plant antioxidants and ALD has not been adequately investigated, plant antioxidants may be preventive for ALD because of their electrophilic and regulatory activities in the MAPK pathway. PMID:26755859

Relationships among alcoholic liver disease, antioxidants, and antioxidant enzymes.

PubMed

Han, Kyu-Ho; Hashimoto, Naoto; Fukushima, Michihiro

2016-01-07

Excessive consumption of alcoholic beverages is a serious cause of liver disease worldwide. The metabolism of ethanol generates reactive oxygen species, which play a significant role in the deterioration of alcoholic liver disease (ALD). Antioxidant phytochemicals, such as polyphenols, regulate the expression of ALD-associated proteins and peptides, namely, catalase, superoxide dismutase, glutathione, glutathione peroxidase, and glutathione reductase. These plant antioxidants have electrophilic activity and may induce antioxidant enzymes via the Kelch-like ECH-associated protein 1-NF-E2-related factor-2 pathway and antioxidant responsive elements. Furthermore, these antioxidants are reported to alleviate cell injury caused by oxidants or inflammatory cytokines. These phenomena are likely induced via the regulation of mitogen-activating protein kinase (MAPK) pathways by plant antioxidants, similar to preconditioning in ischemia-reperfusion models. Although the relationship between plant antioxidants and ALD has not been adequately investigated, plant antioxidants may be preventive for ALD because of their electrophilic and regulatory activities in the MAPK pathway.

Aromatic C-nitrosation of a bioactive molecule. Nitrosation of minoxidil.

PubMed

González-Jiménez, Mario; Arenas-Valgañón, Jorge; Calle, Emilio; Casado, Julio

2011-10-26

Minoxidil (2,4-diamino-6-(piperidin-1'-yl)pyrimidine N(3)-oxide; CASRN 38304-91-5) is a bioactive molecule with several nitrosatable groups widely used as an antihypertensive and antialopecia agent. Here the nitrosation of minoxidil was investigated. The conclusions drawn are as follows: (i) In the pH = 2.3-5.0 range, the minoxidil molecule undergoes aromatic C-nitrosation by nitrite. The dominant reaction was C-5 nitrosation through a mechanism that appears to consist of an electrophilic attack on the nitrosatable substrate by H(2)NO(2)(+)/NO(+), followed by a slow proton transfer; (ii) the reactivity of minoxidil as a C-nitrosatable substrate proved to be 7-fold greater than that of phenol, this being attributed to the preferred para- and ortho-orientations of the two -NH(2) groups at positions 2 and 4 of the minoxidil molecule, which activate electrophilic substitution in the C-5 position through their mesomeric effect. The N-nitrosominoxidil resulting from the nitrosation could be potentially harmful to the minoxidil users.

CO Reduction to CH3OSiMe3: Electrophile-Promoted Hydride Migration at a Single Fe Site.

PubMed

Deegan, Meaghan M; Peters, Jonas C

2017-02-22

One of the major challenges associated with developing molecular Fischer-Tropsch catalysts is the design of systems that promote the formation of C-H bonds from H 2 and CO while also facilitating the release of the resulting CO-derived organic products. To this end, we describe the synthesis of reduced iron-hydride/carbonyl complexes that enable an electrophile-promoted hydride migration process, resulting in the reduction of coordinated CO to a siloxymethyl (L n Fe-CH 2 OSiMe 3 ) group. Intramolecular hydride-to-CO migrations are extremely rare, and to our knowledge the system described herein is the first example where such a process can be accessed from a thermally stable M(CO)(H) complex. Further addition of H 2 to L n Fe-CH 2 OSiMe 3 releases CH 3 OSiMe 3 , demonstrating net four-electron reduction of CO to CH 3 OSiMe 3 at a single Fe site.

Curcumin Protects Skin against UVB-Induced Cytotoxicity via the Keap1-Nrf2 Pathway: The Use of a Microemulsion Delivery System.

PubMed

Ben Yehuda Greenwald, Maya; Frušić-Zlotkin, Marina; Soroka, Yoram; Ben Sasson, Shmuel; Bitton, Ronit; Bianco-Peled, Havazelet; Kohen, Ron

2017-01-01

Curcumin was found to be beneficial in treating several skin pathologies and diseases, providing antioxidant protection due to its reducing properties and its electrophilic properties (the ability to activate the Nrf 2 pathway and induce phase II cytoprotective enzymes). Nevertheless, clinical applications of curcumin are being hampered by its insufficient solubility, chemical instability, and poor absorption, leading to low efficacy in preventing skin pathologies. These limitations can be overcome by using a nanotechnology-based delivery system. Here, we elucidated the possibility of using curcumin encapsulated in a microemulsion preserving its unique chemical structure. We also examined whether curcumin microemulsion would reduce UVB-induced toxicity in skin. A significant curcumin concentration was found in the human skin dermis following topical application of a curcumin microemulsion. Moreover, curcumin microemulsion enhanced the reduction of UV-induced cytotoxicity in epidermal cells, paving the way for other incorporated electrophiles in encapsulated form protecting skin against stress-related diseases.

Blue M2: an intermediate melanoidin studied via conceptual DFT.

PubMed

Frau, Juan; Glossman-Mitnik, Daniel

2018-05-31

In this computational study, ten density functionals, viz. CAM-B3LYP, LC-ω PBE, M11, M11L, MN12L, MN12SX, N12, N12SX, ω B97X, and ω B97XD, related to the Def2TZVP basis sets, are assessed together with the SMD solvation model for calculation of the molecular properties and structure of blue-M2 intermediate melanoidin pigment. All the chemical reactivity descriptors for the system are calculated via conceptual density functional theory (DFT). The active sites suitable for nucleophilic, electrophilic, and radical attacks are selected by linking them with the Fukui function indices, electrophilic Parr functions, and condensed dual descriptors Δf(r), respectively. The prediction of the maximum absorption wavelength is considerably accurate relative to its experimental value. The study reveals that the MN12SX and N12SX density functionals are the most appropriate density functionals for predicting the chemical reactivity of the molecule under study.

Arenium ions are not obligatory intermediates in electrophilic aromatic substitution

PubMed Central

Galabov, Boris; Koleva, Gergana; Simova, Svetlana; Hadjieva, Boriana; Schaefer, Henry F.; Schleyer, Paul von Ragué

2014-01-01

Our computational and experimental investigation of the reaction of anisole with Cl2 in nonpolar CCl4 solution challenges two fundamental tenets of the traditional SEAr (arenium ion) mechanism of aromatic electrophilic substitution. Instead of this direct substitution process, the alternative addition–elimination (AE) pathway is favored energetically. This AE mechanism rationalizes the preferred ortho and para substitution orientation of anisole easily. Moreover, neither the SEAr nor the AE mechanisms involve the formation of a σ-complex (Wheland-type) intermediate in the rate-controlling stage. Contrary to the conventional interpretations, the substitution (SEAr) mechanism proceeds concertedly via a single transition state. Experimental NMR investigations of the anisole chlorination reaction course at various temperatures reveal the formation of tetrachloro addition by-products and thus support the computed addition–elimination mechanism of anisole chlorination in nonpolar media. The important autocatalytic effect of the HCl reaction product was confirmed by spectroscopic (UV-visible) investigations and by HCl-augmented computational modeling. PMID:24972792

Hydrotalcite-derived cobalt-aluminum mixed oxide catalysts for toluene combustion

NASA Astrophysics Data System (ADS)

Białas, Anna; Mazur, Michal; Natkański, Piotr; Dudek, Barbara; Kozak, Marek; Wach, Anna; Kuśtrowski, Piotr

2016-01-01

Hydrotalcite-like compounds (HTlcs) containing cobalt and aluminum (intended Co/Al molar ratio = 3.0) were coprecipitated at 30, 50 and 70 °C. Their crystallinity, which was confirmed by powder X-ray diffraction, increased with the precipitation temperature. Furthermore, HTlcs with various cobalt contents were prepared at 70 °C. Thermogravimetric analysis showed that HTlcs were transformed into stable oxides at 550 °C. The decrease in the crystallite size of the formed spinels with the increase in the precipitation temperature was observed. Low temperature sorption of nitrogen revealed meso-macroporous nature of the oxides with extended interparticle porosity. Aluminum segregated on the samples surface, which contained various amounts of lattice and adsorbed/electrophilic oxygen as detected by X-ray electron spectroscopy. The high ratio of lattice to adsorbed/electrophilic oxygen found for the sample with Co/Al = 3:1 caused that it turned out to be the most efficient catalyst in the total oxidation of toluene (50% conversion at 257 °C).

To the application of the emission Mössbauer and positron annihilation spectroscopies for detection of carcinogens

NASA Astrophysics Data System (ADS)

Bokov, A. V.; Byakov, V. M.; Kulikov, L. A.; Perfiliev, Yu. D.; Stepanov, S. V.

2017-11-01

Being the main cause of cancer, almost all chemical carcinogens are strong electrophiles, that is, they have a high affinity for the electron. We have shown that positron annihilation lifetime spectroscopy (PALS) is able to detect chemical carcinogens by their inhibition of positronium (Ps) formation in liquid media. Electrophilic carcinogens intercept thermalized track electrons, which are precursors of Ps, and as a result, when they are present Ps atom does not practically form. Available biophysical data seemingly indicate that frozen solutions model better an intracellular medium than the liquid ones. So it is reasonable to use emission Mössbauer spectroscopy (EMS) to detect chemical carcinogens, measuring the yield of 57Fe2+ions formed in reactions of Auger electrons and other secondary electrons they produced with 57Fe3+. These reactions are similar to the Ps formation process in the terminal part the positron track: e++ e- =>Ps. So EMS and PALS are complementary methods for detection of carcinogenic compounds.

Chemical trapping and characterization of small oxoacids of sulfur (SOS) generated in aqueous oxidations of H2S.

PubMed

Kumar, Murugaeson R; Farmer, Patrick J

2018-04-01

Small oxoacids of sulfur (SOS) are elusive molecules like sulfenic acid, HSOH, and sulfinic acid, HS(O)OH, generated during the oxidation of hydrogen sulfide, H 2 S, in aqueous solution. Unlike their alkyl homologs, there is a little data on their generation and speciation during H 2 S oxidation. These SOS may exhibit both nucleophilic and electrophilic reactivity, which we attribute to interconversion between S(II) and S(IV) tautomers. We find that SOS may be trapped in situ by derivatization with nucleophilic and electrophilic trapping agents and then characterized by high resolution LC MS. In this report, we compare SOS formation from H 2 S oxidation by a variety of biologically relevant oxidants. These SOS appear relatively long lived in aqueous solution, and thus may be involved in the observed physiological effects of H 2 S. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Total synthesis of marinomycin A using salicylate as a molecular switch to mediate dimerization

NASA Astrophysics Data System (ADS)

Evans, P. Andrew; Huang, Mu-Hua; Lawler, Michael J.; Maroto, Sergio

2012-08-01

Antibiotics play a significant role in human health because of their ability to treat life-threatening bacterial infections. The growing problems with antibiotic resistance have made the development of new antibiotics a World Health Organization priority. Marinomycin A is a member of a new class of bis-salicylate-containing polyene macrodiolides, which have potent antibiotic activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Herein, we describe a triply convergent synthesis of this agent using the salicylate as a novel molecular switch for the chemoselective construction of the macrodiolide. This strategy raises new questions regarding the biosynthetic role of the salicylate and its potential impact on the mechanism of action of these types of agents. For instance, in contrast to penicillin, which enhances the electrophilicity of the cyclic amide through ring strain, salicylates reduce the electrophilicity of the aryl ester through an intramolecular resonance-assisted hydrogen bond to provide an amide surrogate.

Noble gas bond and the behaviour of XeO3 under pressure.

PubMed

Hou, Chunju; Wang, Xianlong; Botana, Jorge; Miao, Maosheng

2017-10-18

Over the past few decades, the concept of hydrogen bonds, in which hydrogen is electrophilic, has been extended to halogen bonds, chalcogen bonds and pnicogen bonds. Herein, we show that such a non-covalent bonding also exists in noble gas compounds. Using first principles calculations, we illustrate the OXe-O bond in molecular crystal XeO 3 and its effect on the behavior of this compound under pressure. Our calculations show that the covalent Xe-O bond lengths were elongated with increasing pressure and correspondingly the Xe-O stretching vibration frequencies were red shifted, which is similar to the change of H-bonds under pressure. The OXe-O bond and related hopping of O between neighboring Xe sites also correspond to the structural changes in the XeO 3 compounds at about 2 GPa. Our study extends the concept of hydrogen bonding to include all p-block elements and show a new bonding type for Noble gas elements in which it acts as an electrophilic species.

Activation of the SN2 Reaction by Adjacent π Systems: The Critical Role of Electrostatic Interactions and of Dissociative Character.

PubMed

Robiette, Raphaël; Trieu-Van, Tran; Aggarwal, Varinder K; Harvey, Jeremy N

2016-01-27

The activation of the SN2 reaction by π systems is well documented in textbooks. It has been shown previously that this is not primarily due to classical (hyper)conjugative effects. Instead, π-conjugated substituents enhance favorable substrate-nucleophile electrostatic interactions, with electron-withdrawing groups (EWG) on the sp(2) system leading to even stronger activation. Herein we report computational and experimental results which show that this activation by sp(2) EWG-substitution only occurs in a fairly limited number of cases, when the nucleophile involves strong electrostatic interactions (usually strongly basic negatively charged nucleophiles). In other cases, where bond breaking is more advanced than bond making at the transition state, electrophile-nucleophile electrostatic interactions are less important. In such cases, (hyper)conjugative electronic effects determine the reactivity, and EWG-substitution leads to decreased reactivity. The basicity of the nucleophile as well as solvent effects can help to determine which of these two regimes occurs for a given electrophile.

Curcumin Protects Skin against UVB-Induced Cytotoxicity via the Keap1-Nrf2 Pathway: The Use of a Microemulsion Delivery System

PubMed Central

Ben Yehuda Greenwald, Maya; Frušić-Zlotkin, Marina; Soroka, Yoram; Ben Sasson, Shmuel; Bitton, Ronit; Bianco-Peled, Havazelet

2017-01-01

Curcumin was found to be beneficial in treating several skin pathologies and diseases, providing antioxidant protection due to its reducing properties and its electrophilic properties (the ability to activate the Nrf2 pathway and induce phase II cytoprotective enzymes). Nevertheless, clinical applications of curcumin are being hampered by its insufficient solubility, chemical instability, and poor absorption, leading to low efficacy in preventing skin pathologies. These limitations can be overcome by using a nanotechnology-based delivery system. Here, we elucidated the possibility of using curcumin encapsulated in a microemulsion preserving its unique chemical structure. We also examined whether curcumin microemulsion would reduce UVB-induced toxicity in skin. A significant curcumin concentration was found in the human skin dermis following topical application of a curcumin microemulsion. Moreover, curcumin microemulsion enhanced the reduction of UV-induced cytotoxicity in epidermal cells, paving the way for other incorporated electrophiles in encapsulated form protecting skin against stress-related diseases. PMID:28757910

Identification of Protein Targets of 12/15-Lipoxygenase-Derived Lipid Electrophiles in Mouse Peritoneal Macrophages Using Omega-Alkynyl Fatty Acid.

PubMed

Isobe, Yosuke; Kawashima, Yusuke; Ishihara, Tomoaki; Watanabe, Kenji; Ohara, Osamu; Arita, Makoto

2018-04-20

The 12/15-lipoxygenase (12/15-LOX) enzyme introduces peroxyl groups, in a position-specific manner, into polyunsaturated fatty acids to form various kinds of bioactive lipid metabolites, including lipid-derived electrophiles (LDE). The resident peritoneal macrophage is the site of highest 12/15-LOX expression in the mouse. However, the role of the enzyme in the regulation of resident macrophages is not fully understood. Here, we describe a chemoproteomic method to identify the targets of enzymatically generated LDE. By treating mouse peritoneal macrophages with omega-alkynyl arachidonic acid (aAA), we identified a series of proteins adducted by LDE generated through a 12/15-LOX catalyzed reaction. Pathway analysis revealed a dramatic enrichment of proteins involved in energy metabolism and found that glycolytic flux and mitochondrial respiration were significantly affected by the expression of 12/15-LOX. Our findings thus highlight the utility of chemoproteomics using aAA for identifying intracellular targets of enzymatically generated LDE.

Induction of quinone reductase (QR) by withanolides isolated from Physalis pubescens L. (Solanaceae).

PubMed

Ji, Long; Yuan, Yonglei; Ma, Zhongjun; Chen, Zhe; Gan, Lishe; Ma, Xiaoqiong; Huang, Dongsheng

2013-09-01

In the present study, it was demonstrated that the dichloromethane extract of Physalis pubescens L. (DEPP) had weak potential quinone reductase (QR) inducing activity, but an UPLC-ESI-MS method with glutathione (GSH) as the substrate revealed that the DEPP had electrophiles (with an α,β-unsaturated ketone moiety). These electrophiles could induce quinone reductase (QR) activity, which might be attributed to the modification of the highly reactive cysteine residues in Keap1. Herein, four withanolides, including three new compounds physapubescin B (2), physapubescin C (3), physapubescin D (4), together with one known steroidal compound physapubescin (1) were isolated. Structures of these compounds were determined by spectroscopic analysis and that of physapubescin C (3) was confirmed by a combination of molecular modeling and quantum chemical DFT-GIAO calculations. Evaluation of the QR inducing activities of all withanolides indicated potent activities of compounds 1 and 2, which had a common α,β-unsaturated ketone moiety. Copyright © 2013 Elsevier Ltd. All rights reserved.

Multiple schwannomatosis caused by the recently described INI1 gene--molecular pathology, and implications for prognosis.

PubMed

Brennan, Paul M; Barlow, Antonio; Geraghty, Alistair; Summers, David; Fitzpatrick, Michael M

2011-06-01

The most common genetic predisposition to multiple schwannoma growth is mutation of the neurofibromatosis type 2 gene. We describe a patient with multiple schwannomas and mutation in the recently described INI1 gene, which also predisposes to the disease. We explore the implications for prognosis and outcome.

Carborane Burning Rate Modifiers

DTIC Science & Technology

1980-03-20

octyne, 1-pentyne and 5-chloro-l-pentyne) are much smaller than those of the less electrophilic acetylenes. - The values of AHt reflect the... fluorine containing derivatives (III) and (V) were prepared by re- acting (I) and (II) with excess PF5 in hexane. Thus, 0.0032 moles of the carborane

Tunable Artificial Receptor as a Chemical Sensor for V- and G-agents

DTIC Science & Technology

2012-06-01

shows the design concept for a fluorescent tether. The highly electrophilic nature of fluorescein required the used of carefully selected protecting...atoms removed for clarity) and a space-filling model (Key to figures: carbon: grey; oxygen: red; nitrogen: blue; phosphorus: orange; fluorine : yellow

Evaluation of functionalized SBA-15 to reduce patulin levels in apple juice

USDA-ARS?s Scientific Manuscript database

Patulin is a low molecular weight mycotoxin associated with the apple rotting fungus, Penicillium expansum. This toxin possesses an electrophilic conjugated double bond system susceptible to formation of harmful adducts with important biomolecules, such as glutathione, proteins, and DNA. In this stu...

Identification of potential genomic biomarkers of hepatotoxicity caused by reactive metabolites of N-methylformamide: Application of stable isotope labeled compounds in toxicogenomic studies.

PubMed

Mutlib, Abdul; Jiang, Ping; Atherton, Jim; Obert, Leslie; Kostrubsky, Seva; Madore, Steven; Nelson, Sidney

2006-10-01

The inability to predict if a metabolically bioactivated compound will cause toxicity in later stages of drug development or post-marketing is of serious concern. One approach for improving the predictive success of compound toxicity has been to compare the gene expression profile in preclinical models dosed with novel compounds to a gene expression database generated from compounds with known toxicity. While this guilt-by-association approach can be useful, it is often difficult to elucidate gene expression changes that may be related to the generation of reactive metabolites. In an effort to address this issue, we compared the gene expression profiles obtained from animals treated with a soft-electrophile-producing hepatotoxic compound against corresponding deuterium labeled analogues resistant to metabolic processing. Our aim was to identify a subset of potential biomarker genes for hepatotoxicity caused by soft-electrophile-producing compounds. The current study utilized a known hepatotoxic compound N-methylformamide (NMF) and its two analogues labeled with deuterium at different positions to block metabolic oxidation at the formyl (d(1)) and methyl (d(3)) moieties. Groups of mice were dosed with each compound, and their livers were harvested at different time intervals. RNA was prepared and analyzed on Affymetrix GeneChip arrays. RNA transcripts showing statistically significant changes were identified, and selected changes were confirmed using TaqMan RT-PCR. Serum clinical chemistry and histopathologic evaluations were performed on selected samples as well. The data set generated from the different groups of animals enabled us to determine which gene expression changes were attributed to the bioactivating pathway. We were able to selectively modulate the metabolism of NMF by labeling various positions of the molecule with a stable isotope, allowing us to monitor gene changes specifically due to a particular metabolic pathway. Two groups of genes were identified, which were associated with the metabolism of a certain part of the NMF molecule. The metabolic pathway leading to the production of reactive methyl isocyanate resulted in distinct expression patterns that correlated with histopathologic findings. There was a clear correlation between the expression of certain genes involved in the cell cycle/apoptosis and inflammatory pathways and the presence of reactive metabolite. These genes may serve as potential genomic biomarkers of hepatotoxicity induced by soft-electrophile-producing compounds. However, the robustness of these potential genomic biomarkers will need to be validated using other hepatotoxicants (both soft- and hard-electrophile-producing agents) and compounds known to cause idiosyncratic liver toxicity before being adopted into the drug discovery screening process.

Chemistry of the oxophosphinidene ligand. 2. Reactivity of the anionic complexes [MCp{P(O)R*}(CO)(2)](-) (M = Mo, W; R* = 2,4,6-C(6)H(2)(t)Bu(3)) toward electrophiles based on elements different from carbon.

PubMed

Alonso, María; Alvarez, M Angeles; García, M Esther; Ruiz, Miguel A; Hamidov, Hayrullo; Jeffery, John C

2010-12-20

The anionic oxophosphinidene complexes (H-DBU)[MCp{P(O)R*}(CO)(2)] (M = Mo, W; R* = 2,4,6-C(6)H(2)(t)Bu(3); Cp = η(5)-C(5)H(5), DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene) displayed multisite reactivity when faced with different electrophilic reagents. The reactions with the group 14 organochloride compounds ER(4-x)Cl(x) (E = Si, Ge, Sn, Pb) led to either phosphide-like, oxophosphinidene-bridged derivatives [MCp{P(OE')R*}(CO)(2)] (E' = SiMe(3), SiPh(3), GePh(3), GeMe(2)Cl) or to terminal oxophosphinidene complexes [MCp{P(O)R*}(CO)(2)(E')] (E' = SnPh(3), SnPh(2)Cl, PbPh(3); Mo-Pb = 2.8845(4) Å for the MoPb compound). A particular situation was found in the reaction with SnMe(3)Cl, this giving a product existing in both tautomeric forms, with the phosphide-like complex [MCp{P(OSnMe(3))R*}(CO)(2)] prevailing at room temperature and the tautomer [MCp{P(O)R*}(CO)(2)(SnMe(3))] being the unique species present below 203 K in dichloromethane solution. The title anions also showed a multisite behavior when reacting with transition-metal based electrophiles. Thus, the reactions with the complexes [M'Cp(2)Cl(2)] (M' = Ti, Zr) gave phosphide-like derivatives [MCp{P(OM')R*}(CO)(2)] (M = Mo, M' = TiCp(2)Cl, ZrCp(2)Cl; M = W, M' = ZrCp(2)Cl), displaying a bridging κ(1),κ(1)-P,O- oxophosphinidene ligand connecting MCp(CO)(2) and M'Cp(2)Cl metal fragments (W-P = 2.233(1) Å, O-Zr = 2.016(4) Å for the WZr compound]. In contrast, the reactions with the complex [AuCl{P(p-tol)(3)}] gave the metal-metal bonded derivatives trans-[MCp{P(O)R*}(CO)(2){AuP(p-tol)(3)}] (M = Mo, W; Mo-Au = 2.7071(7) Å). From all the above results it was concluded that the terminal oxophosphinidene complexes are preferentially formed under conditions of orbital control, while charge-controlled reactions tend to give derivatives with the electrophilic fragment bound to the oxygen atom of the oxophosphinidene ligand (phosphide-like, oxophosphinidene-bridged derivatives).

Hydroxylation of p-substituted phenols by tyrosinase: Further insight into the mechanism of tyrosinase activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Munoz-Munoz, Jose Luis; Berna, Jose; Garcia-Molina, Maria del Mar

2012-07-27

Highlights: Black-Right-Pointing-Pointer The action the copper complexes and tyrosinase on phenols is equivalent. Black-Right-Pointing-Pointer Isotope effect showed that nucleophilic attack to copper atom may be the slower step. Black-Right-Pointing-Pointer The value of {rho} (Hammett constant) supports an electrophilic aromatic substitution. Black-Right-Pointing-Pointer Data obtained in steady state pH 7 conditions support the mechanism of Scheme 1SM. -- Abstract: A study of the monophenolase activity of tyrosinase by measuring the steady state rate with a group of p-substituted monophenols provides the following kinetic information: k{sub cat}{sup m} and the Michaelis constant, K{sub M}{sup m}. Analysis of these data taking into account chemicalmore » shifts of the carbon atom supporting the hydroxyl group ({delta}) and {sigma}{sub p}{sup +}, enables a mechanism to be proposed for the transformation of monophenols into o-diphenols, in which the first step is a nucleophilic attack on the copper atom on the form E{sub ox} (attack of the oxygen of the hydroxyl group of C-1 on the copper atom) followed by an electrophilic attack (attack of the hydroperoxide group on the ortho position with respect to the hydroxyl group of the benzene ring, electrophilic aromatic substitution with a reaction constant {rho} of -1.75). These steps show the same dependency on the electronic effect of the substituent groups in C-4. Furthermore, a study of a solvent deuterium isotope effect on the oxidation of monophenols by tyrosinase points to an appreciable isotopic effect. In a proton inventory study with a series of p-substituted phenols, the representation of k{sub cat}{sup f{sub n}}/k{sub cat}{sup f{sub 0}} against n (atom fractions of deuterium), where k{sub cat}{sup f{sub n}} is the catalytic constant for a molar fraction of deuterium (n) and k{sub cat}{sup f{sub 0}} is the corresponding kinetic parameter in a water solution, was linear for all substrates. These results indicate that only one of the proton transfer processes from the hydroxyl groups involved the catalytic cycle is responsible for the isotope effects. We suggest that this step is the proton transfer from the hydroxyl group of C-1 to the peroxide of the oxytyrosinase form (E{sub ox}). After the nucleophilic attack, the incorporation of the oxygen in the benzene ring occurs by means of an electrophilic aromatic substitution mechanism in which there is no isotopic effect.« less

The Multiple-Use of Accountability Assessments: Implications for the Process of Validation

ERIC Educational Resources Information Center

Koch, Martha J.

2014-01-01

Implications of the multiple-use of accountability assessments for the process of validation are examined. Multiple-use refers to the simultaneous use of results from a single administration of an assessment for its intended use and for one or more additional uses. A theoretical discussion of the issues for validation which emerge from…

Structure and Bonding analysis of the cationic electrophilic phosphinidene complexes of iron, ruthenium, and osmium [(η(5)-C5Me5)(CO)2M{PN(i)Pr2}]+, [(η(5)-C5H5)(CO)2M{PNR2}]+ (R = Me, (i)Pr), and [(η(5)-C5H5)(PMe3)2M{PNMe2}]+ (M = Fe, Ru, Os).

PubMed

Pandey, Krishna K; Tiwari, Pradeep; Patidar, Pankaj

2012-11-29

Quantum-chemical DFT calculations for the electronic, molecular structure and M-PNR(2) bonding analyses of the experimentally known cationic electrophilic phosphinidene complexes [(η(5)-C(5)Me(5))(CO)(2)M{PN(i)Pr(2)}](+) and of the model complexes [(η(5)-C(5)H(5))(CO)(2)M{PNR(2)}](+) (R = (i)Pr, Me) and [(η(5)-C(5)H(5))(PMe(3))(2)M{PNMe(2)}](+) were carried out using BP86/TZ2P/ZORA level of theory. The calculated geometrical parameters of the studied complexes are in good agreement with the reported experimental values. The short M-P bond distances and calculated Pauling bond orders (range of 1.23-1.68), suggest the presence of M-P multiple bond characters. The Hirshfeld charge analysis shows that the overall charge flows from phosphinidene ligand to metal fragment. The M-P σ-bonding orbitals are well-occupied (>1.80e). The energy decomposition analysis revealed that the contribution of the electrostatic interaction ΔE(elstat) is, in all studied complexes, significantly larger (55.2-62.6%) than the orbital interactions ΔE(orb). The orbital interactions between metal and PNR(2) in [(η(5)-C(5)H(5))(L)(2)M{PNR(2)}](+) arise mainly from M ← PNR(2) σ-donation. The π-bonding contribution (19-36%) is much smaller than the σ-bonding. The interaction energies, as well as bond dissociation energies, depend on the auxiliary ligand framework around the metal and decrease in the order (η(5)-C(5)H(5)) > (η(5)-C(5)Me(5)) and CO > PMe(3). Upon substitution of R = (i)Pr with smaller group R = Me, the M-PNR(2) bond strength slightly decreases.

Investigating Mitochondrial Dysfunction in Human Lung Cells Exposed to Redox-Active PM Components

EPA Science Inventory

Exposure to ambient particulate matter (PM) causes cardiopulmonary morbidity and mortality through mechanisms that involve oxidative stress. 1,2-naphthoquinone (1,2-NQ) is a ubiquitous component of PM and a potent redox-active electrophile. We previously reported that 1,2-NQ incr...

Discovering More Chemical Concepts from 3D Chemical Information Searches of Crystal Structure Databases

ERIC Educational Resources Information Center

Rzepa, Henry S.

2016-01-01

Three new examples are presented illustrating three-dimensional chemical information searches of the Cambridge structure database (CSD) from which basic core concepts in organic and inorganic chemistry emerge. These include connecting the regiochemistry of aromatic electrophilic substitution with the geometrical properties of hydrogen bonding…

Synthesis of Bisphenol Z: An Organic Chemistry Experiment

ERIC Educational Resources Information Center

Gregor, Richard W.

2012-01-01

A student achievable synthesis of bisphenol Z, 4,4'-(cyclohexane-1,1-diyl)diphenol, from the acid-catalyzed reaction of phenol with cyclohexanone is presented. The experiment exemplifies all the usual pedagogy for the standard topic of electrophilic aromatic substitution present in the undergraduate organic chemistry curriculum, while providing…

Halogenation of cobalt dicarbollide

DOEpatents

Hurlburt, P.K.; Abney, K.D.; Kinkead, S.A.

1997-05-20

A method for selectively adding chlorine, bromine, or iodine to cobalt dicarbollide anions by means of electrophilic substitution reactions. Halogens are added only to the B10 and B10{prime} positions of the anion. The process involves use of hypohalous acid or N-halosuccinimide or gaseous chlorine in the presence of iron. 1 fig.

Electrophilic aromatic substitution of catechins: Bromination and benzylation

Treesearch

G.W. McGraw; Richard W. Hemingway

1982-01-01

Relative yields of C-6, C-8. and C-6 and C-8 substituted catechins obtained from the reaction of (+)-catechin or 3',4',5-7-tetra-O-methyl-(+)-catechin with pyridinium hydrobromide-perbromide, bromine, p-hydroxybenzyl alcohol, or o-hydroxybenzyl alcohol showed differing selectivities depending upon the...

A fluorescence high throughput screening method for the detection of reactive electrophiles as potential skin sensitizers

USDA-ARS?s Scientific Manuscript database

Skin sensitization is an important toxicological end-point in the risk assessment of chemical allergens. Because of the complexity of the biological mechanisms associated with skin sensitization integrated approaches combining different chemical, biological and in silico methods are recommended to r...

Heme-Containing Metal-Organic Frameworks for the Oxidative Degradation of Chemical Warfare Agents

DTIC Science & Technology

2016-04-14

stability of the oxo without sacrificing its inherent reactivity, we have synthesized a new framework featuring fluorinated groups in the ortho...especially suitable for the degradation of electrophilic phosphorous center, leading to the cleavage of P-S or P-O bond present in VX nerve agents

Characterization and Neutralization of Arsenical-Based WWII Era Chemical Munition Fills

DTIC Science & Technology

2006-08-01

Fluorine 2.23 Hydroxyl Radical 2.06 Atomic Oxygen 1.78 Hydrogen Peroxide 1.31 Perhydroxyl Radical 1.25 Permanganate 1.24 Hypobromous Acid 1.17 Chlorine...containing carbon-carbon double bonds, aldehyde groups or hydroxyl groups. As an electrophile , the permanganate ion is strongly attracted to the

Collaborative Center in Polymer Photonics

DTIC Science & Technology

2006-07-07

to deposit, it "sees" an oxide surface and the polymer formed is deficient in fluorine as compared to the remainder of the film. Once the oxide is...amounts of oxidant and lower reaction temperatures. Functionalization of pyrene at the 2- and 7- positions was carried out via electrophilic substitution

Structure and Properties of Intercalated Graphite Fiber-Polymer Composites.

DTIC Science & Technology

1983-07-07

resistivities of all com- nal graphite. Experimental evidence (1,2) in- plexes were determined both before and after dicated that the electrophilic N02...others show promise as fluorinating agents in chemical synthesisI21. At this point, however, so little is Known of processing parameters and long-term

Halogenation of cobalt dicarbollide

DOEpatents

Hurlburt, Paul K.; Abney, Kent D.; Kinkead, Scott A.

1997-01-01

A method for selectively adding chlorine, bromine, or iodine to cobalt dicarbollide anions by means of electrophilic substitution reactions. Halogens are added only to the B10 and B10' positions of the anion. The process involves use of hypohalous acid or N-halosuccinimide or gaseous chlorine in the presence of iron.

Nitration of Phenols Using Cu(NO[subscript 3])[subscript 2]: Green Chemistry Laboratory Experiment

ERIC Educational Resources Information Center

Yadav, Urvashi; Mande, Hemant; Ghalsasi, Prasanna

2012-01-01

An easy-to-complete, microwave-assisted, green chemistry, electrophilic nitration method for phenol using Cu(NO[subscript 3])[subscript 2] in acetic acid is discussed. With this experiment, students clearly understand the mechanism underlying the nitration reaction in one laboratory session. (Contains 4 schemes.)

Chemical Screening for Bioactivated Electrophilic Metabolites Using Alginate Immobilization of Metabolic Enzymes (AIME) (SOT)

EPA Science Inventory

The US EPA's ToxCast program is designed to assess chemical perturbations of molecular and cellular endpoints using a variety of high-throughput screening (HTS) assays. However, existing HTS assays have limited or no xenobiotic metabolism which could lead to a mischaracterization...

A Computational Study of Structure and Reactivity of N-Substitued-4-Piperidones Curcumin Analogues and Their Radical Anions.

PubMed

Martínez-Cifuentes, Maximiliano; Weiss-López, Boris; Araya-Maturana, Ramiro

2016-12-02

In this work, a computational study of a series of N -substitued-4-piperidones curcumin analogues is presented. The molecular structure of the neutral molecules and their radical anions, as well as their reactivity, are investigated. N -substituents include methyl and benzyl groups, while substituents on the aromatic rings cover electron-donor and electron-acceptor groups. Substitutions at the nitrogen atom do not significantly affect the geometry and frontier molecular orbitals (FMO) energies of these molecules. On the other hand, substituents on the aromatic rings modify the distribution of FMO. In addition, they influence the capability of these molecules to attach an additional electron, which was studied through adiabatic (AEA) and vertical electron affinities (VEA), as well as vertical detachment energy (VDE). To study electrophilic properties of these structures, local reactivity indices, such as Fukui ( f ⁺) and Parr ( P ⁺) functions, were calculated, and show the influence of the aromatic rings substituents on the reactivity of α,β-unsaturated ketones towards nucleophilic attack. This study has potential implications for the design of curcumin analogues based on a 4-piperidone core with desired reactivity.

Reaction of singlet-excited 2,3-diazabicyclo[2.2.2]oct-2-ene and tert-butoxyl radicals with aryl-substituted benzofuranones.

PubMed

Lundgren, Cecilia Vannesjö; Koner, Apurba L; Tinkl, Michael; Pischel, Uwe; Nau, Werner M

2006-03-03

5,7-Di-tert-butyl-3-aryl-3H-benzofuran-2-ones are lactones with potential antioxidant activity, owing to their abstractable benzylic C-H hydrogens. The fluorescence quenching of the azoalkane 2,3-diazabicyclo[2.2.2]oct-2-ene (DBO), an established probe for the hydrogen-donor propensity of chain-breaking antioxidants, was investigated for 16 aryl-substituted benzofuranone derivatives [m,m-(CF3)2, p-CN, m-CN, p-CF3, p-COOCH3, m-CF3, p-Cl, p-F, H, m-CH3, p-CH3, m,p-(CH3)2, p-OCH3, o-CH3, o-CF3, o,m-(CH3)2]. Analysis of the rate data in terms of a linear free energy relationship yielded a reaction constant of rho = +0.35. This implies that n,pi*-excited DBO acts as nucleophilic species. In contrast, hydrogen abstraction of tert-butoxyl radicals from the benzofuranones was accelerated by electron-donating substituents (rho = -0.23), in conformity with the electrophilic character of oxygen-centered alkoxyl radicals. Possible implications for the optimization of the hydrogen-donor propensity of antioxidants through structural variation are discussed.

Molecular insights into cancer therapeutic effects of the dietary medicinal phytochemical withaferin A.

PubMed

Chirumamilla, Chandra Sekhar; Pérez-Novo, Claudina; Van Ostade, Xaveer; Vanden Berghe, Wim

2017-05-01

Despite the worldwide research efforts to combat cancer, it remains a leading cause of death. Although various specific kinase inhibitors already have been approved for clinical cancer treatment, occurrence of intrinsic or acquired resistance and intermittent response over longer periods limits long-term success of single kinase-targeted therapies. In this respect, there is a renewed interest in polypharmaceutical natural compounds, which simultaneously target various hyperactivated kinases involved in tumour-inflammation, angiogenesis, cell survival, proliferation, metastasis and angiogenesis. The dietary medicinal phytochemical withaferin A (WA), isolated from Withaferin somnifera (popular Indian name Ashwagandha), holds promise as a novel anti-cancer agent, which targets multiple cell survival kinase pathways, including IκB kinase/NF-κB, PI3 kinase/protein kinase B/mammalian target of rapamycin and mitogen-activated protein kinase/extracellular signal-regulated kinase amongst others. In this review, we propose a novel mechanism of WA-dependent kinase inhibition via electrophilic covalent targeting of cysteine residues in conserved kinase activation domains (kinase cysteinome), which could underlie its pleiotropic therapeutic effects in cancer signalling.

Palladium-Catalyzed Asymmetric Allylic Alkylation of 3-Substituted 1 H-Indoles and Tryptophan Derivatives with Vinylcyclopropanes.

PubMed

Trost, Barry M; Bai, Wen-Ju; Hohn, Christoph; Bai, Yu; Cregg, James J

2018-05-30

Vinylcyclopropanes (VCPs) are known to generate 1,3-dipoles with a palladium catalyst that initially serve as nucleophiles to undergo [3 + 2] cycloadditions with electron-deficient olefins. In this report, we reverse this reactivity and drive the 1,3-dipoles to serve as electrophiles by employing 3-alkylated indoles as nucleophiles. This represents the first use of VCPs for the completely atom-economic functionalization of 3-substituted 1 H-indoles and tryptophan derivatives via a Pd-catalyzed asymmetric allylic alkylation (Pd-AAA). Excellent yields and high chemo-, regio-, and enantioselectivities have been realized, providing various indolenine and indoline products. The method is amenable to gram scale and works efficiently with tryptophan derivatives that contain a diketopiperazine or diketomorpholine ring, allowing us to synthesize mollenine A in a rapid and ligand-controlled fashion. The obtained indolenine products bear an imine, an internal olefin, and a malonate motif, giving multiple sites with diverse reactivities for product diversification. Complicated polycyclic skeletons can be conveniently constructed by leveraging this unique juxtaposition of functional groups.

The RclR Protein Is a Reactive Chlorine-specific Transcription Factor in Escherichia coli *

PubMed Central

Parker, Benjamin W.; Schwessinger, Emily A.; Jakob, Ursula; Gray, Michael J.

2013-01-01

Reactive chlorine species (RCS) such as hypochlorous acid are powerful antimicrobial oxidants. Used extensively for disinfection in household and industrial settings (i.e. as bleach), RCS are also naturally generated in high quantities during the innate immune response. Bacterial responses to RCS are complex and differ substantially from the well characterized responses to other physiologically relevant oxidants, like peroxide or superoxide. Several RCS-sensitive transcription factors have been identified in bacteria, but most of them respond to multiple stressors whose damaging effects overlap with those of RCS, including reactive oxygen species and electrophiles. We have now used in vivo genetic and in vitro biochemical methods to identify and demonstrate that Escherichia coli RclR (formerly YkgD) is a redox-regulated transcriptional activator of the AraC family, whose highly conserved cysteine residues are specifically sensitive to oxidation by RCS. Oxidation of these cysteines leads to strong, highly specific activation of expression of genes required for survival of RCS stress. These results demonstrate the existence of a widely conserved bacterial regulon devoted specifically to RCS resistance. PMID:24078635

Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol

DOE PAGES

Goedken, Eric R.; Argiriadi, Maria A.; Banach, David L.; ...

2014-12-31

The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. In this paper, we have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). Wemore » found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC 50 < 100 nM) inhibit Jak3 activity in cell-based assays. Finally, these results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases.« less

Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goedken, Eric R.; Argiriadi, Maria A.; Banach, David L.

The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. In this paper, we have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). Wemore » found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC 50 < 100 nM) inhibit Jak3 activity in cell-based assays. Finally, these results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases.« less

The RclR protein is a reactive chlorine-specific transcription factor in Escherichia coli.

PubMed

Parker, Benjamin W; Schwessinger, Emily A; Jakob, Ursula; Gray, Michael J

2013-11-08

Reactive chlorine species (RCS) such as hypochlorous acid are powerful antimicrobial oxidants. Used extensively for disinfection in household and industrial settings (i.e. as bleach), RCS are also naturally generated in high quantities during the innate immune response. Bacterial responses to RCS are complex and differ substantially from the well characterized responses to other physiologically relevant oxidants, like peroxide or superoxide. Several RCS-sensitive transcription factors have been identified in bacteria, but most of them respond to multiple stressors whose damaging effects overlap with those of RCS, including reactive oxygen species and electrophiles. We have now used in vivo genetic and in vitro biochemical methods to identify and demonstrate that Escherichia coli RclR (formerly YkgD) is a redox-regulated transcriptional activator of the AraC family, whose highly conserved cysteine residues are specifically sensitive to oxidation by RCS. Oxidation of these cysteines leads to strong, highly specific activation of expression of genes required for survival of RCS stress. These results demonstrate the existence of a widely conserved bacterial regulon devoted specifically to RCS resistance.

Cytochrome P450 humanised mice

PubMed Central

2004-01-01

Humans are exposed to countless foreign compounds, typically referred to as xenobiotics. These can include clinically used drugs, environmental pollutants, food additives, pesticides, herbicides and even natural plant compounds. Xenobiotics are metabolised primarily in the liver, but also in the gut and other organs, to derivatives that are more easily eliminated from the body. In some cases, however, a compound is converted to an electrophile that can cause cell toxicity and transformation leading to cancer. Among the most important xenobiotic-metabolising enzymes are the cytochromes P450 (P450s). These enzymes represent a superfamily of multiple forms that exhibit marked species differences in their expression and catalytic activities. To predict how humans will metabolise xenobiotics, including drugs, human liver extracts and recombinant P450s have been used. New humanised mouse models are being developed which will be of great value in the study of drug metabolism, pharmacokinetics and pharmacodynamics in vivo, and in carrying out human risk assessment of xenobiotics. Humanised mice expressing CYP2D6 and CYP3A4, two major drug-metabolising P450s, have revealed the feasibility of this approach. PMID:15588489

Electrophilic trifluoromethylselenolation of terminal alkynes with Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate.

PubMed

Ghiazza, Clément; Tlili, Anis; Billard, Thierry

2017-01-01

Herein the nucleophilic addition of Se -(trifluoromethyl) 4-methylbenzenesulfonoselenoate, a stable and easy-to-handle reagent, to alkynes is described. This reaction provides trifluoromethylselenylated vinyl sulfones with good results and the method was extended also to higher fluorinated homologs. The obtained compounds are valuable building blocks for further syntheses of fluoroalkylselenolated molecules.

What Happens when Representations Fail to Represent? Graduate Students' Mental Models of Organic Chemistry Diagrams

ERIC Educational Resources Information Center

Strickland, Amanda M.; Kraft, Adam; Bhattacharyya, Gautam

2010-01-01

As part of our investigations into the development of representational competence, we report results from a study in which we elicited sixteen graduate students' expressed mental models of commonly-used terms for describing organic reactions--functional group, nucleophile/electrophile, acid/base--and for diagrams of transformations and their…

The NBS Reaction: A Simple Explanation for the Predominance of Allylic Substitution over Olefin Addition by Bromine at Low Concentrations.

ERIC Educational Resources Information Center

Wamser, Carl C.; Scott, Lawrence T.

1985-01-01

Examines mechanisms related to use of N-bromosuccinimide (NBS) for bromination at an allylic position. Also presents derived rate laws for three possible reactions of molecular bromine with an alkene: (1) free radical substitution; (2) free radical addition; and (3) electrophilic addition. (JN)

Aromatic Substitution Reactions: When You've Said Ortho, Meta, and Para, You Haven't Said It All.

ERIC Educational Resources Information Center

Traynham, James G.

1983-01-01

Recent investigations show that the ipso position competes effectively with unsubstituted positions in many aromatic substitution reactions, regardless of charge type of reaction. Selected examples available for nucleophilic, electrophilic, and free radical reactions are reviewed to suggest the range of ipso reactions. (JN)

FACTORS AFFECTING THE ELECTROPHILICITY AND NUCLEOPHILICITY OF REAGENTS.

DTIC Science & Technology

The apparent simplicity of the reactions of Malachite Green cation (bis-(p-dimethylaminophenyl), phenylmethyl cation) with nucleophilic reagents...initiated to study the rates of the reactions of a series of Malachite Green cations with a number of nucleophilies in several dipolar aprotic solvents, and the same reactions in water for comparison. (Author)

Fischer and Schrock Carbene Complexes: A Molecular Modeling Exercise

ERIC Educational Resources Information Center

Montgomery, Craig D.

2015-01-01

An exercise in molecular modeling that demonstrates the distinctive features of Fischer and Schrock carbene complexes is presented. Semi-empirical calculations (PM3) demonstrate the singlet ground electronic state, restricted rotation about the C-Y bond, the positive charge on the carbon atom, and hence, the electrophilic nature of the Fischer…

Recent Advances in Cyanamide Chemistry: Synthesis and Applications.

PubMed

Prabhath, M R Ranga; Williams, Luke; Bhat, Shreesha V; Sharma, Pallavi

2017-04-12

The application of alkyl and aryl substituted cyanamides in synthetic chemistry has diversified multi-fold in recent years. In this review, we discuss recent advances (since 2012) in the chemistry of cyanamides and detail their application in cycloaddition chemistry, aminocyanation reactions, as well as electrophilic cyanide-transfer agents and their unique radical and coordination chemistry.

New Bouncing Curved Arrow Technique for the Depiction of Organic Mechanisms

ERIC Educational Resources Information Center

Straumanis, Andrei R.; Ruder, Suzanne M.

2009-01-01

Many students fail to develop a conceptual understanding of organic chemistry. Evidence suggests this failure goes hand-in-hand with a failure to grasp the techniques, meaning, and usefulness of curved arrow notation. Use of curved arrow notation to illustrate electrophilic addition appears to be a critical juncture in student understanding.…

Reactivity III: An Advanced Course in Integrated Organic, Inorganic, and Biochemistry

ERIC Educational Resources Information Center

Schaller, Chris P.; Graham, Kate J.; Jakubowski, Henry V.

2017-01-01

Reactivity III is a new course that presents chemical reactions from the domains of organic, inorganic, and biochemistry that are not readily categorized by electrophile-nucleophile interactions. Many of these reactions involve the transfer of a single electron, in either an intermolecular fashion in the case of oxidation/reduction reactions or an…

Electronic contributions to the sigma(p) parameter of the Hammett equation.

PubMed

Domingo, Luis R; Pérez, Patricia; Contreras, Renato

2003-07-25

A statistical procedure to obtain the intrinsic electronic contributions to the Hammett substituent constant sigma(p) is reported. The method is based on the comparison between the experimental sigma(p) values and the electronic electrophilicity index omega evaluated for a series of 42 functional groups commonly present in organic compounds.

Measuring the Bioenergetic Effects of 1,2-Naphthoquinone Exposure on Human Lung Macrophages Using Seahorse Extracellular Flux Analyses

EPA Science Inventory

Exposure to ambient particulate matter (PM) is one of the leading causes of morbidity and mortality in humans. Quinones are organic PM components that induce inflammatory responses through redox cycling and electrophilic attack. 1,2-naphthoquinone (1,2-NQ) has previously been sho...

A Multistep Synthesis Incorporating a Green Bromination of an Aromatic Ring

ERIC Educational Resources Information Center

Cardinal, Pascal; Greer, Brandon; Luong, Horace; Tyagunova, Yevgeniya

2012-01-01

Electrophilic aromatic substitution is a fundamental topic taught in the undergraduate organic chemistry curriculum. A multistep synthesis that includes a safer and greener method for the bromination of an aromatic ring than traditional bromination methods is described. This experiment is multifaceted and can be used to teach students about…

Cytoprotection of Human Endothelial Cells From Menadione Cytotoxicity by Caffeic Acid Phenethyl Ester: The Role of Heme Oxygenase-1

DTIC Science & Technology

2008-06-08

reported here show that CAPE induces HO-1 in human endothelial cells. The major signaling transduction involved in HO-1 induction by those electrophilic ...phenethyl ester (CAPE) and catechol ring- fluorinated CAPE derivatives against menadione-induced oxidative stress in human endothelial cells. Bioorganic

Advanced, Non-Toxic, Anti-Corrosion, Anti-Fouling and Foul-Release Coatings Based on Covalently Attached Monolayers, Multilayers and Polymers

DTIC Science & Technology

2007-08-08

McCarthy Polymer Science and Engineering Department, University of Massachusetts, Amherst, Massachusetts 01003 Electrophilic aromatic substitution reactions...with a fluorinated silane reagent. Reduction of the amide groups with borane-THF (BH 3-THF) complex leads to a 69% conversion of surface amides to the

Direct fluorination of phenolsulfonphthalein: a method for synthesis of positron-emitting indicators for in vivo pH measurement

PubMed Central

Kachur, Alexander V.; Popov, Anatoliy V.; Karp, Joel S.; Delikatny, E. James

2014-01-01

We report a reaction of direct electrophilic fluorination of phenolsulfonphthalein at mild conditions. This reaction affords the synthesis of novel positron-emitting 18F-labeled pH indicators. These compounds are useful for non-invasive in vivo pH measurement in biological objects. PMID:22790882

N-heterocyclic carbene-catalyzed tandem aza-benzoin/Michael reactions: on site reversal of the reactivity of N-Boc imines.

PubMed

Wu, Ke-Jia; Li, Gong-Qiang; Li, Yi; Dai, Li-Xin; You, Shu-Li

2011-01-07

A tandem NHC-catalyzed aza-benzoin/Michael reaction has been developed as a method to efficiently produce dihydroindenones and pyrrolidinone-containing tricycles. The novel reaction pattern involves tert-butyl aryl(tosyl)methylcarbamates reacting as both electrophile and nucleophile on the same carbon.

How Do Nutritional Antioxidants Really Work: Nucleophilic Tone and Para-Hormesis Versus Free Radical Scavenging in vivo

PubMed Central

Forman, Henry Jay; Davies, Kelvin J. A.; Ursini, Fulvio

2013-01-01

We present arguments for an evolution in our understanding of how antioxidants in fruits and vegetables exert their health-protective effects. There is much epidemiological evidence for disease prevention by dietary antioxidants and chemical evidence that such compounds react in one-electron reactions with free radicals in vitro. Nonetheless, kinetic constraints indicate that in vivo scavenging of radicals is ineffective in antioxidant defense. Instead, enzymatic removal of non-radical electrophiles, such as hydroperoxides, in two-electron redox reactions is the major antioxidant mechanism. Furthermore, we propose that a major mechanism of action for nutritional antioxidants is the paradoxical oxidative activation of the Nrf2 (NF-E2-related factor 2) signaling pathway, which maintains protective oxidoreductases and their nucleophilic substrates. This maintenance of ‘Nucleophilic Tone,’ by a mechanism that can be called ‘Para-Hormesis,’ provides a means for regulating physiological non-toxic concentrations of the non-radical oxidant electrophiles that boost antioxidant enzymes, and damage removal and repair systems (for proteins, lipids, and DNA), at the optimal levels consistent with good health. PMID:23747930

The chemical foundations of nitroalkene fatty acid signaling through addition reactions with thiols.

PubMed

Turell, Lucía; Steglich, Martina; Alvarez, Beatriz

2018-03-22

Nitroalkene fatty acids can be formed in vivo and administered exogenously. They exert pleiotropic signaling actions with cytoprotective and antiinflammatory effects. The presence of the potent electron withdrawing nitro group confers electrophilicity to the adjacent β-carbon. Thiols (precisely, thiolates) are strong nucleophiles and can react with nitroalkene fatty acids through reversible Michael addition reactions. In addition, nitroalkene fatty acids can undergo several other processes including metabolic oxidation, reduction, esterification, nitric oxide release and partition into hydrophobic compartments. The signaling actions of nitroalkenes are mainly mediated by reactions with critical thiols in regulatory proteins. Thus, the thio-Michael addition reaction provides a framework for understanding the molecular basis of the biological effects of nitroalkene fatty acids at the crossroads of thiol signaling and electrophilic lipid signaling. In this review, we describe the reactions of nitroalkene fatty acids in biological contexts. We focus on the Michael addition-elimination reaction with thiols and its mechanism, and extrapolate kinetic and thermodynamic considerations to in vivo settings. Copyright © 2018 Elsevier Inc. All rights reserved.

Salt Effect Accelerates Site-Selective Cysteine Bioconjugation

PubMed Central

2016-01-01

Highly efficient and selective chemical reactions are desired. For small molecule chemistry, the reaction rate can be varied by changing the concentration, temperature, and solvent used. In contrast for large biomolecules, the reaction rate is difficult to modify by adjusting these variables because stringent biocompatible reaction conditions are required. Here we show that adding salts can change the rate constant over 4 orders of magnitude for an arylation bioconjugation reaction between a cysteine residue within a four-residue sequence (π-clamp) and a perfluoroaryl electrophile. Biocompatible ammonium sulfate significantly enhances the reaction rate without influencing the site-specificity of π-clamp mediated arylation, enabling the fast synthesis of two site-specific antibody–drug conjugates that selectively kill HER2-positive breast cancer cells. Computational and structure–reactivity studies indicate that salts may tune the reaction rate through modulating the interactions between the π-clamp hydrophobic side chains and the electrophile. On the basis of this understanding, the salt effect is extended to other bioconjugation chemistry, and a new regioselective alkylation reaction at π-clamp cysteine is developed. PMID:27725962

A new study of iodine complexes of oxidized gum arabic: An interaction between iodine monochloride and aldehyde groups.

PubMed

Ali, Akbar; Ganie, Showkat Ali; Mazumdar, Nasreen

2018-01-15

Gum arabic, a plant polysaccharide was oxidized with periodate to produce aldehyde groups by the cleavage of diols present in the sugar units. The oxidized gum was then iodinated with iodine monochloride (ICl) and the interaction between electrophilic iodine, I + and reactive carbonyl groups of the modified gum was studied.Results of titrimetric estimation performed to determine the extent of oxidation and aldehyde content in the oxidized gum showed that degree of oxidation ranged between 19.68-50.19% which was observed to increase with periodate concentration; the corresponding aldehyde content was calculated to be 5.15-40.42%. Different strengths of ICl were used to iodinate the oxidized gum and the iodine content of the complexes varied from 6.11-11.72% as determined by iodometric titration. Structure elucidation of the iodine complexes conclusively established the attachment of ICl molecules to CHO groups. A reaction scheme has been proposed suggesting an electrophilic addition of the reagent to the aldehyde groups, a mechanism that was also supported by iodide ion release studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

The N-terminal Ankyrin Repeat Domain Is Not Required for Electrophile and Heat Activation of the Purified Mosquito TRPA1 Receptor*

PubMed Central

2016-01-01

Temperature sensors are crucial for animals to optimize living conditions. The temperature response of the ion channel transient receptor potential A1 (TRPA1) is intriguing; some orthologs have been reported to be activated by cold and others by heat, but the molecular mechanisms responsible for its activation remain elusive. Single-channel electrophysiological recordings of heterologously expressed and purified Anopheles gambiae TRPA1 (AgTRPA1), with and without the N-terminal ankyrin repeat domain, demonstrate that both proteins are functional because they responded to the electrophilic compounds allyl isothiocyanate and cinnamaldehyde as well as heat. The proteins' similar intrinsic fluorescence properties and corresponding quenching when activated by allyl isothiocyanate or heat suggest lipid bilayer-independent conformational changes outside the N-terminal domain. The results show that AgTRPA1 is an inherent thermo- and chemoreceptor, and analogous to what has been reported for the human TRPA1 ortholog, the N-terminal domain may tune the response but is not required for the activation by these stimuli. PMID:27875296

Cardiovascular Small Heat Shock Protein HSPB7 Is a Kinetically Privileged Reactive Electrophilic Species (RES) Sensor.

PubMed

Surya, Sanjna L; Long, Marcus J C; Urul, Daniel A; Zhao, Yi; Mercer, Emily J; EIsaid, Islam M; Evans, Todd; Aye, Yimon

2018-02-08

Small heat shock protein (sHSP)-B7 (HSPB7) is a muscle-specific member of the non-ATP-dependent sHSPs. The precise role of HSPB7 is enigmatic. Here, we disclose that zebrafish Hspb7 is a kinetically privileged sensor that is able to react rapidly with native reactive electrophilic species (RES), when only substoichiometric amounts of RES are available in proximity to Hspb7 expressed in living cells. Among the two Hspb7-cysteines, this RES sensing is fulfilled by a single cysteine (C117). Purification and characterizations in vitro reveal that the rate for RES adduction is among the most efficient reported for protein-cysteines with native carbonyl-based RES. Covalent-ligand binding is accompanied by structural changes (increase in β-sheet-content), based on circular dichroism analysis. Among the two cysteines, only C117 is conserved across vertebrates; we show that the human ortholog is also capable of RES sensing in cells. Furthermore, a cancer-relevant missense mutation reduces this RES-sensing property. This evolutionarily conserved cysteine-biosensor may play a redox-regulatory role in cardioprotection.

Roles of the Yap1 Transcription Factor and Antioxidants in Saccharomyces cerevisiae's Tolerance to Furfural and 5-Hydroxymethylfurfural, Which Function as Thiol-Reactive Electrophiles Generating Oxidative Stress

PubMed Central

Kim, Daehee

2013-01-01

Development of the tolerance of Saccharomyces cerevisiae strains to furfural and 5-hydroxymethylfurfural (HMF) is an important issue for cellulosic ethanol production. Although furfural and HMF are known to induce oxidative stress, the underlying mechanisms are largely unknown. In this study, we show that both furfural and HMF act as thiol-reactive electrophiles, thus directly activating the Yap1 transcription factor via the H2O2-independent pathway, depleting cellular glutathione (GSH) levels, and accumulating reactive oxygen species in Saccharomyces cerevisiae. However, furfural showed higher reactivity than did HMF toward GSH in vitro and in vivo. In line with such toxic mechanisms, overexpression of YAP1C620F, a constitutively active mutant of YAP1, and Yap1 target genes encoding catalases (CTA1 and CTT1) increased tolerance to furfural and HMF. However, increasing GSH levels by overexpression of genes for GSH biosynthesis (GSH1 and GLR1) or by the exogenous addition of GSH to the culture medium enhanced tolerance to furfural but not to HMF. PMID:23793623

Roles of the Yap1 transcription factor and antioxidants in Saccharomyces cerevisiae's tolerance to furfural and 5-hydroxymethylfurfural, which function as thiol-reactive electrophiles generating oxidative stress.

PubMed

Kim, Daehee; Hahn, Ji-Sook

2013-08-01

Development of the tolerance of Saccharomyces cerevisiae strains to furfural and 5-hydroxymethylfurfural (HMF) is an important issue for cellulosic ethanol production. Although furfural and HMF are known to induce oxidative stress, the underlying mechanisms are largely unknown. In this study, we show that both furfural and HMF act as thiol-reactive electrophiles, thus directly activating the Yap1 transcription factor via the H2O2-independent pathway, depleting cellular glutathione (GSH) levels, and accumulating reactive oxygen species in Saccharomyces cerevisiae. However, furfural showed higher reactivity than did HMF toward GSH in vitro and in vivo. In line with such toxic mechanisms, overexpression of YAP1(C620F), a constitutively active mutant of YAP1, and Yap1 target genes encoding catalases (CTA1 and CTT1) increased tolerance to furfural and HMF. However, increasing GSH levels by overexpression of genes for GSH biosynthesis (GSH1 and GLR1) or by the exogenous addition of GSH to the culture medium enhanced tolerance to furfural but not to HMF.

Structure of Bacillus subtilis γ-glutamyltranspeptidase in complex with acivicin: diversity of the binding mode of a classical and electrophilic active-site-directed glutamate analogue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ida, Tomoyo; Suzuki, Hideyuki; Fukuyama, Keiichi

2014-02-01

The binding modes of acivicin, a classical and an electrophilic active-site-directed glutamate analogue, to bacterial γ-glutamyltranspeptidases were found to be diverse. γ-Glutamyltranspeptidase (GGT) is an enzyme that plays a central role in glutathione metabolism, and acivicin is a classical inhibitor of GGT. Here, the structure of acivicin bound to Bacillus subtilis GGT determined by X-ray crystallography to 1.8 Å resolution is presented, in which it binds to the active site in a similar manner to that in Helicobacter pylori GGT, but in a different binding mode to that in Escherichia coli GGT. In B. subtilis GGT, acivicin is bound covalentlymore » through its C3 atom with sp{sup 2} hybridization to Thr403 O{sup γ}, the catalytic nucleophile of the enzyme. The results show that acivicin-binding sites are common, but the binding manners and orientations of its five-membered dihydroisoxazole ring are diverse in the binding pockets of GGTs.« less

[Development of boomerang-type intramolecular cascade reactions and application to natural product synthesis].

PubMed

Takasu, K

2001-12-01

Intramolecular cascade reaction has received much attention as a powerful methodology to construct a polycyclic framework in organic synthesis. We have been developing "boomerang-type cascade reaction" to construct a variety of polycyclic skeletons efficiently. In the above reactions, a nucleophilic function of substrates changes the character into an electrophile after the initial reaction, and the electrophilic group acts as a nucleophile in the second reaction. That is, the reaction center stepwise moves from one functional group back to the same one via other functional groups. The stream of the electron concerning the cascade reaction is like a locus of boomerang. We show here three different boomerang-type reactions via ionic species or free radicals. 1) Diastereoselective Michael-aldol reaction based on the chiral auxiliary method and enantioselective Michael-aldol reaction by the use of external chiral sources. 2) Short and efficient total syntheses of longifolane sesquiterpenes utilizing intramolecular double Michael addition as a key step. 3) Development of boomerang-type radical cascade reaction of halopolyenes to construct terpenoid skeletons and its regioselectivity.

Rapid and selective determination of free chlorine in aqueous solution using electrophilic addition to styrene by gas chromatography/mass spectrometry.

PubMed

Wakigawa, Kengo; Gohda, Akinaga; Fukushima, Sunao; Mori, Takeshi; Niidome, Takuro; Katayama, Yoshiki

2013-01-15

We developed a rapid and selective method for determination of free chlorine in aqueous solution by gas chromatography/mass spectrometry for the first time. Free chlorine was converted to styrene chlorohydrin using electrophilic addition to styrene in sodium acetate buffer solution (pH 5). The chlorine derivative obtained was extracted with chloroform, and then analyzed by GC/MS. The calibration curve showed good linearity from 0.2-100 μg/mL (as available chlorine). The detection limit was 0.1 μg/mL, and the intra- and interday accuracy were measured at concentrations of 10, 50, and 75 μg/mL to be -1.3 to 6.9% (intraday) and 3.8-8.0% (interday) as % Bias. The precision was between 1.4 and 4.5% as % RSD. These results indicate that this method is a superior technique for the identification of free chlorine. This method was successfully applied to quantification in commercial samples and in samples of a criminal case. Copyright © 2012 Elsevier B.V. All rights reserved.

Molecular Reactivity and Absorption Properties of Melanoidin Blue-G1 through Conceptual DFT.

PubMed

Frau, Juan; Glossman-Mitnik, Daniel

2018-03-02

This computational study presents the assessment of eleven density functionals that include CAM-B3LYP, LC-wPBE, M11, M11L, MN12L, MN12SX, N12, N12SX, wB97, wB97X and wB97XD related to the Def2TZVP basis sets together with the Solvation Model Density (SMD) solvation model in calculating the molecular properties and structure of the Blue-G1 intermediate melanoidin pigment. The chemical reactivity descriptors for the system are calculated via the conceptual Density Functional Theory (DFT). The choice of the active sites related to the nucleophilic, electrophilic, as well as radical attacks is made by linking them with the Fukui function indices, the electrophilic Parr functions and the condensed dual descriptor Δ f ( r ) . The prediction of the maximum absorption wavelength tends to be considerably accurate relative to its experimental value. The study found the MN12SX and N12SX density functionals to be the most appropriate density functionals in predicting the chemical reactivity of the studied molecule.

Theoretical and conceptual density functional theory (DFT) study on selectivity of 4-hydroxyquinazoline electrophilic aromatic nitration

NASA Astrophysics Data System (ADS)

Makhloufi, A.; Belhadad, O.; Ghemit, R.; Baitiche, M.; Merbah, M.; Benachour, DJ.

2018-01-01

In common with other aza-heterocycles, 4-hydroxyquinazoline and their derivatives are important pharmacophores and versatile lead molecule used in several specific biological activities. The potency of these compounds depends on the nature and/or position of their substituents. In this paper, we report a theoretical study of the most probable nitration reaction centers of 4-hydroxyquinazoline for electrophilic attack, the mono and di-nitration was also discussed. In parallel, a computational study has been performed in gas by using the B3LYP/6311 G(d) level. The stability of the four nitro isomers is rationalized by means of the global index and local reactivity indices. Their molecular electrostatic potential (MEP) and Milliken charge were explored. Molecular geometries and NMR H spectra was examined. In addition, stationary points of reactant, transition state and intermediate were optimized in water condensed phase at the same level. The relative energies of the regioisomeric δ-complexes confirm that the substitution at C6 (6-nitro σ-complexes) is favored in these conditions, what was in agreement with our others calculating results (in gas).

Structural and optical properties of the naked and passivated Al{sub 5}Au{sub 5} bimetallic nanoclusters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grande-Aztatzi, Rafael; Formoso, Elena; Matxain, Jon M.

The structural and optical properties of both the naked and passivated bimetallic Al{sub 5}Au{sub 5} nanoclusters have been analyzed based on data obtained from ab initio density functional theory and quantum molecular dynamics simulations. It has been found that the Al{sub 5}Au{sub 5} nanocluster possesses a hollow shaped minimum energy structure with segregated Al and Au layered domains, the former representing the electrophilic domain and the latter the nucleophilic domain. In particular, it has been shown that alkali metal cations attach in the nucleophilic domain and hop from one Au site to the next one in the picoseconds time scale,more » while anions are bound tightly to the Al atoms of the electrophilic domain. Simulating annealing studies are very suggestive of the proneness of the nanocluster towards coalescence into large cluster units, when the cluster is left unprotected by appropriate ligands. Further passivation studies with NaF salt suggest, nonetheless, the possibility of the isolation of the Al{sub 5}Au{sub 5} cluster in molten salts or ionic liquids.« less

Synthesis and properties of the para-trimethylammonium analogues of green fluorescence protein (GFP) chromophore: The mimic of protonated GFP chromophore.

PubMed

Fanjiang, Ming-Wei; Li, Ming-Ju; Sung, Robert; Sung, Kuangsen

2018-04-01

At low pH, protons from the external, bulk solution can protonate the phenoxide group of the p-HBDI chromophore in wild-type green fluorescent protein (wtGFP) and its mutants, and likely continue to tentatively protonate the phenol hydroxyl group of the same chromophores. Because the protonated GFP chromophore is a transient, we prepare the stable p-trimethylammonium analogues (2a and 2b) of the GFP chromophore to mimic it and explore their properties. What we found is that the p-trimethylammonium analogues of the GFP chromophore have the highly electrophilic amidine carbon, blue-shifted electronic absorption, smaller molar absorptivity, smaller fluorescent quantum yield, and faster E-Z thermoisomerization rate. The amidine carbon of the p-trimethylammonium analogue (2b) of the GFP chromophore is the only site that is attacked by very weak nucleophile of water, resulting in ring-opening of the imidazolinone moiety. The half-life of its decay rate in D 2 O is around 33 days. Actually, acid-catalyzed hydrolysis of p-HBDI also results in ring-opening of the imidazolinone moiety. The ratio of the acid-catalyzed hydrolysis rate constants [k obs (p-HBDI)/k obs (1b)] between p-HBDI and 1b (p-dimethylammonium analogue of the GFP chromophore) is dramatically increased from 0.30 at pH = 2 to 0.63 at pH = 0. This is the evidence that more and more phenol hydroxyl groups of p-HBDI are tentatively protonated in a low-pH aqueous solution and that accelerates hydrolysis of p-HBDI in the way similar to the quaternary ammonium derivatives 2a and 2b in water. With this view point, 2a and 2b still can partially mimic the cationic p-HBDI with the protonated phenol hydroxyl group. Implication of the experiment is that the amidine carbon of the chromophore in wtGFP and its mutants at very low pH should be highly electrophilic. Whether ring-opening of the imidazolinone moiety of the GFP chromophore would occur or not depends on if water molecules can reach the amidine carbon of the chromophore inside wtGFP and its mutants. Copyright © 2018 Elsevier Inc. All rights reserved.

Understanding Mental Illness Stigma Toward Persons With Multiple Stigmatized Conditions: Implications of Intersectionality Theory.

PubMed

Oexle, Nathalie; Corrigan, Patrick W

2018-05-01

People with mental illness are often members of multiple stigmatized social groups. Therefore, experienced disadvantage might not be determined solely by mental illness stigma. Nevertheless, most available research does not consider the effects and implications of membership in multiple stigmatized social groups among people with mental illness. Reflecting on intersectionality theory, the authors discuss two intersectional effects determining disadvantage among people with mental illness who are members of multiple stigmatized social groups, namely double disadvantage and prominence. To be effective, interventions to reduce disadvantage experienced by people with mental illness need to be flexible and targeted rather than universal in order to address the implications of intersectionality. Whereas education-based approaches usually assume homogeneity and use universal strategies, contact-based interventions consider diversity among people with mental illness.

The development of catalytic nucleophilic additions of terminal alkynes in water.

PubMed

Li, Chao-Jun

2010-04-20

One of the major research endeavors in synthetic chemistry over the past two decades is the exploration of synthetic methods that work under ambient atmosphere with benign solvents, that maximize atom utilization, and that directly transform natural resources, such as renewable biomass, from their native states into useful chemical products, thus avoiding the need for protecting groups. The nucleophilic addition of terminal alkynes to various unsaturated electrophiles is a classical (textbook) reaction in organic chemistry, allowing the formation of a C-C bond while simultaneously introducing the alkyne functionality. A prerequisite of this classical reaction is the stoichiometric generation of highly reactive metal acetylides. Over the past decade, our laboratory and others have been exploring an alternative, the catalytic and direct nucleophilic addition of terminal alkynes to unsaturated electrophiles in water. We found that various terminal alkynes can react efficiently with a wide range of such electrophiles in water (or organic solvent) in the presence of simple and readily available catalysts, such as copper, silver, gold, iron, palladium, and others. In this Account, we describe the development of these synthetic methods, focusing primarily on results from our laboratory. Our studies include the following: (i) catalytic reaction of terminal alkynes with acid chloride, (ii) catalytic addition of terminal alkynes to aldehydes and ketones, (iii) catalytic addition of alkynes to C=N bonds, and (iv) catalytic conjugate additions. Most importantly, these reactions can tolerate various functional groups and, in many cases, perform better in water than in organic solvents, clearly defying classical reactivities predicated on the relative acidities of water, alcohols, and terminal alkynes. We further discuss multicomponent and enantioselective reactions that were developed. These methods provide an alternative to the traditional requirement of separate steps in classical alkyne reactions, including the pregeneration of metal acetylides with stoichiometric, highly basic reagents and the preprotection of sensitive functional groups. Accordingly, these techniques have greatly enhanced overall synthetic efficiencies and furthered our long-term objective of developing Grignard-type reactions in water.

Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Higgins, Larry G.; Kelleher, Michael O.; Eggleston, Ian M.

2009-06-15

Sulforaphane can stimulate cellular adaptation to redox stressors through transcription factor Nrf2. Using mouse embryonic fibroblasts (MEFs) as a model, we show herein that the normal homeostatic level of glutathione in Nrf2{sup -/-} MEFs was only 20% of that in their wild-type counterparts. Furthermore, the rate of glutathione synthesis following its acute depletion upon treatment with 3 {mu}mol/l sulforaphane was very substantially lower in Nrf2{sup -/-} MEFs than in wild-type cells, and the rebound leading to a {approx} 1.9-fold increase in glutathione that occurred 12-24 h after Nrf2{sup +/+} MEFs were treated with sulforaphane was not observed in Nrf2{sup -/-}more » fibroblasts. Wild-type MEFs that had been pre-treated for 24 h with 3 {mu}mol/l sulforaphane exhibited between 1.4- and 3.2-fold resistance against thiol-reactive electrophiles, including isothiocyanates, {alpha},{beta}-unsaturated carbonyl compounds (e.g. acrolein), aryl halides and alkene epoxides. Pre-treatment of Nrf2{sup +/+} MEFs with sulforaphane also protected against hydroperoxides (e.g. cumene hydroperoxide, CuOOH), free radical-generating compounds (e.g. menadione), and genotoxic electrophiles (e.g. chlorambucil). By contrast, Nrf2{sup -/-} MEFs were typically {approx} 50% less tolerant of these agents than wild-type fibroblasts, and sulforaphane pre-treatment did not protect the mutant cells against xenobiotics. To test whether Nrf2-mediated up-regulation of glutathione represents the major cytoprotective mechanism stimulated by sulforaphane, 5 {mu}mol/l buthionine sulfoximine (BSO) was used to inhibit glutathione synthesis. In Nrf2{sup +/+} MEFs pre-treated with sulforaphane, BSO diminished intrinsic resistance and abolished inducible resistance to acrolein, CuOOH and chlorambucil, but not menadione. Thus Nrf2-dependent up-regulation of GSH is the principal mechanism by which sulforaphane pre-treatment induced resistance to acrolein, CuOOH and chlorambucil, but not menadione.« less

Electrophilic fluorinating reagent mediated synthesis of fluorinated alpha-keto Ethers, benzil, and 6,6'-dialkoxy-2,2'-bipyridines.

PubMed

Manandhar, Sudha; Singh, Rajendra P; Eggers, Gary V; Shreeve, Jean'ne M

2002-09-06

Interactions of various fluorinated and nonfluorinated alcohols with trans-stilbene in the presence of electrophilic reagents were studied. Under neat conditions, reactions of trans-stilbene (1) with fluorinated alcohols, R(f)OH (R(f) = CF3CH2-, CFH2CH2-, CF3CF2CH2-, CF2H(CF2)3CH2-, (CF3)2CH-, (CF3)3C- (2a-f) in the presence of an electrophilic reagent, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) or N,N-difluoro-2,2'-bipyridinium bis(tetrafluoroborate) (MEC-31), gave alpha-keto ethers (3a-f) and benzil (4) in good to moderate yields. alpha-Keto ether and benzil formation was very much dependent on the reaction time, the degree of fluorination of the alcohols, and whether a solvent such as CH3CN, DMF or DMA was utilized. In solution, alpha-keto ethers and benzil did not form. Interestingly, under neat conditions, nonfluorinated alcohols, ROH (R = CH3-, CH3CH2-, CH3CH2CH2-, CH3CH2CH2CH2-, CH3CH2CH2CH2CH2CH2-) (5g-k) did not react with trans-stilbene in the presence of MEC-31 but gave 6,6'-dialkoxy-2,2'-bipyridines (6g-k), regioselectively, in excellent isolated yields. On the other hand, fluorinated alcohols did not react with MEC-31. Reaction of MEC-31 with an excess of diethylene glycol (7) gave the bipyridine derivative (8) in 88% isolated yield. Reaction of 8 either with diethylaminosulfur trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor) readily produced the corresponding difluoro derivative (9) in 85% isolated yield. All new compounds have been characterized by spectroscopic and elemental analysis.

Inhibition of mitochondrial division through covalent modification of Drp1 protein by 15 deoxy-{Delta}{sup 12,14}-prostaglandin J2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mishra, Nandita; Kar, Rekha; Singha, Prajjal K.

2010-04-23

Arachidonic acid derived endogenous electrophile 15d-PGJ2 has gained much attention in recent years due to its potent anti-proliferative and anti-inflammatory actions mediated through thiol modification of cysteine residues in its target proteins. Here, we show that 15d-PGJ2 at 1 {mu}M concentration converts normal mitochondria into large elongated and interconnected mitochondria through direct binding to mitochondrial fission protein Drp1 and partial inhibition of its GTPase activity. Mitochondrial elongation induced by 15d-PGJ2 is accompanied by increased assembly of Drp1 into large oligomeric complexes through plausible intermolecular interactions. The role of decreased GTPase activity of Drp1 in the formation of large oligomeric complexesmore » is evident when Drp1 is incubated with a non-cleavable GTP analog, GTP{gamma}S or by a mutation that inactivated GTPase activity of Drp1 (K38A). The mutation of cysteine residue (Cys644) in the GTPase effector domain, a reported target for modification by reactive electrophiles, to alanine mimicked K38A mutation induced Drp1 oligomerization and mitochondrial elongation, suggesting the importance of cysteine in GED to regulate the GTPase activity and mitochondrial morphology. Interestingly, treatment of K38A and C644A mutants with 15d-PGJ2 resulted in super oligomerization of both mutant Drp1s indicating that 15d-PGJ2 may further stabilize Drp1 oligomers formed by loss of GTPase activity through covalent modification of middle domain cysteine residues. The present study documents for the first time the regulation of a mitochondrial fission activity by a prostaglandin, which will provide clues for understanding the pathological and physiological consequences of accumulation of reactive electrophiles during oxidative stress, inflammation and degeneration.« less

Multiple Intelligence Theory for Gifted Education: Criticisms and Implications

ERIC Educational Resources Information Center

Calik, Basak; Birgili, Bengi

2013-01-01

This paper scrutinizes giftedness and gifted learners under the implications of multiple intelligence theory with regard to coaching young scientists. It is one of the pluralistic theories toward intelligence while supporting to view individuals as active participants during teaching and learning processes which correspond with the applications of…

Using Monte Carlo Techniques to Demonstrate the Meaning and Implications of Multicollinearity

ERIC Educational Resources Information Center

Vaughan, Timothy S.; Berry, Kelly E.

2005-01-01

This article presents an in-class Monte Carlo demonstration, designed to demonstrate to students the implications of multicollinearity in a multiple regression study. In the demonstration, students already familiar with multiple regression concepts are presented with a scenario in which the "true" relationship between the response and…

Electrophilic activation of alkynes for enyne cycloisomerization reactions with in situ generated early/late heterobimetallic Pt-Ti catalysts.

PubMed

Talley, Michael R; Stokes, Ryjul W; Walker, Whitney K; Michaelis, David J

2016-06-14

In situ formation of heterobimetallic Pt-Ti catalysts enables rapid room temperature catalysis in enyne cycloisomerization reactions. The Lewis acidic titanium atom in the ligand framework is shown to be essential for fast catalysis. A range of enyne substrates are efficiently cyclized to carbocycles and heterocycles in high yield.

Acrolein with an alpha, beta-unsaturated Carbonyl Group Inhibits LPS-induced Homodimerization of Toll-like Receptor 4

USDA-ARS?s Scientific Manuscript database

Acrolein is a highly electrophilic a,ß-unsaturated aldehyde present in a number of environmental sources, especially cigarette smoke. It reacts strongly with the thiol groups of cysteine residues by Michael addition and has been reported to inhibit nuclear factor-kB (NF-kB) activation by lipopolysac...

Polar Addition to C=C Group: Why Is Anti-Markovnikov Hydroboration-Oxidation of Alkenes Not "Anti-"?

ERIC Educational Resources Information Center

Ilich, Predrag-Peter; Rickertsen, Lucas S.; Becker, Erienne

2006-01-01

For 137 years Markovnikov's rule has been extensively used in organic chemical education and research to describe the regioselectivity in electrophilic addition reactions to alkenes and alkynes. When the structures of the final reaction products are used as reference, the rule requests that certain polar addition reactions be termed…

Cyclization Reactions through DDQ-Mediated Vinyl Oxazolidinone Oxidation

PubMed Central

Liu, Lei; Floreancig, Paul E.

2009-01-01

Vinyl oxazolidinones react with DDQ to form α,β-unsaturated acyliminium ions in a new method for forming electrophiles under oxidative conditions. Appended nucleophiles undergo 1,4-addition reactions with these intermediates to form cyclic vinyl oxazolidinones with good levels of diastereocontrol, highlighting a new approach to utilizing oxidative carbon–hydrogen bond functionalization to increase molecular complexity. PMID:19552390

Oxidation Numbers, Oxidants, and Redox Reactions: Variants of the Electrophilic Bromination of Alkenes and Variants of the Application of Oxone

ERIC Educational Resources Information Center

Eissen, Marco; Strudthoff, Merle; Backhaus, Solveig; Eismann, Carolin; Oetken, Gesa; Kaling, Soren; Lenoir, Dieter

2011-01-01

Oxidation-state and donor-acceptor concepts are important areas in the chemical education. Student worksheets containing problems that emphasize oxidation numbers, redox reactions of organic compounds, and stoichiometric reaction equations are presented. All of the examples are incorporated under one unifying topic: the production of vicinal…

Vibrational spectroscopy of biological molecules: halocompound/nucleic acid component interactions

NASA Astrophysics Data System (ADS)

Bottura, J.; Filippetti, P.; Tinti, A.

1991-05-01

Organohalogen compounds play a crucial role in cancer induction due to the ability of some electrophilic species produced in their enzymatic oxidative metabolism to damage DNA. Vibrational Ftjr spectra showing the molecular interactions between chioroacetaldehyde metabolite of 1 dichioroethane and adenosine and cytidine leading to the tautomeric iminic forms are reported and discussed. 1 .

Computational Study of Low-Temperature Catalytic C-C Bond Activation of Alkanes for Portable Power

DTIC Science & Technology

2013-06-05

inhibiting the reaction. We found that Fluorinated phosphines are sufficiently π-accepting to satisfy this role. In our next step, we wanted to determine...of butane by Sen’s catalyst, Chepaikin et al. [5] proposed that CH cleavage occurs first. But the resulting catalyst fragment “X” is so electrophilic

How Cinchona Alkaloid-Derived Primary Amines Control Asymmetric Electrophilic Fluorination of Cyclic Ketones

PubMed Central

2015-01-01

The origin of selectivity in the α-fluorination of cyclic ketones catalyzed by cinchona alkaloid-derived primary amines is determined with density functional calculations. The chair preference of a seven-membered ring at the fluorine transfer transition state is key in determining the sense and level of enantiofacial selectivity. PMID:24967514

In Situ Grafting of Hyperbranched Poly(Etherketone)s onto Multiwalled Carbon Nanotubes Via A3 + B2 Approach (Preprint)

DTIC Science & Technology

2007-04-01

MWNTs.20 These defects would provide sites for the electrophilic substitution reaction. In our previous work, FT-IR had been used to characterize the...various surface functionalities.22 In this study, MWNTs containing polar surface groups such as amino-, hydroxyl-, and fluorine groups displayed similar

Non-directed aromatic C–H amination: catalytic and mechanistic studies enabled by Pd catalyst and reagent design†

PubMed Central

Bandara, H. M. D.; Jin, D.; Mantell, M. A.; Field, K. D.; Wang, A.; Narayanan, R. P.; Deskins, N. A.; Emmert, M. H.

2016-01-01

This manuscript describes the systematic development of pyridine-type ligands, which promote the Pd catalyzed, non-directed amination of benzene in combination with novel, hydroxylamine-based electrophilic amination reagents. DFT calculations and mechanistic experiments provide insights into the factors influencing the arene C–H amination protocol. PMID:28066540

Electric Hindrance and Precursor Complexes in the Regiochemistry of Some Nitrations

ERIC Educational Resources Information Center

Sanchez-Viesca, Francisco; Gomez, Maria Reina Gomez; Berros, Martha

2011-01-01

There are still gaps in the theory of supposedly well-known chemical reactions. For example, there is no explanation why there is a notorious preponderance of one of the expected isomers in some electrophilic aromatic substitutions. The preferred ortho orientation of acetyl nitrate has been used widely to obtain ortho nitro compounds; however,…

Cationic Cyclizations and Rearrangements Promoted by a Heterogeneous Gold Catalyst

PubMed Central

2015-01-01

A heterogeneous gold catalyst with remarkable activity for promoting the electrophilic reactions of aryl vinyl ketones and aryl dienyl ketones is described. The catalyst is easy to prepare, is robust, and can be recycled. Low loadings are effective for different types of cationic reactions, including Nazarov cyclizations, lactonizations, and [1,2] shifts. PMID:24432741

LC/MSMS STUDY OF BENZO[A]PYRENE-7,8-QUINONE ADDUCTION TO GLOBIN TRYPTIC PEPTIDES AND N-ACETYLAMINO ACIDS

EPA Science Inventory

Benzo[a]pyrene-7,8-quinone (BPQ) is regarded as a reactive genotoxic compound enzymatically formed from a xenobiotic precursor benzo[a]pyrene-7,8-diol by aldo-keto-reductase family of enzymes. Because BPQ, a Michael electrophile, was previously shown to react with oligonucleotide...

Dual Studies on a Hydrogen-Deuterium Exchange of Resorcinol and the Subsequent Kinetic Isotope Effect

ERIC Educational Resources Information Center

Giles, Richard; Kim, Iris; Chao, Weyjuin Eric; Moore, Jennifer; Jung, Kyung Woon

2014-01-01

An efficient laboratory experiment has been developed for undergraduate students to conduct hydrogen-deuterium (H-D) exchange of resorcinol by electrophilic aromatic substitution using D[subscript 2]O and a catalytic amount of H[subscript 2]SO[subscript 4]. The resulting labeled product is characterized by [superscript 1]H NMR. Students also…

Genotoxic effect of N-hydroxy-4-acetylaminobiphenyl on human DNA: implications in bladder cancer.

PubMed

Shahab, Uzma; Moinuddin; Ahmad, Saheem; Dixit, Kiran; Habib, Safia; Alam, Khursheed; Ali, Asif

2013-01-01

The interaction of environmental chemicals and their metabolites with biological macromolecules can result in cytotoxic and genotoxic effects. 4-Aminobiphenyl (4-ABP) and several other related arylamines have been shown to be causally involved in the induction of human urinary bladder cancers. The genotoxic and the carcinogenic effects of 4-ABP are exhibited only when it is metabolically converted to a reactive electrophile, the aryl nitrenium ions, which subsequently binds to DNA and induce lesions. Although several studies have reported the formation of 4-ABP-DNA adducts, no extensive work has been done to investigate the immunogenicity of 4-ABP-modified DNA and its possible involvement in the generation of antibodies in bladder cancer patients. Human DNA was modified by N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP), a reactive metabolite of 4-ABP. Structural perturbations in the N-OH-AABP modified DNA were assessed by ultraviolet, fluorescence, and circular dichroic spectroscopy as well as by agarose gel electrophoresis. Genotoxicity of N-OH-AABP modified DNA was ascertained by comet assay. High performance liquid chromatography (HPLC) analysis of native and modified DNA samples confirmed the formation of N-(deoxyguanosine-8-yl)-4-aminobiphenyl (dG-C8-4ABP) in the N-OH-AABP damaged DNA. The experimentally induced antibodies against N-OH-AABP-modified DNA exhibited much better recognition of the DNA isolated from bladder cancer patients as compared to the DNA obtained from healthy individuals in competitive binding ELISA. This work shows epitope sharing between the DNA isolated from bladder cancer patients and the N-OH-AABP-modified DNA implicating the role of 4-ABP metabolites in the DNA damage and neo-antigenic epitope generation that could lead to the induction of antibodies in bladder cancer patients.

One-pot conversion of biomass-derived xylose and furfural into levulinate esters via acid catalysis.

PubMed

Hu, Xun; Jiang, Shengjuan; Wu, Liping; Wang, Shuai; Li, Chun-Zhu

2017-03-07

Direct conversion of biomass-derived xylose and furfural into levulinic acid, a platform molecule, via acid-catalysis has been accomplished for the first time in dimethoxymethane/methanol. Dimethoxymethane acted as an electrophile to transform furfural into 5-hydroxymethylfurfural (HMF). Methanol suppressed both the polymerisation of the sugars/furans and the Aldol condensation of levulinic acid/ester.

Facile synthesis of covalent probes to capture enzymatic intermediates during E1 enzyme catalysis.

PubMed

An, Heeseon; Statsyuk, Alexander V

2016-02-11

We report a facile synthetic strategy to prepare UBL-AMP electrophilic probes that form a covalent bond with the catalytic cysteine of cognate E1s, mimicking the tetrahedral intermediate of the E1-UBL-AMP complex. These probes enable the structural and biochemical study of both canonical- and non-canonical E1s.

A Tyrosine-Reactive Irreversible Inhibitor for Glutathione S-Transferase Pi (GSTP1)

PubMed Central

Crawford, L. A.; Weerapana, E.

2016-01-01

Glutathione S-Transferase Pi (GSTP1) mediates cellular defense against reactive electrophiles. Here, we report LAS17, a dichlorotriazine-containing compound that irreversibly inhibits GSTP1 and is selective for GSTP1 within cellular proteomes. Mass spectrometry and mutational studies identified Y108 as the site of modification, providing a unique mode of GSTP1 inhibition. PMID:27113843

A tyrosine-reactive irreversible inhibitor for glutathione S-transferase Pi (GSTP1).

PubMed

Crawford, L A; Weerapana, E

2016-05-24

Glutathione S-transferase Pi (GSTP1) mediates cellular defense against reactive electrophiles. Here, we report LAS17, a dichlorotriazine-containing compound that irreversibly inhibits GSTP1 and is selective for GSTP1 within cellular proteomes. Mass spectrometry and mutational studies identified Y108 as the site of modification, providing a unique mode of GSTP1 inhibition.

One-Pot Anti-Markovnikov Hydroamination of Unactivated Alkenes by Hydrozirconation and Amination

PubMed Central

Strom, Alexandra E.

2013-01-01

A one-pot hydroamination of alkenes is reported. The synthesis of primary and secondary amines from unactivated olefins was accomplished in the presence of a variety of functional groups. Hydrozirconation, followed by amination with nitrogen electrophiles, provides exclusive anti-Markovnikov selectivity, and most products are isolated in high yields without the use of column chromatography. PMID:23899320

Transition Metal Free C-N Bond Forming Dearomatizations and Aryl C-H Aminations by in Situ Release of a Hydroxylamine-Based Aminating Agent.

PubMed

Farndon, Joshua J; Ma, Xiaofeng; Bower, John F

2017-10-11

We outline a simple protocol that accesses directly unprotected secondary amines by intramolecular C-N bond forming dearomatization or aryl C-H amination. The method is dependent on the generation of a potent electrophilic aminating agent released by in situ deprotection of O-Ts activated N-Boc hydroxylamines.

Catalytic Hydroamination of Alkynes and Norbornene with Neutral and Cationic Tantalum Imido Complexes

PubMed Central

Anderson, Laura L.; Arnold, John; Bergman, Robert G.

2005-01-01

Several tantalum imido complexes have been synthesized and shown to efficiently catalyze the hydroamination of internal and terminal alkynes. An unusual hydroamination/hydroarylation reaction of norbornene catalyzed by a highly electrophilic cationic tantalum imido complex is also reported. Factors affecting catalyst activity and selectivity are discussed along with mechanistic insights gained from stoichiometric reactions. PMID:15255680

Introduction of a Simple Experiment for the Undergraduate Organic Chemistry Laboratory Demonstrating the Lewis Acid and Shape-Selective Properties of Zeolite Na-Y

ERIC Educational Resources Information Center

Maloney, Vincent; Szczepanski, Zach

2017-01-01

A simple, inexpensive, discovery-based experiment for undergraduate organic laboratories has been developed that demonstrates the Lewis acid and shape-selective properties of zeolites. Calcined zeolite Na-Y promotes the electrophilic aromatic bromination of toluene with a significantly higher para/ortho ratio than observed under conventional…

Process for removing sulfur from coal

DOEpatents

Aida, Tetsuo; Squires, Thomas G.; Venier, Clifford G.

1985-02-05

A process for the removal of divalent organic and inorganic sulfur compounds from coal and other carbonaceous material. A slurry of pulverized carbonaceous material is contacted with an electrophilic oxidant which selectively oxidizes the divalent organic and inorganic compounds to trivalent and tetravalent compounds. The carbonaceous material is then contacted with a molten caustic which dissolves the oxidized sulfur compounds away from the hydrocarbon matrix.

How Mg2+ ions lower the SN2@P barrier in enzymatic triphosphate hydrolysis.

PubMed

van Bochove, Marc A; Roos, Goedele; Fonseca Guerra, Célia; Hamlin, Trevor A; Bickelhaupt, F Matthias

2018-04-03

Our quantum chemical activation strain analyses demonstrate how Mg2+ lowers the barrier of the enzymatic triphosphate hydrolysis through two distinct mechanisms: (a) weakening of the leaving-group bond, thereby decreasing activation strain; and (b) transition state (TS) stabilization through enhanced electrophilicity of the triphosphate PPP substrate, thereby strengthening the interaction with the nucleophile.

Computational study of frontier orbitals, moments, chemical reactivity and thermodynamic parameters of sildenafil

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sachdeva, Ritika, E-mail: ritika.sachdeva21@gmail.com; Kaur, Prabhjot; Singh, V. P.

2016-05-06

Analysis of frontier orbitals of sildenafil has been carried using Density Functional Theory. On the basis of HOMO-LUMO energy, values of global chemical reactivity descriptors such as electronegativity, chemical hardness, softness, chemical potential, electrophilicity index have been calculated. Calculated values of dipole moment, polarizability, hyperpolarizability have also been reported for sildenafil along with its thermodynamic parameters.

Crystal Structure, Conformational Analysis, and Charge Density Distribution for Eng-Epifisetinidol: An Explanation for Regiospecific Aromatic Substitution of 5-Deoxyflavan

Treesearch

Fred L. Tobiason; Frank R. Fronczek; Jan P. Steynberg; Elizabeth C. Steynberg; Richard W. Hemingway; Wayne L. Mattice

1993-01-01

Molecular modeling and molecular orbital analyses of ent-epifisetinidol gave &ood predictions of the approximate "reverse half-chair" conformation found for the crystal structure. MNDO and AM1 analyses of HOMO electron densities provided an explanation for the stereospecific electrophilic aromatic substitution at C(6) in 5-deoxy-flavans...

Nickel-Catalyzed Coupling Reactions of Alkyl Electrophiles, Including Unactivated Tertiary Halides, to Generate Carbon–Boron Bonds

PubMed Central

Dudnik, Alexander S.

2012-01-01

Through the use of a catalyst formed in situ from NiBr2•diglyme and a pybox ligand (both of which are commercially available), we have achieved our first examples of coupling reactions of unactivated tertiary alkyl electrophiles, as well as our first success with nickel-catalyzed couplings that generate bonds other than C–C bonds. Specifically, we have determined that this catalyst accomplishes Miyaura-type borylations of unactivated tertiary, secondary, and primary alkyl halides with diboron reagents to furnish alkylboronates, a family of compounds with substantial (and expanding) utility, under mild conditions; indeed, the umpolung borylation of a tertiary alkyl bromide can be achieved at a temperature as low as −10 °C. The method exhibits good functional-group compatibility and is regiospecific, both of which can be issues with traditional approaches to the synthesis of alkylboronates. In contrast to seemingly related nickel-catalyzed C–C bond-forming processes, tertiary halides are more reactive than secondary or primary halides in this nickel-catalyzed C–B bond-forming reaction; this divergence is particularly noteworthy in view of the likelihood that both transformations follow an inner-sphere electron-transfer pathway for oxidative addition. PMID:22668072

In situ generation, metabolism and immunomodulatory signaling actions of nitro-conjugated linoleic acid in a murine model of inflammation.

PubMed

Villacorta, Luis; Minarrieta, Lucia; Salvatore, Sonia R; Khoo, Nicholas K; Rom, Oren; Gao, Zhen; Berman, Rebecca C; Jobbagy, Soma; Li, Lihua; Woodcock, Steven R; Chen, Y Eugene; Freeman, Bruce A; Ferreira, Ana M; Schopfer, Francisco J; Vitturi, Dario A

2018-05-01

Conjugated linoleic acid (CLA) is a prime substrate for intra-gastric nitration giving rise to the formation of nitro-conjugated linoleic acid (NO 2 -CLA). Herein, NO 2 -CLA generation is demonstrated within the context of acute inflammatory responses both in vitro and in vivo. Macrophage activation resulted in dose- and time-dependent CLA nitration and also in the production of secondary electrophilic and non-electrophilic derivatives. Both exogenous NO 2 -CLA as well as that generated in situ, attenuated NF-κB-dependent gene expression, decreased pro-inflammatory cytokine production and up-regulated Nrf2-regulated proteins. Importantly, both CLA nitration and the corresponding downstream anti-inflammatory actions of NO 2 -CLA were recapitulated in a mouse peritonitis model where NO 2 -CLA administration decreased pro-inflammatory cytokines and inhibited leukocyte recruitment. Taken together, our results demonstrate that the formation of NO 2 -CLA has the potential to function as an adaptive response capable of not only modulating inflammation amplitude but also protecting neighboring tissues via the expression of Nrf2-dependent genes. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Pyridoxylamine reactivity kinetics as an amine based nucleophile for screening electrophilic dermal sensitizers

PubMed Central

Chipinda, Itai; Mbiya, Wilbes; Adigun, Risikat Ajibola; Morakinyo, Moshood K.; Law, Brandon F.; Simoyi, Reuben H.; Siegel, Paul D.

2015-01-01

Chemical allergens bind directly, or after metabolic or abiotic activation, to endogenous proteins to become allergenic. Assessment of this initial binding has been suggested as a target for development of assays to screen chemicals for their allergenic potential. Recently we reported a nitrobenzenethiol (NBT) based method for screening thiol reactive skin sensitizers, however, amine selective sensitizers are not detected by this assay. In the present study we describe an amine (pyridoxylamine (PDA)) based kinetic assay to complement the NBT assay for identification of amine-selective and non-selective skin sensitizers. UV-Vis spectrophotometry and fluorescence were used to measure PDA reactivity for 57 chemicals including anhydrides, aldehydes, and quinones where reaction rates ranged from 116 to 6.2 × 10−6 M−1 s−1 for extreme to weak sensitizers, respectively. No reactivity towards PDA was observed with the thiol-selective sensitizers, non-sensitizers and prohaptens. The PDA rate constants correlated significantly with their respective murine local lymph node assay (LLNA) threshold EC3 values (R2 = 0.76). The use of PDA serves as a simple, inexpensive amine based method that shows promise as a preliminary screening tool for electrophilic, amine-selective skin sensitizers. PMID:24333919

Vibrational and structural study of onopordopicrin based on the FTIR spectrum and DFT calculations.

PubMed

Chain, Fernando E; Romano, Elida; Leyton, Patricio; Paipa, Carolina; Catalán, César A N; Fortuna, Mario; Brandán, Silvia Antonia

2015-01-01

In the present work, the structural and vibrational properties of the sesquiterpene lactone onopordopicrin (OP) were studied by using infrared spectroscopy and density functional theory (DFT) calculations together with the 6-31G(∗) basis set. The harmonic vibrational wavenumbers for the optimized geometry were calculated at the same level of theory. The complete assignment of the observed bands in the infrared spectrum was performed by combining the DFT calculations with Pulay's scaled quantum mechanical force field (SQMFF) methodology. The comparison between the theoretical and experimental infrared spectrum demonstrated good agreement. Then, the results were used to predict the Raman spectrum. Additionally, the structural properties of OP, such as atomic charges, bond orders, molecular electrostatic potentials, characteristics of electronic delocalization and topological properties of the electronic charge density were evaluated by natural bond orbital (NBO), atoms in molecules (AIM) and frontier orbitals studies. The calculated energy band gap and the chemical potential (μ), electronegativity (χ), global hardness (η), global softness (S) and global electrophilicity index (ω) descriptors predicted for OP low reactivity, higher stability and lower electrophilicity index as compared with the sesquiterpene lactone cnicin containing similar rings. Copyright © 2015 Elsevier B.V. All rights reserved.

Functionalized Poly(3-hexylthiophene)s via Lithium–Bromine Exchange

PubMed Central

2015-01-01

Poly(3-hexylthiophene) (P3HT) is one of the most extensively investigated conjugated polymers and has been employed as the active material in many devices including field-effect transistors, organic photovoltaics and sensors. As a result, methods to further tune the properties of P3HT are desirable for specific applications. Herein, we report a facile postpolymerization modification strategy to functionalize the 4-position of commercially available P3HT in two simple steps–bromination of the 4-position of P3HT (Br–P3HT) followed by lithium−bromine exchange and quenching with an electrophile. We achieved near quantitative lithium–bromine exchange with Br–P3HT, which requires over 100 thienyl lithiates to be present on a single polymer chain. The lithiated-P3HT is readily combined with functional electrophiles, resulting in P3HT derivatives with ketones, secondary alcohols, trimethylsilyl (TMS) group, fluorine, or an azide at the 4-position. We demonstrated that the azide-modified P3HT could undergo Cu-catalyzed or Cu-free click chemistry, significantly expanding the complexity of the structures that can be appended to P3HT using this method. PMID:25620811

Sulfone-stabilized carbanions for the reversible covalent capture of a posttranslationally-generated cysteine oxoform found in protein tyrosine phosphatase 1B (PTP1B).

PubMed

Parsons, Zachary D; Ruddraraju, Kasi Viswanatharaju; Santo, Nicholas; Gates, Kent S

2016-06-15

Redox regulation of protein tyrosine phosphatase 1B (PTP1B) involves oxidative conversion of the active site cysteine thiolate into an electrophilic sulfenyl amide residue. Reduction of the sulfenyl amide by biological thiols regenerates the native cysteine residue. Here we explored fundamental chemical reactions that may enable covalent capture of the sulfenyl amide residue in oxidized PTP1B. Various sulfone-containing carbon acids were found to react readily with a model peptide sulfenyl amide via attack of the sulfonyl carbanion on the electrophilic sulfur center in the sulfenyl amide. Both the products and the rates of these reactions were characterized. The results suggest that capture of a peptide sulfenyl amide residue by sulfone-stabilized carbanions can slow, but not completely prevent, thiol-mediated generation of the corresponding cysteine-containing peptide. Sulfone-containing carbon acids may be useful components in the construction of agents that knock down PTP1B activity in cells via transient covalent capture of the sulfenyl amide oxoform generated during insulin signaling processes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Design of a Photoredox Catalyst that Enables the Direct Synthesis of Carbamate-Protected Primary Amines via Photoinduced, Copper-Catalyzed N-Alkylation Reactions of Unactivated Secondary Halides.

PubMed

Ahn, Jun Myun; Peters, Jonas C; Fu, Gregory C

2017-12-13

Despite the long history of S N 2 reactions between nitrogen nucleophiles and alkyl electrophiles, many such substitution reactions remain out of reach. In recent years, efforts to develop transition-metal catalysts to address this deficiency have begun to emerge. In this report, we address the challenge of coupling a carbamate nucleophile with an unactivated secondary alkyl electrophile to generate a substituted carbamate, a process that has not been achieved effectively in the absence of a catalyst; the product carbamates can serve as useful intermediates in organic synthesis as well as bioactive compounds in their own right. Through the design and synthesis of a new copper-based photoredox catalyst, bearing a tridentate carbazolide/bisphosphine ligand, that can be activated upon irradiation by blue-LED lamps, we can achieve the coupling of a range of primary carbamates with unactivated secondary alkyl bromides at room temperature. Our mechanistic observations are consistent with the new copper complex serving its intended role as a photoredox catalyst, working in conjunction with a second copper complex that mediates C-N bond formation in an out-of-cage process.

Electrophilic fluorination of pyroglutamic acid derivatives: application of substrate-dependent reactivity and diastereoselectivity to the synthesis of optically active 4-fluoroglutamic acids.

PubMed

Konas, D W; Coward, J K

2001-12-28

Electrophilic fluorination of enantiomerically pure 2-pyrrolidinones (4) derived from (L)-glutamic acid has been investigated as a method for the synthesis of single stereoisomers of 4-fluorinated glutamic acids. Reaction of the lactam enolate derived from 9 with NFSi results in a completely diastereoselective monofluorination reaction to yield the monocyclic trans-substituted alpha-fluoro lactam product 21. Unfortunately, a decreased kinetic acidity in 21 and other structurally related monofluorinated products renders them resistant to a second fluorination. In contrast, the bicyclic lactam 12 is readily difluorinated under the standard conditions described to yield the alpha,alpha-difluoro lactam 24. The difference in reactivity between the two types of related lactams is attributed mainly to the presence or lack of a steric interaction between the base used for deprotonation and the protecting group present in the pyrrolidinone substrates. This conclusion was reached based on analysis of the X-ray crystal structure of 21, molecular modeling, and experimental evidence. The key intermediates 21 and 24 are converted to (2S,4R)-4-fluoroglutamic acid and (2S)-4,4-difluoroglutamic acid, respectively.

Soft Cysteine Signaling Network: The Functional Significance of Cysteine in Protein Function and the Soft Acids/Bases Thiol Chemistry That Facilitates Cysteine Modification.

PubMed

Wible, Ryan S; Sutter, Thomas R

2017-03-20

The unique biophysical and electronic properties of cysteine make this molecule one of the most biologically critical amino acids in the proteome. The defining sulfur atom in cysteine is much larger than the oxygen and nitrogen atoms more commonly found in the other amino acids. As a result of its size, the valence electrons of sulfur are highly polarizable. Unique protein microenvironments favor the polarization of sulfur, thus increasing the overt reactivity of cysteine. Here, we provide a brief overview of the endogenous generation of reactive oxygen and electrophilic species and specific examples of enzymes and transcription factors in which the oxidation or covalent modification of cysteine in those proteins modulates their function. The perspective concludes with a discussion of cysteine chemistry and biophysics, the hard and soft acids and bases model, and the proposal of the Soft Cysteine Signaling Network: a hypothesis proposing the existence of a complex signaling network governed by layered chemical reactivity and cross-talk in which the chemical modification of reactive cysteine in biological networks triggers the reorganization of intracellular biochemistry to mitigate spikes in endogenous or exogenous oxidative or electrophilic stress.

Synthesis, spectroscopic and DFT studies of novel 4-(morpholinomethyl)-5-oxo-1-phenylpyrrolidine-3-carboxylic acid

NASA Astrophysics Data System (ADS)

Devi, Poornima; Fatma, Shaheen; Bishnoi, Abha; Srivastava, Krishna; Shukla, Shraddha; Kumar, Roop

2018-04-01

A novel 4-(morpholinomethyl)-5-oxo-1-phenylpyrrolidine-3-carboxylic acid has been synthesized and its structural elucidation has been done by UV, FT-IR, 1H and 13C NMR spectroscopy. All quantum chemical calculations were carried out at level of density functional theory (DFT) with B3LYP function using 6-31G (d, p) basis atomic set. AIM approach has been incorporated for the analysis of various intermolecular interactions. Polarizability and hyperpolarizabilities values have been calculated along with the exploration of nonlinear optical properties of the title compound. DFT computed total first static hyperpolarizability (β0 = 0.2747 × 10-30 esu) indicates that title molecule could be an area of interest as an attractive future NLO material. For the analysis of thermal behaviour of title molecule, thermodynamic properties such as heat capacity, entropy and enthalpy change at various temperatures have been calculated. The NBO computations were done for the correlation of possible transitions with the electronic transitions. Electrophilic and nucleophilic regions were identified with the help of MESP plot. Determination of energy gap has been done by using HOMO and LUMO energy values, along with the computation of electronegativity and electrophilicity indices.

Nrf2 and HSF-1 Pathway Activation via Hydroquinone-Based Proelectrophilic Small Molecules Is Regulated by Electrochemical Oxidation Potential

PubMed Central

Stalder, Romain; McKercher, Scott R.; Williamson, Robert E.; Roth, Gregory P.; Lipton, Stuart A.

2015-01-01

Activation of the Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2 and heat-shock protein 90/heat-shock factor-1 signal-transduction pathways plays a central role in combatting cellular oxidative damage and related endoplasmic reticulum stress. Electrophilic compounds have been shown to be activators of these transcription-mediated responses through S-alkylation of specific regulatory proteins. Previously, we reported that a prototype compound (D1, a small molecule representing a proelectrophilic, para-hydroquinone species) exhibited neuroprotective action by activating both of these pathways. We hypothesized that the para-hydroquinone moiety was critical for this activation because it enhanced transcription of these neuroprotective pathways to a greater degree than that of the corresponding ortho-hydroquinone isomer. This notion was based on the differential oxidation potentials of the isomers for the transformation of the hydroquinone to the active, electrophilic quinone species. Here, to further test this hypothesis, we synthesized a pair of para- and ortho-hydroquinone-based proelectrophilic compounds and measured their redox potentials using analytical cyclic voltammetry. The redox potential was then compared with functional biological activity, and the para-hydroquinones demonstrated a superior neuroprotective profile. PMID:26243592

Brain ischemic preconditioning protects against ischemic injury and preserves the blood-brain barrier via oxidative signaling and Nrf2 activation.

PubMed

Yang, Tuo; Sun, Yang; Mao, Leilei; Zhang, Meijuan; Li, Qianqian; Zhang, Lili; Shi, Yejie; Leak, Rehana K; Chen, Jun; Zhang, Feng

2018-05-06

Brain ischemic preconditioning (IPC) with mild ischemic episodes is well known to protect the brain against subsequent ischemic challenges. However, the underlying mechanisms are poorly understood. Here we demonstrate the critical role of the master redox transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), in IPC-mediated neuroprotection and blood-brain barrier (BBB) preservation. We report that IPC causes generation of endogenous lipid electrophiles, including 4-hydroxy-2-nonenal (4-HNE), which release Nrf2 from inhibition by Keap1 (via Keap1-C288) and inhibition by glycogen synthase kinase 3β (via GSK3β-C199). Nrf2 then induces expression of its target genes, including a new target, cadherin 5, a key component of adherens junctions of the BBB. These effects culminate in mitigation of BBB leakage and of neurological deficits after stroke. Collectively, these studies are the first to demonstrate that IPC protects the BBB against ischemic injury by generation of endogenous electrophiles and activation of the Nrf2 pathway through inhibition of Keap1- and GSK3β-dependent Nrf2 degradation. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Mechanisms and dynamics of protonation and lithiation of ferrocene.

PubMed

Sharma, Nishant; Ajay, Jayanth K; Venkatasubbaiah, Krishnan; Lourderaj, Upakarasamy

2015-09-14

By elucidating the mechanism of the simplest electrophilic substitution reaction of ferrocene, it was found that the verification of the protonation reaction has been a difficulty. In the work reported here, ab initio chemical dynamics simulations were performed at B3LYP/DZVP level of theory to understand the atomic level mechanisms of protonation and lithiation of ferrocene. Protonation of ferrocene resulted in the agostic and metal-protonated forms. Trajectory calculations revealed that protonation of ferrocene occurs by exo and endo mechanisms, with exo being the major path. H(+) was found to be mobile and hopped from the Cp ring to the metal center and vice versa after the initial attack on ferrocene, with the metal-complex having a shorter lifetime. These results remove the ambiguity surrounding the mechanism, as proposed in earlier experimental and computational studies. Lithiation of ferrocene resulted in the formation of cation-π and metal-lithiated complexes. Similar to protonation, trajectory results revealed that both exo and endo paths were followed, with the exo path being the major one. In addition, lithiated-ferrocene exhibited planetary motion. The major path (exo) followed in the protonation and lithiation of ferrocene is consistent with the observations in earlier experimental studies for other hard electrophiles.

Nrf2 and HSF-1 Pathway Activation via Hydroquinone-Based Proelectrophilic Small Molecules is Regulated by Electrochemical Oxidation Potential.

PubMed

Satoh, Takumi; Stalder, Romain; McKercher, Scott R; Williamson, Robert E; Roth, Gregory P; Lipton, Stuart A

2015-01-01

Activation of the Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2 and heat-shock protein 90/heat-shock factor-1 signal-transduction pathways plays a central role in combatting cellular oxidative damage and related endoplasmic reticulum stress. Electrophilic compounds have been shown to be activators of these transcription-mediated responses through S-alkylation of specific regulatory proteins. Previously, we reported that a prototype compound (D1, a small molecule representing a proelectrophilic, para-hydroquinone species) exhibited neuroprotective action by activating both of these pathways. We hypothesized that the para-hydroquinone moiety was critical for this activation because it enhanced transcription of these neuroprotective pathways to a greater degree than that of the corresponding ortho-hydroquinone isomer. This notion was based on the differential oxidation potentials of the isomers for the transformation of the hydroquinone to the active, electrophilic quinone species. Here, to further test this hypothesis, we synthesized a pair of para- and ortho-hydroquinone-based proelectrophilic compounds and measured their redox potentials using analytical cyclic voltammetry. The redox potential was then compared with functional biological activity, and the para-hydroquinones demonstrated a superior neuroprotective profile. © The Author(s) 2015.

Research to Significantly Enhance Composite Survivability at 550 F in Oxidative Environments

NASA Technical Reports Server (NTRS)

Byrd, Jim; Guinn, LaToya; Tilley, Kendra; Carson, Laura; Carty, Antoine; Meador, Michael (Technical Monitor)

2001-01-01

Prairie View A&M University using the NASA FAR grant has embarked on several paths to accomplish the initial goals of: (1) synthesizing three ring aromatic diamines to be used as monomers in the synthesis of polyamide resins; and (2) study hydrothermal aging behaviors and glass transition changes of composites synthesized at NASA Glenn Research Center. In establishing the synthesis of the three ring aromatic diamine, it has become necessary to conduct preliminary synthesis to include the nitration of diphenylmethane. The concentration and temperature were altered to assess the effect of purity of isomeric product distribution in such electrophilic aromatic substitution reaction. Products were analyzed using H and C-NMR, Thin Layer Chromatography, High Pressure Liquid Chromatography and GC-Mass Spectrometry (in progress). Results indicate that by varying the concentration of the reaction, a mixture of products can be obtained. Other electrophilic aromatic substitution reactions are also in progress such as Friedel-Craft acylation reaction using diphenylmethane with 4-nitrobenzoyl chloride to afford other diamine products. Furthermore, PVAMU has nearly completed the hydrothermal studies to assess the oxidative stability of DSP443B and DSP442A panels formulated at NASA Glenn Research Center.

Isoform-specific modulation of the chemical sensitivity of conserved TRPA1 channel in the major honeybee ectoparasitic mite, Tropilaelaps mercedesae

PubMed Central

Dong, Xiaofeng; Kashio, Makiko; Peng, Guangda; Wang, Xinyue; Tominaga, Makoto

2016-01-01

We identified and characterized the TRPA1 channel of Tropilaelaps mercedesae (TmTRPA1), one of two major species of honeybee ectoparasitic mite. Three TmTRPA1 isoforms with unique N-terminal sequences were activated by heat, and the isoform highly expressed in the mite's front legs, TmTRPA1b, was also activated by 27 plant-derived compounds including electrophiles. This suggests that the heat- and electrophile-dependent gating mechanisms as nocisensitive TRPA1 channel are well conserved between arthropod species. Intriguingly, one TmTRPA1 isoform, TmTRPA1a, was activated by only six compounds compared with two other isoforms, demonstrating that the N-terminal sequences are critical determinants for the chemical sensitivity. This is the first example of isoform-specific modulation of chemical sensitivity of TRPA1 channel in one species. α-terpineol showed repellent activity towards T. mercedesae in a laboratory assay and repressed T. mercedesae entry for reproduction into the brood cells with fifth instar larvae in hives. Thus, α-terpineol could be used as the potential compound to control two major honeybee ectoparasitic mites, T. mercedesae and Varroa destructor, in the apiculture industry. PMID:27307515

NRF2-regulation in brain health and disease: implication of cerebral inflammation

PubMed Central

Sandberg, Mats; Patil, Jaspal; D’Angelo, Barbara; Weber, Stephen G; Mallard, Carina

2014-01-01

The nuclear factor erythroid 2 related factor 2 (NRF2) is a key regulator of endogenous inducible defense systems in the body. Under physiological conditions NRF2 is mainly located in the cytoplasm. However, in response to oxidative stress, NRF2 translocates to the nucleus and binds to specific DNA sites termed “anti-oxidant response elements” or “electrophile response elements” to initiate transcription of cytoprotective genes. Acute oxidative stress to the brain, such as stroke and traumatic brain injury is increased in animals that are deficient in NRF2. Insufficient NRF2 activation in humans has been linked to chronic diseases such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis. New findings have also linked activation of the NRF2 system to anti-inflammatory effects via interactions with NF-κB. Here we review literature on cellular mechanisms of NRF2 regulation, how to maintain and restore NRF2 function and the relationship between NRF2 regulation and brain damage. We bring forward the hypothesis that inflammation via prolonged activation of key kinases (p38 and GSK-3β) and activation of histone deacetylases gives rise to dysregulation of the NRF2 system in the brain, which contributes to oxidative stress and injury. PMID:24262633

Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2

PubMed Central

2015-01-01

Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme that catalyzes the posttranslational modification of glutamine residues on protein or peptide substrates. A growing body of literature has implicated aberrantly regulated activity of TG2 in the pathogenesis of various human inflammatory, fibrotic, and other diseases. Taken together with the fact that TG2 knockout mice are developmentally and reproductively normal, there is growing interest in the potential use of TG2 inhibitors in the treatment of these conditions. Targeted-covalent inhibitors based on the weakly electrophilic 3-bromo-4,5-dihydroisoxazole (DHI) scaffold have been widely used to study TG2 biology and are well tolerated in vivo, but these compounds have only modest potency, and their selectivity toward other transglutaminase homologues is largely unknown. In the present work, we first profiled the selectivity of existing inhibitors against the most pertinent TG isoforms (TG1, TG3, and FXIIIa). Significant cross-reactivity of these small molecules with TG1 was observed. Structure–activity and −selectivity analyses led to the identification of modifications that improved potency and isoform selectivity. Preliminary pharmacokinetic analysis of the most promising analogues was also undertaken. Our new data provides a clear basis for the rational selection of dihydroisoxazole inhibitors as tools for in vivo biological investigation. PMID:25333388

Dual descriptors within the framework of spin-polarized density functional theory.

PubMed

Chamorro, E; Pérez, P; Duque, M; De Proft, F; Geerlings, P

2008-08-14

Spin-polarized density functional theory (SP-DFT) allows both the analysis of charge-transfer (e.g., electrophilic and nucleophilic reactivity) and of spin-polarization processes (e.g., photophysical changes arising from electron transitions). In analogy with the dual descriptor introduced by Morell et al. [J. Phys. Chem. A 109, 205 (2005)], we introduce new dual descriptors intended to simultaneously give information of the molecular regions where the spin-polarization process linking states of different multiplicity will drive electron density and spin density changes. The electronic charge and spin rearrangement in the spin forbidden radiative transitions S(0)-->T(n,pi(*)) and S(0)-->T(pi,pi(*)) in formaldehyde and ethylene, respectively, have been used as benchmark examples illustrating the usefulness of the new spin-polarization dual descriptors. These quantities indicate those regions where spin-orbit coupling effects are at work in such processes. Additionally, the qualitative relationship between the topology of the spin-polarization dual descriptors and the vertical singlet triplet energy gap in simple substituted carbene series has been also discussed. It is shown that the electron density and spin density rearrangements arise in agreement with spectroscopic experimental evidence and other theoretical results on the selected target systems.

Quantitative structure-activity relationships of the antimalarial agent artemisinin and some of its derivatives - a DFT approach.

PubMed

Rajkhowa, Sanchaita; Hussain, Iftikar; Hazarika, Kalyan K; Sarmah, Pubalee; Deka, Ramesh Chandra

2013-09-01

Artemisinin form the most important class of antimalarial agents currently available, and is a unique sesquiterpene peroxide occurring as a constituent of Artemisia annua. Artemisinin is effectively used in the treatment of drug-resistant Plasmodium falciparum and because of its rapid clearance of cerebral malaria, many clinically useful semisynthetic drugs for severe and complicated malaria have been developed. However, one of the major disadvantages of using artemisinins is their poor solubility either in oil or water and therefore, in order to overcome this difficulty many derivatives of artemisinin were prepared. A comparative study on the chemical reactivity of artemisinin and some of its derivatives is performed using density functional theory (DFT) calculations. DFT based global and local reactivity descriptors, such as hardness, chemical potential, electrophilicity index, Fukui function, and local philicity calculated at the optimized geometries are used to investigate the usefulness of these descriptors for understanding the reactive nature and reactive sites of the molecules. Multiple regression analysis is applied to build up a quantitative structure-activity relationship (QSAR) model based on the DFT based descriptors against the chloroquine-resistant, mefloquine-sensitive Plasmodium falciparum W-2 clone.

C- and N-Metalated Nitriles: The Relationship between Structure and Selectivity.

PubMed

Yang, Xun; Fleming, Fraser F

2017-10-17

Metalated nitriles are exceptional nucleophiles capable of forging highly hindered stereocenters in cases where enolates are unreactive. The excellent nucleophilicity emanates from the powerful inductive stabilization of adjacent negative charge by the nitrile, which has a miniscule steric demand. Inductive stabilization is the key to understanding the reactivity of metalated nitriles because this permits a continuum of structures that range from N-metalated ketenimines to nitrile anions. Solution and solid-state analyses reveal two different metal coordination sites, the formally anionic carbon and the nitrile nitrogen, with the site of metalation depending intimately on the solvent, counterion, temperature, and ligands. The most commonly encountered structures, C- and N-metalated nitriles, have either sp 3 or sp 2 hybridization at the nucleophilic carbon, which essentially translates into two distinct organometallic species with similar but nonidentical stereoselectivity, regioselectivity, and reactivity preferences. The hybridization differences are particularly important in S N i displacements of cyclic nitriles because the orbital orientations create very precise trajectories that control the cyclization selectivity. Harnessing the orbital differences between C- and N-metalated nitriles allows selective cyclization to afford nitrile-containing cis- or trans-hydrindanes, decalins, or bicyclo[5.4.0]undecanes. Similar orbital constraints favor preferential S N i displacements with allylic electrophiles on sp 3 centers over sp 2 centers. The strategy permits stereoselective displacements on secondary centers to set contiguous tertiary and quaternary stereocenters or even contiguous vicinal quaternary centers. Stereoselective alkylations of acyclic nitriles are inherently more challenging because of the difficulty in creating steric differentiation in a dynamic system with rotatable bonds. However, judicious substituent placement of vicinal dimethyl groups and a trisubstituted alkene sufficiently constrains C- and N-metalated nitriles to install quaternary stereocenters with excellent 1,2-induction. The structural differences between C- and N-metalated nitriles permit a rare series of chemoselective alkylations with bifunctional electrophiles. C-Magnesiated nitriles preferentially react with carbonyl electrophiles, whereas N-lithiated nitriles favor S N 2 displacement of alkyl halides. The chemoselective alkylations potentially provide a strategy for late-stage alkylations of polyfunctional electrophiles en route to bioactive targets. In this Account, the bonding of metalated nitriles is summarized as a prelude to the different strategies for selectively preparing C- and N-metalated nitriles. With this background, the Account then transitions to applications in which C- or N-metalated nitriles allow complementary diastereoselectivity in alkylations and arylations, and regioselective alkylations and arylations, with acyclic and cyclic nitriles. In the latter sections, a series of regiodivergent cyclizations are described that provide access to cis- and trans-hydrindanes and decalins, structural motifs embedded within a plethora of natural products. The last section describes chemoselective alkylations and acylations of C- and N-metalated nitriles that offer the tantalizing possibility of selectively manipulating functional groups in bioactive medicinal leads without recourse to protecting groups. Collectively, the unusual reactivity profiles of C- and N-metalated nitriles provide new strategies for rapidly and selectively accessing valuable synthetic precursors.

Exploring the anionic reactivity of ynimines, useful precursors of metalated ketenimines.

PubMed

Laouiti, Anouar; Couty, François; Marrot, Jérome; Boubaker, Taoufik; Rammah, Mohamed M; Rammah, Mohamed B; Evano, Gwilherm

2014-04-18

Insights into the reactivity of ynimines under anionic conditions are reported. They were shown to be excellent precursors of metalated ketenimines, which can be generated in situ by the reaction of ynimines with organolithium reagents or strong bases. The metalated ketenimines can then be trapped with various electrophiles and, depending on their substitution pattern, afford original and divergent entries to various building blocks.

Just Click It: Undergraduate Procedures for the Copper(I)-Catalyzed Formation of 1,2,3-Triazoles from Azides and Terminal Acetylenes

ERIC Educational Resources Information Center

Sharpless, William D.; Peng Wu; Hansen, Trond Vidar; Lindberg, James G.

2005-01-01

The click chemistry uses only the most reliable reactions to build complex molecules from olefins, electrophiles and heteroatom linkers. A variation on Huisgen's azide-alkyne 1,2,3-triazole synthesis, the addition of the copper (I), the premium example of the click reaction, catalyst strongly activates terminal acetylenes towards the 1,3-dipole in…

Stereoselective Synthesis of [alpha, alpha][superscript ']-Biprolines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vartak, Ashish P.; Young, Jr., Victor G.; Johnson, Rodney L.

2010-11-10

A means to induce dehydrodimerization of Seebach's oxazolidinone (5), the stereochemical outcome of which is entirely temperature dependent, is described. The resultant dimers 3 and 4 are precursors to (R,R)-alpha,alpha'-biproline (1) and meso-alpha,alpha'-biproline (2), respectively. An organohypobromite and an iminium halide are proposed to serve as electrophiles in the reaction with the enolate of 5 to give 3 and 4, respectively.

Structural Insights into the Dual Activities of the Nerve Agent Degrading Organophosphate Anhydrolase/Prolidase

DTIC Science & Technology

2009-12-11

class of bimetalloenzymes that hydrolyze a variety of toxic acetylcholinesterase-inhibiting organophosphorus compounds, including fluorine ... electrophilicity of the phosphorus center. Similar interactions and functions have been proposed for the carbonyl oxygen of the scissile peptide bond...163, 261–276. 2. Mazur, A. (1946) An enzyme in animal tissues capable of hydrolyzing the phosphorus- fluorine bond of alkyl fluorophosphate. J. Biol

Facile synthesis of unsymmetrical acridines and phenazines by a Rh(III)-catalyzed amination/cyclization/aromatization cascade.

PubMed

Lian, Yajing; Hummel, Joshua R; Bergman, Robert G; Ellman, Jonathan A

2013-08-28

We report formal [3 + 3] annulations of aromatic azides with aromatic imines and azobenzenes to give acridines and phenazines, respectively. These transformations proceed through a cascade process of Rh(III)-catalyzed amination followed by intramolecular electrophilic aromatic substitution and aromatization. Acridines can be directly prepared from aromatic aldehydes by in situ imine formation using catalytic benzylamine.

Trend of Mathematical Models in Microbial Fuel Cell for Environmental Energy Refinery from Waste/Water

NASA Astrophysics Data System (ADS)

Oh, Sung Taek

A microbial fuel cell (MFC) is a device to use for bio electrochemical energy production. Electrophilic bacteria produce electrons in their metabolic pathway and the electrons can be extracted and concentrated on electrode by the electric potential difference (i.e. Galvanic cell). The bio-electrode may provide new opportunities for the renewable energy in waste water/swage treatment plants.

Process for removing sulfur from coal

DOEpatents

Aida, T.; Squires, T.G.; Venier, C.G.

1983-08-11

A process is disclosed for the removal of divalent organic and inorganic sulfur compounds from coal and other carbonaceous material. A slurry of pulverized carbonaceous material is contacted with an electrophilic oxidant which selectively oxidizes the divalent organic and inorganic compounds to trivalent and tetravalent compounds. The carbonaceous material is then contacted with a molten caustic which dissolves the oxidized sulfur compounds away from the hydrocarbon matrix.

Computational Study of Chemical Reactivity Using Information-Theoretic Quantities from Density Functional Reactivity Theory for Electrophilic Aromatic Substitution Reactions.

PubMed

Wu, Wenjie; Wu, Zemin; Rong, Chunying; Lu, Tian; Huang, Ying; Liu, Shubin

2015-07-23

The electrophilic aromatic substitution for nitration, halogenation, sulfonation, and acylation is a vastly important category of chemical transformation. Its reactivity and regioselectivity is predominantly determined by nucleophilicity of carbon atoms on the aromatic ring, which in return is immensely influenced by the group that is attached to the aromatic ring a priori. In this work, taking advantage of recent developments in quantifying nucleophilicity (electrophilicity) with descriptors from the information-theoretic approach in density functional reactivity theory, we examine the reactivity properties of this reaction system from three perspectives. These include scaling patterns of information-theoretic quantities such as Shannon entropy, Fisher information, Ghosh-Berkowitz-Parr entropy and information gain at both molecular and atomic levels, quantitative predictions of the barrier height with both Hirshfeld charge and information gain, and energetic decomposition analyses of the barrier height for the reactions. To that end, we focused in this work on the identity reaction of the monosubstituted-benzene molecule reacting with hydrogen fluoride using boron trifluoride as the catalyst in the gas phase. We also considered 19 substituting groups, 9 of which are ortho/para directing and the other 9 meta directing, besides the case of R = -H. Similar scaling patterns for these information-theoretic quantities found for stable species elsewhere were disclosed for these reactions systems. We also unveiled novel scaling patterns for information gain at the atomic level. The barrier height of the reactions can reliably be predicted by using both the Hirshfeld charge and information gain at the regioselective carbon atom. The energy decomposition analysis ensued yields an unambiguous picture about the origin of the barrier height, where we showed that it is the electrostatic interaction that plays the dominant role, while the roles played by exchange-correlation and steric effects are minor but indispensable. Results obtained in this work should shed new light for better understanding of the factors governing the reactivity for this class of reactions and assisting ongoing efforts for the design of new and more efficient catalysts for such kind of transformations.

Lewis Acid Promoted Hydrogenation of CO2 and HCOO- by Amine Boranes: Mechanistic Insight from a Computational Approach.

PubMed

Roy, Lisa; Ghosh, Boyli; Paul, Ankan

2017-07-13

We employ quantum chemical calculations to study the hydrogenation of carbon dioxide by amine boranes, NMe 3 BH 3 ( Me3 AB) and NH 3 BH 3 (AB) weakly bonded to a bulkier Lewis acid, Al(C 6 F 5 ) 3 (LA). Additionally, computations have also been conducted to elucidate the mechanism of hydrogenation of carbon dioxide by Me3 AB while captured between one Lewis base (P(o-tol 3 ), LB) and two Lewis acids, Al(C 6 F 5 ) 3 . In agreement with the experiments, our computational study predicts that hydride transfer to conjugated HCO 2 - , generated in the reaction of Me3 AB-LA with CO 2 , is not feasible. This is in contrast to the potential hydrogenation of bound HCO 2 H, developed in the reduction of CO 2 with AB-LA, to further reduced species like H 2 C(OH) 2 . However, the FLP-trapped CO 2 effortlessly undergoes three hydride (H - ) transfers from Me3 AB to produce a CH 3 O - derivative. DFT calculations reveal that the preference for a H - abstraction by an intrinsically anionic formate moiety is specifically dependent on the electrophilicity of the 2 e - reduced carbon center, which in particular is controlled by the electron-withdrawing capability of the associated substituents on the oxygen. These theoretical predictions are justified by frontier molecular orbitals and molecular electrostatic potential plots. The global electrophicility index, which is a balance of electron affinity and hardness, reveals that the electrophilicity of the formate species undergoing hydrogenation is twice the electrophilicity of the ones where hydrogenation is not feasible. The computed activation energies at M06-2X/6-31++G(d,p) closely predict the observed reactivity. In addition, the possibility of a dissociative channel of the frustrated Lewis pair trapped CO 2 system has been ruled out on the basis of predominantly high endergonicity. Knowledge of the underlying principle of these reactions would be helpful in recruiting appropriate Lewis acids/amine boranes for effective reduction of CO 2 and its hydrogenated forms in a catalytic fashion.

The isothiocyanate class of bioactive nutrients covalently inhibit the MEKK1 protein kinase

PubMed Central

Cross, Janet V; Foss, Frank W; Rady, Joshua M; Macdonald, Timothy L; Templeton, Dennis J

2007-01-01

Background Dietary isothiocyanates (ITCs) are electrophilic compounds that have diverse biological activities including induction of apoptosis and effects on cell cycle. They protect against experimental carcinogenesis in animals, an activity believed to result from the transcriptional induction of "Phase 2" enzymes. The molecular mechanism of action of ITCs is unknown. Since ITCs are electrophiles capable of reacting with sulfhydryl groups on amino acids, we hypothesized that ITCs induce their biological effects through covalent modification of proteins, leading to changes in cell regulatory events. We previously demonstrated that stress-signaling kinase pathways are inhibited by other electrophilic compounds such as menadione. We therefore tested the effects of nutritional ITCs on MEKK1, an upstream regulator of the SAPK/JNK signal transduction pathway. Methods The activity of MEKK1 expressed in cells was monitored using in vitro kinase assays to measure changes in catalytic activity. The activity of endogenous MEKK1, immunopurified from ITC treated and untreated LnCAP cells was also measured by in vitro kinase assay. A novel labeling and affinity reagent for detection of protein modification by ITCs was synthesized and used in competition assays to monitor direct modification of MEKK1 by ITC. Finally, immunoblots with phospho-specific antibodies were used to measure the activity of MAPK protein kinases. Results ITCs inhibited the MEKK1 protein kinase in a manner dependent on a specific cysteine residue in the ATP binding pocket. Inhibition of MEKK1 catalytic activity was due to direct, covalent and irreversible modification of the MEKK1 protein itself. In addition, ITCs inhibited the catalytic activity of endogenous MEKK1. This correlated with inhibition of the downstream target of MEKK1 activity, i.e. the SAPK/JNK kinase. This inhibition was specific to SAPK, as parallel MAPK pathways were unaffected. Conclusion These results demonstrate that MEKK1 is directly modified and inhibited by ITCs, and that this correlates with inhibition of downstream activation of SAPK. These results support the conclusion that ITCs may carry out many of their actions by directly targeting important cell regulatory proteins. PMID:17894894

HMOX1 and NQO1 genes are upregulated in response to contact sensitizers in dendritic cells and THP-1 cell line: role of the Keap1/Nrf2 pathway.

PubMed

Ade, Nadège; Leon, Fanny; Pallardy, Marc; Peiffer, Jean-Luc; Kerdine-Romer, Saadia; Tissier, Marie-Hélène; Bonnet, Pierre-Antoine; Fabre, Isabelle; Ourlin, Jean-Claude

2009-02-01

Electrophilicity is one of the most common features of skin contact sensitizers and is necessary for protein haptenation. The Keap1 (Kelch-like ECH-associated protein 1)/Nrf2 -signaling pathway is dedicated to the detection of electrophilic stress in cells leading to the upregulation of genes involved in protection or neutralization of chemical reactive species. Signals provided by chemical stress could play an important role in dendritic cell activation and the aim of this work was to test whether contact sensitizers were specific activators of the Keap1/Nrf2 pathway. CD34-derived dendritic cells (CD34-DC) and the THP-1 myeloid cell line were treated by a panel of sensitizers (Ni, 1-chloro 2,4-dinitrobenzene, cinnamaldehyde, 7-hydroxycitronellal, 1,4-dihydroquinone, alpha-methyl-trans-cinnamaldehyde, 2-4-tert-(butylbenzyl)propionaldehyde or Lilial, and 1,4-phenylenediamine), irritants (sodium dodecyl sulfate, benzalkonium chloride), and a nonsensitizer molecule (chlorobenzene). Three well-known Nrf2 activators (tert-butylhydroquinone, lipoic acid, sulforaphane) were also tested. Expression of hmox1 and nqo1 was measured using real-time PCR and cellular accumulation of Nrf2 was assessed by Western blot. Our results showed an increased expression at early time points of hmox1 and nqo1 mRNAs in response to sensitizers but not to irritants. Accumulation of the Nrf2 protein was also observed only with chemical sensitizers. A significant inhibition of the expression of hmox1 and nqo1 mRNAs and CD86 expression was found in 1-chloro 2,4-dinitrobenzene-treated THP-1 cells preincubated with N-acetyl cysteine, a glutathione precursor. Altogether, these data suggested that the Keap1/Nrf2-signaling pathway was activated by electrophilic molecules including sensitizers in dendritic cells and in the THP-1 cell line. Monitoring of this pathway may provide new biomarkers (e.g., Nrf2, hmox1) for the detection of the sensitization potential of chemicals.

Differences between Homicides Committed by Lone and Multiple Offenders in Korea.

PubMed

Park, Jisun; Cho, Joon Tag

2018-05-16

The aim of this study was to differentiate between homicides committed by multiple offenders and homicides committed by lone offenders. Using data on homicide incidents that occurred in South Korea between 1985 and 2008, we compared 134 homicides committed by multiple offenders, with 369 homicides committed by lone offenders. A greater proportion of homicides committed by multiple offenders involved injuries to the victim's head compared to homicides by lone offenders. Homicides committed by multiple offenders were more likely to involve blunt instruments and ligatures, whereas homicides by lone offenders were more likely to involve sharp instruments. In addition, a majority of the homicides committed by multiple offenders were planned. The results of this study have practical implications for homicide investigations, as well as theoretical implications for homicide research on the difference in offense behaviors based on the number of offenders. © 2018 American Academy of Forensic Sciences.

Palladium-Catalyzed Direct C-H Allylation of Electron-Deficient Polyfluoroarenes with Alkynes.

PubMed

Zheng, Jun; Breit, Bernhard

2018-04-06

A palladium-catalyzed intermolecular direct C-H allylation of polyfluoroarenes with alkynes is reported. Unlike classic hydroarylation reactions, alkynes are used as allylic electrophile surrogates in this direct aromatic C-H allylation. As an atom-economic and efficient method, various linear allylated fluoroarenes were synthesized from two simple and easy-to-access feedstocks in good to excellent yields, as well as regio- and stereoselectivity.

Assembly of Terpenoid Cores by a Simple, Tunable Strategy.

PubMed

Lahtigui, Ouidad; Emmetiere, Fabien; Zhang, Wei; Jirmo, Liban; Toledo-Roy, Samira; Hershberger, John C; Macho, Jocelyn M; Grenning, Alexander J

2016-12-19

Oxygenated, polycyclic terpenoid natural products have important biological activities. Although total synthesis of such terpenes is widely studied, synthetic strategies that allow for controlled placement of oxygen atoms and other functionality remains a challenge. Herein, we present a simple, scalable, and tunable synthetic strategy to assemble terpenoid-like polycycloalkanes from cycloalkanones, malononitrile, and allylic electrophiles, abundantly available reagent classes. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cyclopentadienyl Rhenium (Technetium) Tricarbonyl Complexes Integrated in Estrogen Receptor Ligands for ER+ Tumor Imaging

DTIC Science & Technology

2006-10-01

determined by imaging correlate well with those determined by immunoassay methods on surgical biopsies. Because of the short half-life of fluorine -18, this...immunoassay methods on surgical biopsies. Currently, the most effective ER imaging agent is a fluorine -18 labeled estrogen. However, because of the short...substituent to the central pentacycle, including nucleophilic addition of organometallic reagents, addition of electrophiles to the cyclopentadiene

Cytoprotection of Human Endothelial Cells Against Oxidative Stress by 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im): Application of Systems Biology to Understand the Mechanism of Action

DTIC Science & Technology

2014-04-03

and exogenous oxidants, electrophiles , and toxicants. Activation of this pathway was reported to facilitate the induction of HMOX1 (Heiss et al., 2009...cytoprotective effect of caffeic acid phenethyl ester (CAPE) and fluorinated derivatives: effects on heme oxygenase-1 induction and antioxidant

Facile Synthesis of Unsymmetrical Acridines and Phenazines by a Rhodium(III)-Catalyzed Amination, Cyclization and Aromatization Cascade

PubMed Central

Lian, Yajing; Hummel, Joshua R.; Bergman, Robert G.; Ellman, Jonathan A.

2013-01-01

New formal [3 + 3] annulations have been developed to obtain acridines and phenazines from aromatic azides and aromatic imines and azobenzenes, respectively. These transformations proceed through a cascade process of Rh(III)-catalyzed amination followed by intramolecular electrophilic aromatic substitution and aromatization. Acridines can be directly prepared from aromatic aldehydes by in situ imine formation using catalytic benzylamine. PMID:23957711

Zinc-catalyzed allenylations of aldehydes and ketones.

PubMed

Fandrick, Daniel R; Saha, Jaideep; Fandrick, Keith R; Sanyal, Sanjit; Ogikubo, Junichi; Lee, Heewon; Roschangar, Frank; Song, Jinhua J; Senanayake, Chris H

2011-10-21

The general zinc-catalyzed allenylation of aldehydes and ketones with an allenyl boronate is presented. Preliminary mechanistic studies support a kinetically controlled process wherein, after a site-selective B/Zn exchange to generate a propargyl zinc intermediate, the addition to the electrophile effectively competes with propargyl-allenyl zinc equilibration. The utility of the methodology was demonstrated by application to a rhodium-catalyzed [4+2] cycloaddition. © 2011 American Chemical Society

Dual Visible Light Photoredox and Gold-Catalyzed Arylative Ring Expansion

PubMed Central

2015-01-01

A combination of visible light photocatalysis and gold catalysis is applied to a ring expansion–oxidative arylation reaction. The reaction provides an entry into functionalized cyclic ketones from the coupling reaction of alkenyl and allenyl cycloalkanols with aryl diazonium salts. A mechanism involving generation of an electrophilic gold(III)–aryl intermediate is proposed on the basis of mechanistic studies, including time-resolved FT-IR spectroscopy. PMID:24730447

Synthesis of 2-aryl and 3-aryl benzo[b]furan thioethers using aryl sulfonyl hydrazides as sulfenylation reagents.

PubMed

Zhao, Xia; Zhang, Lipeng; Lu, Xiaoyu; Li, Tianjiao; Lu, Kui

2015-03-06

An efficient, metal-free protocol used to synthesize aryl benzo[b]furan thioethers based on the I2-catalyzed cross-coupling of benzo[b]furans as well as the electrophilic cyclization of 2-alkynylphenol derivatives with aryl sulfonyl hydrazides was developed. Various 2-aryl and 3-aryl benzo[b]furan thioethers were obtained in moderate to good yields.

An exceptionally potent inducer of cytoprotective enzymes: elucidation of the structural features that determine inducer potency and reactivity with Keap1.

PubMed

Dinkova-Kostova, Albena T; Talalay, Paul; Sharkey, John; Zhang, Ying; Holtzclaw, W David; Wang, Xiu Jun; David, Emilie; Schiavoni, Katherine H; Finlayson, Stewart; Mierke, Dale F; Honda, Tadashi

2010-10-29

The Keap1/Nrf2/ARE pathway controls a network of cytoprotective genes that defend against the damaging effects of oxidative and electrophilic stress, and inflammation. Induction of this pathway is a highly effective strategy in combating the risk of cancer and chronic degenerative diseases, including atherosclerosis and neurodegeneration. An acetylenic tricyclic bis(cyano enone) bearing two highly electrophilic Michael acceptors is an extremely potent inducer in cells and in vivo. We demonstrate spectroscopically that both cyano enone functions of the tricyclic molecule react with cysteine residues of Keap1 and activate transcription of cytoprotective genes. Novel monocyclic cyano enones, representing fragments of rings A and C of the tricyclic compound, reveal that the contribution to inducer potency of the ring C Michael acceptor is much greater than that of ring A, and that potency is further enhanced by spatial proximity of an acetylenic function. Critically, the simultaneous presence of two cyano enone functions in rings A and C within a rigid three-ring system results in exceptionally high inducer potency. Detailed understanding of the structural elements that contribute to the reactivity with the protein sensor Keap1 and to high potency of induction is essential for the development of specific and selective lead compounds as clinically relevant chemoprotective agents.

Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents.

PubMed

Abed, Dhulfiqar Ali; Goldstein, Melanie; Albanyan, Haifa; Jin, Huijuan; Hu, Longqin

2015-07-01

The Keap1-Nrf2-ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1-Nrf2 protein-protein interaction (PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of Keap1-Nrf2 PPI and they are electrophilic species that act by modifying the sulfhydryl groups of Keap1׳s cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of Keap1-Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target Keap1 Kelch domain protein. These non-covalent direct inhibitors of Keap1-Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions.

Changes in Dissolved Organic Matter Composition and Disinfection Byproduct Precursors in Advanced Drinking Water Treatment Processes.

PubMed

Phungsai, Phanwatt; Kurisu, Futoshi; Kasuga, Ikuro; Furumai, Hiroaki

2018-03-20

Molecular changes in dissolved organic matter (DOM) from treatment processes at two drinking water treatment plants in Japan were investigated using unknown screening analysis by Orbitrap mass spectrometry. DOM formulas with carbon, hydrogen and oxygen (CHO-DOM) were the most abundant class in water samples, and over half of them were commonly found at both plants. Among the treatment processes, ozonation induced the most drastic changes to DOM. Mass peak intensities of less saturated CHO-DOM (positive (oxygen subtracted double bond equivalent per carbon (DBE-O)/C)) decreased by ozonation, while more saturated oxidation byproducts (negative (DBE-O)/C) increased and new oxidation byproducts (OBPs) were detected. By Kendrick mass analysis, ozone reactions preferred less saturated CHO-DOM in the same alkylation families and produced more saturated alkylation families of OBPs. Following ozonation, biological activated carbon filtration effectively removed <300 Da CHO-DOM, including OBPs. Following chlorination, over 50 chlorinated formulas of disinfection byproducts (DBPs) were found in chlorinated water samples where at least half were unknown. Putative precursors of these DBPs were determined based on electrophilic substitutions and addition reactions. Ozonation demonstrated better decomposition of addition reaction-type precursors than electrophilic substitution-type precursors; over half of both precursor types decreased during biological activated carbon filtration.

Conceptual DFT Study of the Local Chemical Reactivity of the Colored BISARG Melanoidin and Its Protonated Derivative

PubMed Central

Frau, Juan; Glossman-Mitnik, Daniel

2018-01-01

This computational study assessed eight fixed RSH (range-separated hybrid) density functionals that include CAM-B3LYP, LC-ωPBE, M11, MN12SX, N12SX, ωB97, ωB97X, and ωB97XD related to the Def2TZVP basis sets together with the SMD solvation model in the calculation the molecular structure and reactivity properties of the BISARG intermediate melanoidin pigment (5-(2-(E)-(Z)-5-[(2-furyl)methylidene]-3-(4-acetylamino-4-carboxybutyl)-2-imino-1,3-dihydroimidazol-4-ylideneamino(E)-4-[(2-furyl)methylidene]-5-oxo-1H-imidazol-1-yl)-2-acetylaminovaleric acid) and its protonated derivative, BISARG(p). The chemical reactivity descriptors for the systems were calculated via the Conceptual Density Functional Theory. The choice of active sites applicable to nucleophilic, electrophilic as well as radical attacks were made by linking them with Fukui functions indices, electrophilic and nucleophilic Parr functions, and the condensed Dual Descriptor Δf(r). The study found the MN12SX and N12SX density functionals to be the most appropriate in predicting the chemical reactivity of the molecular systems under study starting from the knowledge of the HOMO, LUMO, and HOMO-LUMO gap energies. PMID:29765937

Targeted Mutagenesis of the Mycobacterium smegmatis mca Gene, Encoding a Mycothiol-Dependent Detoxification Protein

PubMed Central

Rawat, Mamta; Uppal, Mandeep; Newton, Gerald; Steffek, Micah; Fahey, Robert C.; Av-Gay, Yossef

2004-01-01

Mycothiol (MSH), a functional analogue of glutathione (GSH) that is found exclusively in actinomycetes, reacts with electrophiles and toxins to form MSH-toxin conjugates. Mycothiol S-conjugate amidase (Mca) then catalyzes the hydrolysis of an amide bond in the S conjugates, producing a mercapturic acid of the toxin, which is excreted from the bacterium, and glucosaminyl inositol, which is recycled back to MSH. In this study, we have generated and characterized an allelic exchange mutant of the mca gene of Mycobacterium smegmatis. The mca mutant accumulates the S conjugates of the thiol-specific alkylating agent monobromobimane and the antibiotic rifamycin S. Introduction of M. tuberculosis mca epichromosomally or introduction of M. smegmatis mca integratively resulted in complementation of Mca activity and reduced levels of S conjugates. The mutation in mca renders the mutant strain more susceptible to electrophilic toxins, such as N-ethylmalemide, iodoacetamide, and chlorodinitrobenzene, and to several oxidants, such as menadione and plumbagin. Additionally we have shown that the mca mutant is also more susceptible to the antituberculous antibiotic streptomycin. Mutants disrupted in genes belonging to MSH biosynthesis are also more susceptible to streptomycin, providing further evidence that Mca detoxifies streptomycin in the mycobacterial cell in an MSH-dependent manner. PMID:15342574

Surface Organometallic Chemistry of Supported Iridium(III) as a Probe for Organotransition Metal–Support Interactions in C–H Activation

DOE PAGES

Kaphan, David M.; Klet, Rachel C.; Perras, Frederic A.; ...

2018-05-11

Systematic study of the interactions between organometallic catalysts and metal oxide support materials is essential for the realization of rational design in heterogeneous catalysis. Herein we describe the stoichiometric and catalytic chemistry of a [Cp*(PMe 3)Ir(III)] complex chemisorbed on a variety of acidic metal oxides as a multifaceted probe for stereoelectronic communication between the support and organometallic center. Electrophilic bond activation was explored in the context of stoichiometric hydrogenolysis as well as catalytic H/D exchange. Further information was obtained from the observation of processes related to dynamic exchange between grafted organometallic species and those in solution. The supported organometallic speciesmore » were characterized by a variety of spectroscopic techniques including dynamic nuclear polarization-enhanced solid-state NMR spectroscopy, diffuse reflectance infrared Fourier transform spectroscopy, and X-ray absorption spectroscopy. Finally, strongly acidic modified metal oxides such as sulfated zirconia engender high levels of activity toward electrophilic bond activation of both sp 2 and sp 3 C–H bonds, including the rapid deuteration of methane at room temperature; however, the global trend for the supports studied here does not suggest a direct correlation between activity and surface Brønsted acidity.« less

Surface Organometallic Chemistry of Supported Iridium(III) as a Probe for Organotransition Metal–Support Interactions in C–H Activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaphan, David M.; Klet, Rachel C.; Perras, Frederic A.

Systematic study of the interactions between organometallic catalysts and metal oxide support materials is essential for the realization of rational design in heterogeneous catalysis. Herein we describe the stoichiometric and catalytic chemistry of a [Cp*(PMe 3)Ir(III)] complex chemisorbed on a variety of acidic metal oxides as a multifaceted probe for stereoelectronic communication between the support and organometallic center. Electrophilic bond activation was explored in the context of stoichiometric hydrogenolysis as well as catalytic H/D exchange. Further information was obtained from the observation of processes related to dynamic exchange between grafted organometallic species and those in solution. The supported organometallic speciesmore » were characterized by a variety of spectroscopic techniques including dynamic nuclear polarization-enhanced solid-state NMR spectroscopy, diffuse reflectance infrared Fourier transform spectroscopy, and X-ray absorption spectroscopy. Finally, strongly acidic modified metal oxides such as sulfated zirconia engender high levels of activity toward electrophilic bond activation of both sp 2 and sp 3 C–H bonds, including the rapid deuteration of methane at room temperature; however, the global trend for the supports studied here does not suggest a direct correlation between activity and surface Brønsted acidity.« less

Conceptual DFT Study of the Local Chemical Reactivity of the Colored BISARG Melanoidin and Its Protonated Derivative.

PubMed

Frau, Juan; Glossman-Mitnik, Daniel

2018-01-01

This computational study assessed eight fixed RSH (range-separated hybrid) density functionals that include CAM-B3LYP, LC-ωPBE, M11, MN12SX, N12SX, ωB97, ωB97X, and ωB97XD related to the Def2TZVP basis sets together with the SMD solvation model in the calculation the molecular structure and reactivity properties of the BISARG intermediate melanoidin pigment (5-(2-(E)-(Z)-5-[(2-furyl)methylidene]-3-(4-acetylamino-4-carboxybutyl)-2-imino-1,3-dihydroimidazol-4-ylideneamino(E)-4-[(2-furyl)methylidene]-5-oxo-1H-imidazol-1-yl)-2-acetylaminovaleric acid) and its protonated derivative, BISARG(p). The chemical reactivity descriptors for the systems were calculated via the Conceptual Density Functional Theory. The choice of active sites applicable to nucleophilic, electrophilic as well as radical attacks were made by linking them with Fukui functions indices, electrophilic and nucleophilic Parr functions, and the condensed Dual Descriptor Δf( r ). The study found the MN12SX and N12SX density functionals to be the most appropriate in predicting the chemical reactivity of the molecular systems under study starting from the knowledge of the HOMO, LUMO, and HOMO-LUMO gap energies.

Hydrogen sulfide deactivates common nitrobenzofurazan-based fluorescent thiol labeling reagents.

PubMed

Montoya, Leticia A; Pluth, Michael D

2014-06-17

Sulfhydryl-containing compounds, including thiols and hydrogen sulfide (H2S), play important but differential roles in biological structure and function. One major challenge in separating the biological roles of thiols and H2S is developing tools to effectively separate the reactivity of these sulfhydryl-containing compounds. To address this challenge, we report the differential responses of common electrophilic fluorescent thiol labeling reagents, including nitrobenzofurazan-based scaffolds, maleimides, alkylating agents, and electrophilic aldehydes, toward cysteine and H2S. Although H2S reacted with all of the investigated scaffolds, the photophysical response to each scaffold was significantly different. Maleimide-based, alkylating, and aldehydic thiol labeling reagents provided a diminished fluorescence response when treated with H2S. By contrast, nitrobenzofurazan-based labeling reagents were deactivated by H2S addition. Furthermore, the addition of H2S to thiol-activated nitrobenzofurazan-based reagents reduced the fluorescence signal, thus establishing the incompatibility of nitrobenzofurazan-based thiol labeling reagents in the presence of H2S. Taken together, these studies highlight the differential reactivity of thiols and H2S toward common thiol-labeling reagents and suggest that sufficient care must be taken when labeling or measuring thiols in cellular environments that produce H2S due to the potential for both false-positive and eroded responses.

Thiol-Based Redox Switches and Gene Regulation

PubMed Central

2011-01-01

Abstract Cysteine is notable among the universal, proteinogenic amino acids for its facile redox chemistry. Cysteine thiolates are readily modified by reactive oxygen species (ROS), reactive electrophilic species (RES), and reactive nitrogen species (RNS). Although thiol switches are commonly triggered by disulfide bond formation, they can also be controlled by S-thiolation, S-alkylation, or modification by RNS. Thiol-based switches are common in both prokaryotic and eukaryotic organisms and activate functions that detoxify reactive species and restore thiol homeostasis while repressing functions that would be deleterious if expressed under oxidizing conditions. Here, we provide an overview of the best-understood examples of thiol-based redox switches that affect gene expression. Intra- or intermolecular disulfide bond formation serves as a direct regulatory switch for several bacterial transcription factors (OxyR, OhrR/2-Cys, Spx, YodB, CrtJ, and CprK) and indirectly regulates others (the RsrA anti-σ factor and RegB sensory histidine kinase). In eukaryotes, thiol-based switches control the yeast Yap1p transcription factor, the Nrf2/Keap1 electrophile and oxidative stress response, and the Chlamydomonas NAB1 translational repressor. Collectively, these regulators reveal a remarkable range of chemical modifications exploited by Cys residues to effect changes in gene expression. Antioxid. Redox Signal. 14, 1049—1063. PMID:20626317

Creating the Multiple Personality: An Experiential Demonstration for an Undergraduate Abnormal Psychology Class.

ERIC Educational Resources Information Center

Rabinowitz, Fredric E.

1989-01-01

Discusses a classroom role-playing exercise in which students and teacher re-enact interviewing techniques that cause subjects to assume characteristics of the multiple personality. Demonstrates the social psychological aspects of multiple personality disorder. Considers the pedagogical and ethical implications of creating the multiple personality…

Design requirements for SRB production control system. Volume 2: System requirements and conceptual description

NASA Technical Reports Server (NTRS)

1981-01-01

In the development of the business system for the SRB automated production control system, special attention had to be paid to the unique environment posed by the space shuttle. The issues posed by this environment, and the means by which they were addressed, are reviewed. The change in management philosphy which will be required as NASA switches from one-of-a-kind launches to multiple launches is discussed. The implications of the assembly process on the business system are described. These issues include multiple missions, multiple locations and facilities, maintenance and refurbishment, multiple sources, and multiple contractors. The implications of these aspects on the automated production control system are reviewed including an assessment of the six major subsystems, as well as four other subsystem. Some general system requirements which flow through the entire business system are described.

Cooperation evolution in random multiplicative environments

NASA Astrophysics Data System (ADS)

Yaari, G.; Solomon, S.

2010-02-01

Most real life systems have a random component: the multitude of endogenous and exogenous factors influencing them result in stochastic fluctuations of the parameters determining their dynamics. These empirical systems are in many cases subject to noise of multiplicative nature. The special properties of multiplicative noise as opposed to additive noise have been noticed for a long while. Even though apparently and formally the difference between free additive vs. multiplicative random walks consists in just a move from normal to log-normal distributions, in practice the implications are much more far reaching. While in an additive context the emergence and survival of cooperation requires special conditions (especially some level of reward, punishment, reciprocity), we find that in the multiplicative random context the emergence of cooperation is much more natural and effective. We study the various implications of this observation and its applications in various contexts.

A general framework for the solvatochromism of pyridinium phenolate betaine dyes

NASA Astrophysics Data System (ADS)

Rezende, Marcos Caroli; Aracena, Andrés

2013-02-01

A general framework for the solvatochromic behavior of pyridinium phenolate betaine dyes is presented, based on the variations with the medium of the electrophilic Fukui functions of their electron-pair donor and acceptor moieties. The model explains the ‘anomalous' solvatochromic behavior of large betaines, which change their behavior from negative to inverted, when electron-pair donor and acceptor groups are separated by a conjugated chain of variable size.

Aryl imidazylates and aryl sulfates as electrophiles in metal-free ArS(N)1 reactions.

PubMed

Qrareya, Hisham; Protti, Stefano; Fagnoni, Maurizio

2014-12-05

Some oxygen-bonded substituents were investigated as leaving groups in photoinduced ArS(N)1 reactions. Irradiation of aryl imidazylates and of the corresponding imidazolium salts mainly caused homolysis of the ArO-S bond. However, previously unexplored trifluoroethoxy aryl sulfates were found to undergo efficient metal-free arylation. The sulfates were conveniently generated in situ by dissolving the corresponding imidazolium salts in basic 2,2,2-trifluoroethanol.

Magnesium Bisamide-Mediated Halogen Dance of Bromothiophenes.

PubMed

Yamane, Yoshiki; Sunahara, Kazuhiro; Okano, Kentaro; Mori, Atsunori

2018-03-16

A magnesium bisamide-mediated halogen dance of bromothiophenes is described. The thienylmagnesium species generated in situ is more stable than the corresponding thienyllithium species, which was applied to trap the transient anion species with several electrophiles, such as allyl iodide, phenyl isocyanate, and tributylstannyl chloride. The utility of the magnesium bisamide-mediated halogen dance is useful in the concise synthesis of a medicinally advantageous compound via a one-pot, ester-directed halogen dance/Negishi cross coupling.

Diastereoselective synthesis of enantiopure morpholines by electrophilic selenium-induced 6-exo cyclizations on chiral 3-allyl-2-hydroxymethylperhydro-1,3-benzoxazine derivatives.

PubMed

Pedrosa, Rafael; Andrés, Celia; Mendiguchía, Pilar; Nieto, Javier

2006-11-10

Enantiopure morpholine derivatives have been prepared by selenocyclofunctionalization of chiral 3-allyl-2-hydroxymethyl-substituted perhydro-1,3-benzoxazine derivatives. The cyclization occurs in high yields and diastereoselection, although the temperature of the reaction and the structure of the substituent at C-2 and the substitution pattern of the double bond can modify the regio- and stereochemistry of the final products.

Research in Energetic Compounds.

DTIC Science & Technology

1981-01-01

The ring is thus amenable to electrophilic opening. Efforts to polymerize 3, 3-dinitrooxetane will be continued. An intermediate In the preparation of...r- nitronate salts and formaldehyde.2 This reaction is ported to give a stable dialkoxide salt. In order to explore markedly inhibited by a fluorine ...a to nitro as a manifes- further the chemistry of 2-fluoro-2-nitro-I,3-propanediol, tation of the " fluorine effect" or the destabilization of a we

Structural Investigation of Fluoridated POSS Cages Using Ion Mobility Mass Spectrometry and Molecular Mechanics (Preprint)

DTIC Science & Technology

2008-01-09

organic polymer. For example, the low surface energy properties of fluorinated POSS compounds have been used to augment both fluorinated and non... fluorinated polymers.10-13 Many POSS monomers have been successfully characterized using MALDI techniques14-16 in conjunction with ion mobility mass...nucleophilic attack, are shown in blue. Negative contours, showing susceptibility to electrophilic attack, are shown in red. The positive contour of

Efficient catalysis of Nazarov cyclization using a cationic iridium complex possessing adjacent labile coordination sites.

PubMed

Janka, Mesfin; He, Wei; Frontier, Alison J; Eisenberg, Richard

2004-06-09

The dicationic Ir(III) complex [IrMe(CO)(dppe)(DIB)](BARF)2 having adjacent labile sites has been found to be a very effective catalyst for promoting the Nazarov cyclization of aryl vinyl and divinyl ketones. Spectroscopic evidence for a substate-catalyst complex before cyclization is presented. The efficiency of the cyclization is attributed to the electrophilicity of the Ir(III) complex and substrate activation via chelation.

Interaction of learning approach with concept integration and achievement in a large guided inquiry organic class

NASA Astrophysics Data System (ADS)

Mewhinney, Christina

A study was conducted to investigate the relationship of students' concept integration and achievement with time spent within a topic and across related topics in a large first semester guided inquiry organic chemistry class. Achievement was based on evidence of algorithmic problem solving; and concept integration was based on demonstrated performance explaining, applying, and relating concepts to each other. Twelve individual assessments were made of both variables over three related topics---acid/base, nucleophilic substitution and electrophilic addition reactions. Measurements included written, free response and ordered multiple answer questions using a classroom response system. Results demonstrated that students can solve problems without conceptual understanding. A second study was conducted to compare the students' learning approach at the beginning and end of the course. Students were scored on their preferences for a deep, strategic, or surface approach to learning based on their responses to a pre and post survey. Results suggest that students significantly decreased their preference for a surface approach during the semester. Analysis of the data collected was performed to determine the relationship between students' learning approach and their concept integration and achievement in this class. Results show a correlation between a deep approach and concept integration and a strong negative correlation between a surface approach and concept integration.

An Unconventional Redox Cross Claisen Condensation-Aromatization of 4-Hydroxyprolines with Ketones.

PubMed

Tang, Mi; Sun, Rengwei; Li, Hao; Yu, Xinhong; Wang, Wei

2017-08-18

Reaction of α-amino acids, particularly prolines and their derivatives with carbonyl compounds via decarboxylative redox process, is a viable strategy for synthesis of structurally diverse nitrogen centered heterocyclics. In these processes, the decarboxylation is the essential driving force for the processes. The realization of the redox process without decarboxylation may offer an opportunity to explore new reactions. Herein, we report the discovery of an unprecedented redox Claisen-type condensation aromatization cascade reaction of 4-substituted 4-hydroxyproline and its esters with unreactive ketones. We found that the use of propionic acid as a catalyst and a co-solvent can change the reaction course. The commonly observed redox decarboxylation and aldol condensation reactions are significantly minimized. Moreover, unreactive ketones can effectively participate in the Claisen condensation reaction. The new reactivity enables a redox cyclization via an unconventional Claisen-type condensation reaction of in situ formed enamine intermediates from ketone precursors with 4-substituted 4-hydroxyproline and its esters as electrophilic acylation partners. Under the reaction conditions, the cascade process proceeds highly regio- and stereoselectively to afford highly synthetically and biologically valued cis-2,3-dihydro-1H-pyrrolizin-1-ones with a broad substrate scope in efficient 'one-pot' operation, whereas such structures generally require multiple steps.

Ebselen induces reactive oxygen species (ROS)-mediated cytotoxicity in Saccharomyces cerevisiae with inhibition of glutamate dehydrogenase being a target.

PubMed

Azad, Gajendra Kumar; Singh, Vikash; Mandal, Papita; Singh, Prabhat; Golla, Upendarrao; Baranwal, Shivani; Chauhan, Sakshi; Tomar, Raghuvir S

2014-01-01

Ebselen is a synthetic, lipid-soluble seleno-organic compound. The high electrophilicity of ebselen enables it to react with multiple cysteine residues of various proteins. Despite extensive research on ebselen, its target molecules and mechanism of action remains less understood. We performed biochemical as well as in vivo experiments employing budding yeast as a model organism to understand the mode of action of ebselen. The growth curve analysis and FACS (florescence activated cell sorting) assays revealed that ebselen exerts growth inhibitory effects on yeast cells by causing a delay in cell cycle progression. We observed that ebselen exposure causes an increase in intracellular ROS levels and mitochondrial membrane potential, and that these effects were reversed by addition of antioxidants such as reduced glutathione (GSH) or N-acetyl-l-cysteine (NAC). Interestingly, a significant increase in ROS levels was noticed in gdh3-deleted cells compared to wild-type cells. Furthermore, we showed that ebselen inhibits GDH function by interacting with its cysteine residues, leading to the formation of inactive hexameric GDH. Two-dimensional gel electrophoresis revealed protein targets of ebselen including CPR1, the yeast homolog of Cyclophilin A. Additionally, ebselen treatment leads to the inhibition of yeast sporulation. These results indicate a novel direct connection between ebselen and redox homeostasis.

Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases.

PubMed

Ranza, E; Huber, C; Levin, N; Baujat, G; Bole-Feysot, C; Nitschke, P; Masson, C; Alanay, Y; Al-Gazali, L; Bitoun, P; Boute, O; Campeau, P; Coubes, C; McEntagart, M; Elcioglu, N; Faivre, L; Gezdirici, A; Johnson, D; Mihci, E; Nur, B G; Perrin, L; Quelin, C; Terhal, P; Tuysuz, B; Cormier-Daire, V

2017-06-01

The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical reactivity parameters (HSAB) applied to magma evolution and ore formation

NASA Astrophysics Data System (ADS)

Vigneresse, Jean-Louis

2012-11-01

Magmas are commonly described through the usual content of 10 major oxides. This requires a complex dimensional plot. Concepts of hard-soft acid-base (HSAB) interactions allow estimating chemical reactivity of elements, such as electronegativity, i.e. the chemical potential changed of sign, hardness and electrophilicity. For complex system, those values result from equalization methods, i.e. the equalization of the respective chemical potentials, or from ab-initio computations through density functional theory (DFT). They help to characterize silicate magmas by a single value describing their reactivity. Principles of minimum electrophilicity (mEP), maximum hardness (MHP) and minimum polarizability (mPP) indicate trends towards regions of higher stability. Those parameters are plotted within a fitness landscape diagram, highlighting toward which principle reactions trend. Major oxides, main minerals and magmas determine the respective fields in which evolve natural rocks. Three poles are identified, represented by silica and alkalis, whereas oxidation forms the third trend. Mantle-derived rocks show a large variation in electrophilicity compared to hardness. They present all characters of a closed chemical system, being simply described by the free Gibbs energy. Conversely, rocks contaminated within the continental crust show a large variation in hardness between a silica pole and an alkaline, defining two separate trends. The trends show the character of an open chemical system, requiring a Grand Potential description (i.e. taking into account the difference in chemical potential). The terms open and closed systems refer to thermodynamical description, implying contamination for the crust and recycling for the mantle. The specific role of alkalis contrasts with other cations, pointing to their behavior in modifying silicate polymer structures. A second application deals with the reactivity of the melt and its fluid phase. It leads to a better understanding on the mechanisms that control sequestration and transport of metals within the different phases during igneous activity. Based on high gas/melt partitioning for metals and similar reactivity, the gaseous phase is more attractive for metals than silicate melts. The presence of halogens in the fluid phase tends to reinforce hardness, making the fluid phase attractive for hard metals such as Sn or W. Conversely, the presence of S decreases hardness of the fluid phase that becomes attractive for soft metals such as Au, Ag and Cu.

Arene-mercury complexes stabilized by gallium chloride: relative rates of H/D and arene exchange.

PubMed

Branch, Catherine S; Barron, Andrew R

2002-11-27

We have previously proposed that the Hg(arene)(2)(GaCl(4))(2) catalyzed H/D exchange reaction of C(6)D(6) with arenes occurs via an electrophilic aromatic substitution reaction in which the coordinated arene protonates the C(6)D(6). To investigate this mechanism, the kinetics of the Hg(C(6)H(5)Me)(2)(GaCl(4))(2) catalyzed H/D exchange reaction of C(6)D(6) with naphthalene has been studied. Separate second-order rate constants were determined for the 1- and 2-positions on naphthalene; that is, the initial rate of H/D exchange = k(1i)[Hg][C-H(1)] + k(2i)[Hg][C-H(2)]. The ratio of k(1i)/k(2i) ranges from 11 to 2.5 over the temperature range studied, commensurate with the proposed electrophilic aromatic substitution reaction. Observation of the reactions over an extended time period shows that the rates change with time, until they again reach a new and constant second-order kinetics regime. The overall form of the rate equation is unchanged: final rate = k(1f)[Hg][C-H(1)] + k(2f)[Hg][C-H(2)]. This change in the H/D exchange is accompanied by ligand exchange between Hg(C(6)D(6))(2)(GaCl(4))(2) and naphthalene to give Hg(C(10)H(8))(2)(GaCl(4))(2,) that has been characterized by (13)C CPMAS NMR and UV-visible spectroscopy. The activation parameters for the ligand exchange may be determined and are indicative of a dissociative reaction and are consistent with our previously calculated bond dissociation for Hg(C(6)H(6))(2)(AlCl(4))(2). The initial Hg(arene)(2)(GaCl(4))(2) catalyzed reaction of naphthalene with C(6)D(6) involves the deuteration of naphthalene by coordinated C(6)D(6); however, as ligand exchange progresses, the pathway for H/D exchange changes to where the protonation of C(6)D(6) by coordinated naphthalene dominates. The site selectivity for the H/D exchange is initially due to the electrophilic aromatic substitution of naphthalene. As ligand exchange occurs, this selectivity is controlled by the activation of the naphthalene C-H bonds by mercury.

An Holistic Approach for Counsellors: Embracing Multiple Intelligences

ERIC Educational Resources Information Center

Booth, Rosslyn; O'Brien, Patrick John

2008-01-01

This paper explores a range of therapeutic modalities used by counsellors of children and positions those modalities within Gardner's theory of multiple intelligences. Research by O'Brien ("Gardner's theory of multiple intelligence and its implications for the counselling of children." Unpublished doctoral dissertation, Queensland University of…

Reactivity of etoricoxib based on computational study of molecular orbitals, molecular electrostatic potential surface and Mulliken charge analysis

NASA Astrophysics Data System (ADS)

Sachdeva, Ritika; Soni, Abhinav; Singh, V. P.; Saini, G. S. S.

2018-05-01

Etoricoxib is one of the selective cyclooxygenase inhibitor drug which plays a significant role in the pharmacological management of arthritis and pain. The theoretical investigation of its reactivity is done using Density Functional Theory calculations. Molecular Electrostatic Potential Surface of etoricoxib and its Mulliken atomic charge distribution are used for the prediction of its electrophilic and nucleophilic sites. The detailed analysis of its frontier molecular orbitals is also done.

A Practical Methylation Procedure for (1H)-1,2,4-Triazole (Preprint)

DTIC Science & Technology

2007-06-01

on alkylations with higher molecular weight electrophiles, rather than on synthesizing the methyl homologue, the simple reaction to obtain the...an equivalent of the 25% w/w methanolic sodium methoxide solution with heating to 65 °C for 5 minutes in a 5 mL sealed microwave reaction vessel ...requisite neat iodomethane, and recrimping the 5 mL reaction vessel , the reaction vessel was reinserted into the microwave apparatus . The reaction mixture

An Eco-Friendly Improved Protocol for the Synthesis of Bis(3-indolyl)methanes Using Poly(4-vinylpyridinium)hydrogen Sulfate as Efficient, Heterogeneous, and Recyclable Solid Acid Catalyst

PubMed Central

Banothu, Janardhan; Gali, Rajitha; Velpula, Ravibabu; Bavantula, Rajitha; Crooks, Peter A.

2013-01-01

Highly efficient and eco-friendly protocol for the synthesis of bis(3-indolyl)methanes by the electrophilic substitution reaction of indole with aldehydes catalyzed by poly(4-vinylpyridinium)hydrogen sulfate was described. Excellent yields, shorter reaction times, simple work-up procedure, avoiding hazardous organic solvents, and reusability of the catalyst are the most obvious advantages of this method. PMID:24052864

Facile Synthesis of Highly Functionalized Ethyltrifluoroborates

PubMed Central

Molander, Gary A.; Febo-Ayala, Wilma; Ortega-Guerra, Montserrat

2008-01-01

Organotrifluoroborates are generating increased interest because of their ease of preparation and purification, and indefinite shelf-life. Herein we report the preparation of Organotrifluoroborates bearing functional groups that can be manipulated at different stages of the synthetic route, exploiting the inertness of their carbon-boron bonds. The alkylation of 2,2-dicyanoethyltrifluoroborate with a variety of electrophiles and of (EWG)2CH2 with potassium iodomethyltrifluoroborate resulted in di- and trisubstituted ethyltrifluoroborates in good to excellent yields. PMID:18588349

The Productive Merger of Iodonium Salts and Organocatalysis. A Non-Photolytic Approach to the Enantioselective α-Trifluoromethylation of Aldehydes

PubMed Central

Allen, Anna E.; MacMillan, David W. C.

2010-01-01

An enantioselective organocatalytic α-trifluoromethylation of aldehydes has been accomplished using a commercially available, electrophilic trifluoromethyl source. The merging of Lewis acid and organocatalysis provides a new strategy for the enantioselective construction of trifluoromethyl stereogenicity, an important chiral synthon for pharmaceutical, material, and agrochemical applications. This mild and operationally simple protocol allows rapid access to enantioenriched α-trifluoromethylated aldehydes through a non-photolytic pathway. PMID:20297822

Stereoselective Synthesis of Tetrahydroindolizines through the Catalytic Formation of Pyridinium Ylides from Diazo Compounds.

PubMed

Day, Jonathan; McKeever-Abbas, Ben; Dowden, James

2016-05-04

Commercially available iron(III) and copper(I) complexes catalyzed multicomponent cycloaddition reactions between diazo compounds, pyridines, and electrophilic alkenes to give alkaloid-inspired tetrahydroindolizidines in high yield with high diastereoselectivity. Hitherto, the catalytic formation of versatile pyridinium ylides from metal carbenes has been poorly developed; the broad utility demonstrated herein sets the stage for the invention of further multicomponent reactions in future. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Barbier Continuous Flow Preparation and Reactions of Carbamoyllithiums for Nucleophilic Amidation.

PubMed

Ganiek, Maximilian A; Becker, Matthias R; Berionni, Guillaume; Zipse, Hendrik; Knochel, Paul

2017-08-01

An ambient temperature continuous flow method for nucleophilic amidation and thioamidation is described. Deprotonation of formamides by lithium diisopropylamine (LDA) affords carbamoyllithium intermediates that are quenched in situ with various electrophiles such as ketones, allyl bromides, Weinreb and morpholino amides. The nature of the reactive lithium intermediates and the thermodynamics of the metalation were further investigated by ab initio calculations and kinetic experiments. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

A chameleon catalyst for nonheme iron-promoted olefin oxidation.

PubMed

Iyer, Shyam R; Javadi, Maedeh Moshref; Feng, Yan; Hyun, Min Young; Oloo, Williamson N; Kim, Cheal; Que, Lawrence

2014-11-18

We report the chameleonic reactivity of two nonheme iron catalysts for olefin oxidation with H2O2 that switch from nearly exclusive cis-dihydroxylation of electron-poor olefins to the exclusive epoxidation of electron-rich olefins upon addition of acetic acid. This switching suggests a common precursor to the nucleophilic oxidant proposed to Fe(III)-η(2)-OOH and electrophilic oxidant proposed to Fe(V)(O)(OAc), and reversible coordination of acetic acid as a switching pathway.

2-(4-aminophenyl) benzothiazole: a potent and selective pharmacophore with novel mechanistic action towards various tumour cell lines.

PubMed

Dubey, Raghvendra; Shrivastava, Prabhat K; Basniwal, Pawan K; Bhattacharya, Snehendu; Moorthy, Narayana S Hari Narayana

2006-06-01

2-(4-aminophenyl) benzothiazole (CJM -126) (Table 1 (1) and its analogues represent a potent and highly selective class of antitumor agents. These compounds in nanomolar range elicit potent growth inhibition in human-derived breast, colon, ovarian and renal tumour cell lines. Metabolism of benzothiazole plays a central role in its mode of action. Cytocrome P450 isoform, CYP1A1, biotransforms benzothiazoles, to active, as well as inactive metabolites. In vitro studies had confirmed that N-oxidation and N-acetylation (only 3' halogen congener) as main active metabolic transformation (generating cytotoxic electrophilic species), while C-6 oxidation and N-acetylation (except 3' halogen congener) as inactive metabolic transformation pathway. Generation of an inactive metabolite 2-(4-aminophenyl)-6-hydoxybenzothiazole [6-OH 126, (Table 1) (10)] is blocked by fluorinated analogue, substituted around benzothiazole nucleus, especially at 5-position. National Cancer Institute (NCI), USA, confirms this series as a unique mechanistic class distinct from clinically used chemotherapeutic agents. Benzothiazoles are potent aryl hydrocarbon receptor (AhR) agonists, binding to AhR results in induction of CYP1A1, causes generation of electrophilic reactive species which forms DNA adduct, ultimately resulting in cell death by activation of apoptotic machinery. To overcome the poor physiochemical and pharmaceutical properties (bioavailability problem) of this compounds, prodrug of benzothiazole derivatives were synthesized, which are introduced in clinical trails.

Reactivity measurement in estimation of benzoquinone and benzoquinone derivatives’ allergenicity

PubMed Central

Mbiya, Wilbes; Chipinda, Itai; Simoyi, Reuben H.; Siegel, Paul D.

2015-01-01

Benzoquinone (BQ) and benzoquinone derivatives (BQD) are used in the production of dyes and cosmetics. While BQ, an extreme skin sensitizer, is an electrophile known to covalently modify proteins via Michael Addition (MA) reaction whilst halogen substituted BQD undergo nucleophilic vinylic substitution (SNV) mechanism onto amine and thiol moieties on proteins, the allergenic effects of adding substituents on BQ have not been reported. The effects of inserting substituents on the BQ ring has not been studied in animal assays. However, mandated reduction/elimination of animals used in cosmetics testing in Europe has led to an increased need for alternatives for the prediction of skin sensitization potential. Electron withdrawing and electron donating substituents on BQ were assessed for effects on BQ reactivity toward nitrobenzene thiol (NBT). The NBT binding studies demonstrated that addition of EWG to BQ as exemplified by the chlorine substituted BQDs increased reactivity while addition of EDG as in the methyl substituted BQDs reduced reactivity. BQ and BQD skin allerginicity was evaluated in the murine local lymph node assay (LLNA). BQD with electron withdrawing groups had the highest chemical potency followed by unsubstituted BQ and the least potent were the BQD with electron donating groups. The BQD results demonstrate the impact of inductive effects on both BQ reactivity and allergenicity, and suggest the potential utility of chemical reactivity data for electrophilic allergen identification and potency ranking. PMID:26612505

Heterolytic Cleavage of H2 by Bifunctional Manganese(I) Complexes: Impact of Ligand Dynamics, Electrophilicity, and Base Positioning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hulley, Elliott B.; Helm, Monte L.; Bullock, R. Morris

2014-12-01

We report the synthesis, characterization, and reactivity with H2 of a series of MnI complexes of the type [(P-P)Mn(L2)CO]+ (L2 = dppm, bppm, or (CO)2; P-P = PPhNMePPh or PPh2 NBn2 ) that bear pendant amine ligands designed to function as proton relays. The pendant amine was found to function as a hemilabile ligand; its binding strength is strongly affected by the ancillary ligand environment around Mn. Tuning the electrophilicity of the Mn center leads to systems capable of reversible heterolytic cleavage of the H-H bond. The strength of pendant amine binding can be balanced to protect the Mn centermore » while still leading to facile reactivity with H2. Neutral amine-bearing MnIH species were found to react with one-electron oxidants and, after proton and electron transfer reactions, regenerate MnI cationic species. The reactivity presented herein indicate that the Mn complexes we have developed are a promising platform for Mn-based H2 oxidation electrocatalyst development. The research was supported as part of the Center for Molecular Electrocatalysis, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences. Pacific Northwest National Laboratory is operated by Battelle for DOE.« less

Study of vibrational spectra and hydrogen bonding network in dimeric and tetrameric model of ampicillin using DFT and AIM approach

NASA Astrophysics Data System (ADS)

Shukla, Anuradha; Khan, Eram; Tandon, Poonam; Sinha, Kirti

2017-03-01

Ampicillin is a β-lactam antibiotic that is active against both gram-positive and gram-negative bacteria and is widely used for the treatment of infections. In this work, molecular properties of ampicillin are calculated on the basis of calculations on its dimeric and tetrameric models using DFT/B3LYP/6-311G(d,p). HOMO-LUMO energy gap shows that chemical reactivity of tetrameric model of ampicillin is higher than the dimeric and monomeric model of ampicillin. To get a better understanding of intra and intermolecular bonding and interactions among bonds, NBO analysis is carried out with tetrameric model of ampicillin, and is further finalized with an 'quantum theory of atoms-in-molecules' (QTAIM) analysis. The binding energy of dimeric model of ampicillin is calculated as -26.84 kcal/mol and -29.34 kcal/mol using AIM and DFT calculations respectively. The global electrophilicity index (ω = 2.8118 eV) of tetrameric model of ampicillin shows that this behaves as a strong electrophile in comparison to dimeric and monomeric model of ampicillin. The FT-Raman and FT-IR spectra were recorded in the solid phase, and interpreted in terms of potential energy distribution analysis. A collective theoretical and experimental vibrational analysis approves the presence of hydrogen bonds in the ampicillin molecule.

Development of Selective Colorimetric Probes for Hydrogen Sulfide Based on Nucleophilic Aromatic Substitution

PubMed Central

Montoya, Leticia A.; Pearce, Taylor F.; Hansen, Ryan J.; Zakharov, Lev N.; Pluth, Michael D.

2013-01-01

Hydrogen sulfide is an important biological signalling molecule and an important environmental target for detection. A major challenge in developing H2S detection methods is separating the often similar reactivity of thiols and other nucleophiles from H2S. To address this need, the nucleophilic aromatic substitution (SNAr) reaction of H2S with electron-poor aromatic electrophiles was developed as a strategy to separate H2S and thiol reactivity. Treatment of aqueous solutions of nitrobenzofurazan (7-nitro-1,2,3-benzoxadiazole, NBD) thioethers with H2S resulted in thiol extrusion and formation of nitrobenzofurazan thiol (λmax = 534 nm). This reactivity allows for unwanted thioether products to be converted to the desired nitrobenzofurazan thiol upon reaction with H2S. The scope of the reaction was investigated using a Hammett linear free energy relationship study, and the determined ρ = +0.34 is consistent with the proposed SN2Ar reaction mechanism. The efficacy of the developed probes was demonstrated in buffer and in serum with associated sub-micromolar detection limits as low as 190 nM (buffer) and 380 nM (serum). Furthermore, the sigmoidal response of nitrobenzofurazan electrophiles with H2S can be fit to accurately quantify H2S. The developed detection strategy offers a manifold for H2S detection that we foresee being applied in various future applications. PMID:23735055

Solvolysis of para-substituted cumyl chlorides. Brown and Okamoto's electrophilic substituent constants revisited using continuum solvent models.

PubMed

DiLabio, Gino A; Ingold, K U

2004-03-05

Brown and Okamoto (J. Am. Chem. Soc. 1958, 80, 4979) derived their electrophilic substitutent constants, sigma(p)+, from the relative rates of solvolysis of ring-substituted cumyl chlorides in an acetone/water solvent mixture. Application of the Hammett equation to the rates for the meta-substituted cumyl chlorides, where there could be no resonance interaction with the developing carbocation, gave a slope, rho(+) = -4.54 ( identical with 6.2 kcal/mol free energy). Rates for the para-substituted chlorides were then used to obtain sigma(p)+ values. We have calculated gas-phase C-Cl heterolytic bond dissociation enthalpy differences, Delta BDE(het) (= BDE(het)(4-YC(6)H(4)CMe(2)Cl) - BDE(het)(C(6)H(5)CMe(2)Cl)), for 16 of the 4-Y substituents employed by Brown and Okamoto. The plot of Delta BDE(het) vs sigma(p)+ gave rho(+) (SD) = 16.3 (2.3) kcal/mol, i.e., a rho(+) value roughly 2.5 times greater than experiment. Inclusion of solvation (water) energies, calculated using three continuum solvent models, reduced rho(+) and SD. The computationally least expensive model used, SM5.42R (Li et al. Theor. Chem. Acc. 1999, 103, 9) gave the best agreement with experiment. This model yielded rho(+) (SD) = 7.7 (0.9) kcal/mol, i.e., a rho(+) value that is only 24% larger than experiment.

Testing a chemical series inspired by plant stress oxylipin signalling agents for herbicide safening activity

PubMed Central

Brazier‐Hicks, Melissa; Knight, Kathryn M; Sellars, Jonathan D

2018-01-01

Abstract BACKGROUND Herbicide safening in cereals is linked to a rapid xenobiotic response (XR), involving the induction of glutathione transferases (GSTs). The XR is also invoked by oxidized fatty acids (oxylipins) released during plant stress, suggesting a link between these signalling agents and safening. To examine this relationship, a series of compounds modelled on the oxylipins 12‐oxophytodienoic acid and phytoprostane 1, varying in lipophilicity and electrophilicity, were synthesized. Compounds were then tested for their ability to invoke the XR in Arabidopsis and protect rice seedlings exposed to the herbicide pretilachlor, as compared with the safener fenclorim. RESULTS Of the 21 compounds tested, three invoked the rapid GST induction associated with fenclorim. All compounds possessed two electrophilic carbon centres and a lipophilic group characteristic of both oxylipins and fenclorim. Minor effects observed in protecting rice seedlings from herbicide damage positively correlated with the XR, but did not provide functional safening. CONCLUSION The design of safeners based on the characteristics of oxylipins proved successful in deriving compounds that invoke a rapid XR in Arabidopsis but not in providing classical safening in a cereal. The results further support a link between safener and oxylipin signalling, but also highlight species‐dependent differences in the responses to these compounds. © 2018 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID:29330904

Monitoring of photoluminescence decay by alkali and alkaline earth metal cations using a photoluminescent bolaamphiphile self-assembly as an optical probe.

PubMed

Kim, Sunhyung; Kwak, Jinyoung; Lee, Sang-Yup

2014-05-01

Photoluminescence (PL) decay induced by the displacement of an ionic fluorescence component, Tb(3+), with alkali and alkaline earth metal cations was investigated using photoluminescent spherical self-assemblies as optical probes. The photoluminescent spherical self-assembly was prepared by the self-organization of a tyrosine-containing bolaamphiphile molecule with a photosensitizer and Tb(3+) ion. The lanthanide ion, Tb(3+), electrically bound to the carboxyl group of the bolaamphiphile molecule, was displaced by alkali and alkaline earth metal cations that had stronger electrophilicity. The PL of the self-assembly decayed remarkably due to the substitution of lanthanide ions with alkali and alkaline earth metal cations. The PL decay showed a positive correlation with cation concentration and was sensitive to the cation valency. Generally, the PL decay was enhanced by the electrophilicity of the cations. However, Ca(2+) showed greater PL decay than Mg(2+) because Ca(2+) could create various complexes with the carboxyl groups of the bolaamphiphile molecule. Microscopic and spectroscopic investigations were conducted to study the photon energy transfer and displacement of Tb(3+) by the cation exchange. This study demonstrated that the PL decay by the displacement of the ionic fluorescent compound was applied to the detection of various cations in aqueous media and is applicable to the development of future optical sensors. Copyright © 2014 Elsevier B.V. All rights reserved.

2,6-Dithiopurine blocks toxicity and mutagenesis in human skin cells exposed to sulfur mustard analogues, 2-chloroethyl ethyl sulfide and 2-chloroethyl methyl sulfide.

PubMed

Powell, K Leslie; Boulware, Stephen; Thames, Howard; Vasquez, Karen M; MacLeod, Michael C

2010-03-15

Sulfur mustard (bis-(2-chloroethyl)sulfide) is a well-known chemical warfare agent that induces debilitating cutaneous toxicity in exposed individuals. It is also known to be carcinogenic and mutagenic because of its ability to damage DNA via electrophilic attack. We previously showed that a nucleophilic scavenger, 2,6-dithiopurine (DTP), reacts chemically with several electrophilic carcinogens, blocking DNA damage in vitro and in vivo and abolishing tumor formation in a two-stage mouse skin carcinogenesis model. To assess the potential of DTP as an antagonist of sulfur mustard, we have utilized monofunctional chemical analogues of sulfur mustard, 2-chloroethyl ethyl sulfide (CEES) and 2-chloroethyl methyl sulfide (CEMS), to induce toxicity and mutagenesis in a cell line, NCTC2544, derived from a human skin tumor. We show that DTP blocks cytotoxicity in CEMS- and CEES-treated cells when present at approximately equimolar concentration. A related thiopurine, 9-methyl-6-mercaptopurine, is similarly effective. Correlated with this, we find that DTP is transported into these cells and that adducts between DTP and CEES are found intracellularly. Using a shuttle vector-based mutagenesis system, which allows enumeration of mutations induced in the skin cells by a blue/white colony screen, we find that DTP completely abolishes the mutagenesis induced by CEMS and CEES in human cells.

Solvent-free iodination of organic molecules using the I(2)/urea-H(2)O(2) reagent system.

PubMed

Pavlinac, Jasminka; Zupan, Marko; Stavber, Stojan

2007-02-21

Introduction of iodine under solvent-free conditions into several aromatic compounds activated toward electrophilic functionalization was found to proceed efficiently using elemental iodine in the presence of a solid oxidizer, the urea-H(2)O(2) (UHP) adduct. Two types of iodo-functionalization through an electrophilic process were observed: iodination of an aromatic ring, and side-chain iodo-functionalization in the case of arylalkyl ketones. Two reaction routes were established based on the required substrate : iodine : oxidizer ratio for the most efficient iodo-transformation, and the role of UHP was elucidated in each route. The first, requiring a 1 : 0.5 : 0.6 stoichiometric ratio of substrate to iodine to UHP, followed the atom economy concept in regard to iodine and was valid in the case of aniline, 4-t-Bu-phenol, 1,2-dimethoxy benzene, 1,3-dimethoxy benzene, 1,2,3-trimethoxy benzene, 1,2,4-trimethoxy benzene, 1,3,5-trimethoxy benzene, 1-indanone and 1-tetralone. The second reaction route, where a 1 : 1 : 1 stoichiometric ratio of substrate : I(2) : UHP was needed for efficient iodination, was suitable for side-chain iodo-functionalization of acetophenone and methoxy-substituted acetophenones. Moreover, addition of iodine to 1-octene and some phenylacetylenic derivatives was found to proceed efficiently without the presence of any oxidizer and solvent at room temperature.

Nucleophilically assisted and cationic ring-opening polymerization of tin-bridged [1]ferrocenophanes.

PubMed

Baumgartner, Thomas; Jäkle, Frieder; Rulkens, Ron; Zech, Gernot; Lough, Alan J; Manners, Ian

2002-08-28

To obtain mechanistic insight, detailed studies of the intriguing "spontaneous" ambient temperature ring-opening polymerization (ROP) of tin-bridged [1]ferrocenophanes Fe(eta-C(5)H(4))(2)SnR(2) 3a (R = t-Bu) and 3b (R = Mes) in solution have been performed. The investigations explored the influence of non-nucleophilic additives such as radicals and radical traps, neutral and anionic nucleophiles, Lewis acids, protic species, and other cationic electrophiles. Significantly, two novel methodologies and mechanisms for the ROP of strained [1]ferrocenophanes are proposed based on this study. First, as the addition of amine nucleophiles such as pyridine was found to strongly accelerate the polymerization rate in solution, a new nucleophilicallyassisted ROP methodology was proposed. This operates at ambient temperature in solution even in the presence of chlorosilanes but, unlike the anionic polymerization of ferrocenophanes, does not involve cyclopentadienyl anions. Second, the addition of small quantities of the electrophilic species H(+) and Bu(3)Sn(+) was found to lead to a cationic ROP process. These studies suggest that the "spontaneous" ROP of tin-bridged [1]ferrocenophanes may be a consequence of the presence of spurious, trace quantities of Lewis basic or acidic impurities. The new ROP mechanisms reported are likely to be of general significance for the ROP of other metallocenophanes (e.g., for thermal ROP in the melt) and for other metallacycles containing group 14 elements.

Development of selective colorimetric probes for hydrogen sulfide based on nucleophilic aromatic substitution.

PubMed

Montoya, Leticia A; Pearce, Taylor F; Hansen, Ryan J; Zakharov, Lev N; Pluth, Michael D

2013-07-05

Hydrogen sulfide is an important biological signaling molecule and an important environmental target for detection. A major challenge in developing H2S detection methods is separating the often similar reactivity of thiols and other nucleophiles from H2S. To address this need, the nucleophilic aromatic substitution (SNAr) reaction of H2S with electron-poor aromatic electrophiles was developed as a strategy to separate H2S and thiol reactivity. Treatment of aqueous solutions of nitrobenzofurazan (7-nitro-1,2,3-benzoxadiazole, NBD) thioethers with H2S resulted in thiol extrusion and formation of nitrobenzofurazan thiol (λmax = 534 nm). This reactivity allows for unwanted thioether products to be converted to the desired nitrobenzofurazan thiol upon reaction with H2S. The scope of the reaction was investigated using a Hammett linear free energy relationship study, and the determined ρ = +0.34 is consistent with the proposed SN2Ar reaction mechanism. The efficacy of the developed probes was demonstrated in buffer and in serum with associated submicromolar detection limits as low as 190 nM (buffer) and 380 nM (serum). Furthermore, the sigmoidal response of nitrobenzofurazan electrophiles with H2S can be fit to accurately quantify H2S. The developed detection strategy offers a manifold for H2S detection that we foresee being applied in various future applications.

Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis

PubMed Central

Malhotra, Deepti; Portales-Casamar, Elodie; Singh, Anju; Srivastava, Siddhartha; Arenillas, David; Happel, Christine; Shyr, Casper; Wakabayashi, Nobunao; Kensler, Thomas W.; Wasserman, Wyeth W.; Biswal, Shyam

2010-01-01

The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidative and electrophilic environmental stresses by circumventing repression by Keap1, translocating to the nucleus, and activating cytoprotective genes. Nrf2 responses provide protection against chemical carcinogenesis, chronic inflammation, neurodegeneration, emphysema, asthma and sepsis in murine models. Nrf2 regulates the expression of a plethora of genes that detoxify oxidants and electrophiles and repair or remove damaged macromolecules, such as through proteasomal processing. However, many direct targets of Nrf2 remain undefined. Here, mouse embryonic fibroblasts (MEF) with either constitutive nuclear accumulation (Keap1−/−) or depletion (Nrf2−/−) of Nrf2 were utilized to perform chromatin-immunoprecipitation with parallel sequencing (ChIP-Seq) and global transcription profiling. This unique Nrf2 ChIP-Seq dataset is highly enriched for Nrf2-binding motifs. Integrating ChIP-Seq and microarray analyses, we identified 645 basal and 654 inducible direct targets of Nrf2, with 244 genes at the intersection. Modulated pathways in stress response and cell proliferation distinguish the inducible and basal programs. Results were confirmed in an in vivo stress model of cigarette smoke-exposed mice. This study reveals global circuitry of the Nrf2 stress response emphasizing Nrf2 as a central node in cell survival response. PMID:20460467

Redox signaling: An evolution from free radicals to aging.

PubMed

Forman, Henry Jay

2016-08-01

Redox biology has evolved from studies of the pathology that involves oxidants to an understanding of how oxidants participate in normal as well as aberrant signal transduction. Although the concept that signal transduction involved changes in the redox state dates from the 1930s, the modern history of redox biology began with the discovery of superoxide dismutase by McCord and Fridovich. The initial focus was on free radicals and damage of macromolecules, which remains an important topic. But, over time it was realized that hydroperoxides, especially H2O2 produced by NADPH oxidases, and electrophiles derived from lipid peroxidation or metabolism, played essential roles in physiologically relevant signaling. The mechanisms through which H2O2 and other electrophiles signal became an important area of study that provided insight into how these reactive molecules were involved in major signaling pathways and regulation of transcription factors. Thus, the field of redox signaling that is the overlap of signal transduction with redox biology was established. Alterations in redox signaling are observed in aging, but we also now know that redox signaling is essential in physiological homeostasis and that sustained deviation from redox homeostasis results in disease. This is a review of the history of redox biology from a personal perspective of nearly fifty years working in this field that hopefully provides some insights for the reader. Copyright © 2016 Elsevier Inc. All rights reserved.

[Current description of multiple sclerosis].

PubMed

Río, Jordi; Montalbán, Xavier

2014-12-01

Multiple sclerosis is a multifocal demyelinating disease leading to progressive neurodegeneration caused by an autoimmune response in genetically predisposed individuals. In the last few years, the knowledge and management of this disease has been revolutionized by a series of findings. The present article reviews pathological features of the disease, in which cortical involvement is increasingly implicated, and aspects related to novel pathogenic mechanisms, such as the role of the microbiota in the genesis of multiple sclerosis, as well as recent contributions from the fields of epidemiology and genetics. Also reviewed are the latest diagnostic criteria, which currently allow a much earlier diagnosis, with clear therapeutic implications. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Multiplicity and Its Discontents: Life on the Counseling Farm

ERIC Educational Resources Information Center

Hansen, James

2010-01-01

This paper argues that a recurrent ideological theme of counseling history is the transition from viewing people as singular to conceptualizing them as multiple or diverse. Unfortunately, however, these laudable multiplicity movements regularly revert to a position of singularity. The implications of this ideological cycle for counseling practice…

Electronic Structure and Multisite Basicity of the Pyramidal Phosphinidene-Bridged Dimolybdenum Complex [Mo2(η(5)-C5H5)(μ-κ(1):κ(1),η(5)-PC5H4)(η(6)-C6H3(t)Bu3)(CO)2(PMe3)].

PubMed

Albuerne, Isabel G; Alvarez, M Angeles; García, M Esther; García-Vivó, Daniel; Ruiz, Miguel A

2015-10-19

The title phosphinidene complex could be sequentially protonated with HBF4·OEt2 or [H(OEt2)2](BAr'4) to give the phosphido-bridged derivatives [Mo2Cp(μ-κ(1):κ(1),η(5)-HPC5H4)(η(6)-HMes*)(CO)2(PMe3)]X and then the hydrides [Mo2Cp(H)(μ-κ(1):κ(1),η(5)-HPC5H4)(η(6)-HMes*)(CO)2(PMe3)]X2 (X = BF4, BAr'4; Ar' = 3,5-C6H3(CF3)2; Mes* = 2,4,6-C6H2(t)Bu3). Density functional theory (DFT) calculations revealed that the most favored site for initial electrophilic attack is the metallocene Mo atom, but attachment of the electrophile to the phosphinidene P atom gives more stable products. This was in agreement with all other reactions investigated, which invariably involved the attachment of the added electrophile at the P site. Thus, the title compound reacted with S8 at 223 K to give the thiophosphinidene-bridged complex [Mo2Cp{μ-κ(1):κ(1),η(5)-P(S)C5H4}(η(6)-HMes*)(CO)2(PMe3)], a poorly stable molecule which reacted with MeI at room temperature to give the corresponding thiolatophosphido derivative, isolated as [Mo2Cp{μ-κ(1):κ(1),η(5)-P(SMe)C5H4}(η(6)-HMes*)(CO)2(PMe3)](BAr'4) (P-S = 2.128(4) Å) after anion exchange with Na(BAr'4). Reaction of the title compound with MeI proceeded smoothly to give the corresponding methylphosphido derivative, isolated analogously as [Mo2Cp{μ-κ(1):κ(1),η(5)-P(Me)C5H4}(η(6)-HMes*)(CO)2(PMe3)](BAr'4). The related complex [Mo2Cp{μ-κ(1):κ(1),η(5)-P(Me)C5H4}(η(6)-HMes*)(CO)2(PMe2Ph)](BAr'4) (P-C(Me) = 1.841(5) Å) could be prepared analogously from the neutral precursor [Mo2Cp{μ-κ(1):κ(1),η(5)-PC5H4}(η(6)-HMes*)(CO)2(PMe2Ph)]. In contrast, reaction of the title complex with ethylene sulfide involved opening of the C2S ring and formation of new P-C and Mo-S bonds (1.886(7) and 2.493(2) Å, respectively), with displacement of the PMe3 ligand, to give the phosphido-thiolato complex [Mo2Cp{μ-κ(2)(P,S):κ(1)P,η(5)-P(C2H4S)C5H4}(η(6)-HMes*)(CO)2]. All these derivatives of the title complex displayed an unusual trigonal pyramidal-like environment around the bridging P atom, with the added electrophile placed in the Mo2P plane as a result of the directionality of the relevant frontier orbital of the phosphinidene complex, according to DFT calculations.

Episodic Mood Changes Preceding an Exacerbation of Multiple Sclerosis

PubMed Central

Sharma, Priya; Morrow, Sarah A.; Owen, Richard J.

2015-01-01

Multiple sclerosis is a neurologic inflammatory disease that can manifest with psychiatric symptoms. Although depression is the most common psychiatric diagnosis in patients with multiple sclerosis, how depression develops is not fully understood. We present the case of an individual who displayed episodic mood changes preceding an exacerbation of multiple sclerosis symptoms. The clinical and research implications of this association are discussed. PMID:26835163

Investigating Children's Multiplicative Thinking: Implications for Teaching

ERIC Educational Resources Information Center

Hurst, Chris; Hurrell, Derek

2016-01-01

Multiplicative thinking is a "big idea" of mathematics that underpins much of the mathematics learned beyond the early primary school years. This article reports on a recent study that utilised an interview tool and a written quiz to gather data about children's multiplicative thinking. Our research has so far revealed that many primary…

Efficacy in Teaching through "Multiple Intelligence" Instructional Strategies

ERIC Educational Resources Information Center

Tamilselvi, B.; Geetha, D.

2015-01-01

Multiple intelligence is the theory that "people are smart in more ways than one has immense implication for educators". Howard Gardner proposed a new view of intelligence that is rapidly being incorporated in school curricula. In his theory of Multiple Intelligences, Gardner expanded the concept of intelligence with such areas as music,…

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Xinxing; Bowen, Kit, E-mail: kbowen@jhu.edu

We report a combined photoelectron spectroscopic and computational study of the o-dicarbadodecaborane (o-carborane) parent anion, (C{sub 2}B{sub 10}H{sub 12}){sup −}. Previous studies that focused on the electrophilic nature of o-carborane led to tantalizing yet mixed results. In our study, we confirmed that o-carborane does in fact form a parent anion and that it has considerable stability. This anion is an isomer (“Anion iso 2”) where unlike in neutral o-carborane, the two carbon atoms are not bound.

Metal Vinylidenes as Catalytic Species in Organic Reactions

PubMed Central

McClory, Andrew

2008-01-01

Organic vinylidene species have found limited use in organic synthesis due to their inaccessibility. In contrast, metal vinylidenes are much more stable, and may be readily accessed through transition metal activation of terminal alkynes. These electrophilic species may be trapped by a number of nucleophiles. Additionally, metal vinylidenes can participate in pericyclic reactions and processes involving migration of a metal ligand to the vinylidene species. This review addresses the reactions and applications of metal vinylidenes in organic synthesis. PMID:18172846

Remarkable Regioselective Position-10 Bromination of Bacteriopyropheophorbide-a and Ring-B Reduced Pyropheophorbide-a

PubMed Central

Ethirajan, Manivannan; Joshi, Penny; William, White H.; Ohkubo, Kei; Fukuzumi, Shunichi; Pandey, Ravindra K.

2011-01-01

Both bacteriopyropheophorbide-a and ring-B reduced pyropheophorbide-a on reacting with NBS (N-bromosuccinamide) undergo electrophilic bromination to provide 10-bromo analogs. The electronic nature of the substituents present at position-3 did not make any difference in regioselective outcome of the brominated products. These relatively stable brominated chlorins and bacteriochlorins provide an easy way of introducing a wide variety of functionalities, which could be extremely useful in developing improved agents for biomedical applications and supramolecular chemistry. PMID:21417431

Conversion of alkanes to organoseleniums and organotelluriums

DOEpatents

Periana, Roy A.; Konnick, Michael M.; Hashiguchi, Brian G.

2016-11-29

The invention provides processes and materials for the efficient and costeffective functionalization of alkanes and heteroalkanes, comprising contacting the alkane or heteroalkane and a soft oxidizing electrophile comprising Se(VI) or Te(VI), in an acidic medium, optionally further comprising an aprotic medium, which can be carried out at a temperature of less than 300 C. Isolation of the alkylselenium or alkyltellurium intermediate allows the subsequent conversion to products not necessarily compatible with the initial reaction conditions, such as amines, stannanes, organosulfur compounds, acyls, halocarbons, and olefins.

Original Synthesis of Fluorenyl Alcohol Derivatives by Reductive Dehalogenation Initiated by TDAE.

PubMed

Giuglio-Tonolo, Alain Gamal; Terme, Thierry; Vanelle, Patrice

2016-10-24

We report here a novel and easy-to-handle reductive dehalogenation of 9-bromofluorene in the presence of arylaldehydes and dicarbonyl derivatives to give the corresponding fluorenyl alcohol derivatives and Darzens epoxides as by-products in tetrakis(dimethylamino)ethylene (TDAE) reaction conditions. The reaction is believed to proceed via two successive single electron transfers to generate the fluorenyl anion which was able to react with different electrophiles. A mechanistic study was conducted to understand the formation of the epoxide derivatives.

Tandem Carbocupration/Oxygenation of Terminal Alkynes

PubMed Central

Zhang, Donghui; Ready, Joseph M.

2008-01-01

A direct and general synthesis of α-branched aldehydes and their enol derivatives is described. Carbocupration of terminal alkynes and subsequent oxygenation with lithium tert-butyl peroxide generates a metallo-enolate. Trapping with various electrophiles provides α-branched aldehydes or stereo-defined trisubstituted enol esters or silyl ethers. The tandem carbocupration/oxygenation tolerates alkyl and silyl ethers, esters and tertiary amines. The reaction is effective with organocopper complexes derived from primary, secondary and tertiary Grignard reagents and from n-butyllithium. PMID:16321021

Transition metal catalyzed borylation of functional π-systems

PubMed Central

SHINOKUBO, Hiroshi

2014-01-01

Borylated functional π-systems are useful building blocks to enable efficient synthesis of novel molecular architectures with beautiful structures, intriguing properties and unique functions. Introduction of boronic ester substituents to a variety of extended π-systems can be achieved through either iridium-catalyzed direct C–H borylation or the two-step procedure via electrophilic halogenation followed by palladium-catalyzed borylation. This review article focuses on our recent progress on borylation of large π-conjugated systems such as porphyrins, perylene bisimides, hexabenzocoronenes and dipyrrins. PMID:24492644

New and Improved Methods of Production of Energy Rich Materials

DTIC Science & Technology

1990-11-01

present in its molecular form (with some N2 03 also present). In acid solutions above 60-65% concentration it is present as nitrosonium ions . In an excess...Electrophilic Aromatic Nitration b~y the Nitronium Ion 1.2 Effect of Nitrous Acid 1.3 Nitration of Carbazoic. 1.4 Nitration of Dibenzothiophene -1.5...HLt~ron i un Ion The nitration -of aromatic compounds can he, achieved in a variety of media. Mixed acid nitration is the most common type used in

Copper-Catalyzed Synthesis of Trifluoroethylarenes from Benzylic Bromodifluoroacetates.

PubMed

Ambler, Brett R; Zhu, Lingui; Altman, Ryan A

2015-08-21

Trifluoroethylarenes are found in a variety of biologically active molecules, and strategies for accessing this substructure are important for developing therapeutic candidates and biological probes. Trifluoroethylarenes can be directly accessed via nucleophilic trifluoromethylation of benzylic electrophiles; however, current catalytic methods do not effectively transform electron-deficient substrates and heterocycles. To address this gap, we report a Cu-catalyzed decarboxylative trifluoromethylation of benzylic bromodifluoroacetates. To account for the tolerance of sensitive functional groups, we propose an inner-sphere mechanism of decarboxylation.

Synthesis and Properties of N7O+ (PREPRINT)

DTIC Science & Technology

2009-11-23

isolated by pumping off the solvent and gaseous products at low temperature. With an excess of HN3, replacement of the second fluorine atom started to...was analyzed and involves the electrophilic attack of the terminal gamma-N atom of one azide ligand on the electron rich alpha-N atom of the second...Chem. Soc. 1995, 117, 6136. (8) Christe, K. O., Wilson, W. W., Schack, C. J., J. Fluorine . Chem. 1978, 11, 71. (9) Moller, C., Plesset, M. S., Phys

International Conference on Low Temperature Chemistry (6th) Held in Chernogolovka, Russia on 27 August - 1 September 2006

DTIC Science & Technology

2006-09-20

The stabilized free radicals FC60 (or FC70) were generated in sold argon by means of chemical reaction of the photogenerated fluorine atoms with...strong electrophile . Using quantum chemistry methods stability and structure of homoleptic Xe-containing molecules XeM2 and MXen with transition metal...apart from the main CH...F interaction, secondary interactions are present in which the fluorine of the chlorine atoms located in the haloform

Chiral copper(II) complex-catalyzed reactions of partially protected carbohydrates.

PubMed

Allen, C Liana; Miller, Scott J

2013-12-20

Catalyst-controlled regioselective functionalization of partially protected saccharide molecules is a highly important yet under-developed area of carbohydrate chemistry. Such reactions allow for the reduction of protecting group manipulation steps required in syntheses involving sugars. Herein, an approach to these processes using enantiopure copper-bis(oxazoline) catalysts to control couplings of electrophiles to various partially protected sugars is reported. In a number of cases, divergent regioselectivity was observed as a function of the enantiomer of catalyst that is used.