Mild Oxidative Conditions Research Articles

Iron-Catalyzed Ortho C-H Methylation of Aromatics Bearing a Simple Carbonyl Group with Methylaluminum and Tridentate Phosphine Ligand.

Iron-catalyzed C-H functionalization of aromatics has attracted widespread attention from chemists in recent years, while the requirement of an elaborate directing group on the substrate has so far hampered the use of simple aromatic carbonyl compounds such as benzoic acid and ketones, much reducing its synthetic utility. We describe here a combination of a mildly reactive methylaluminum reagent and a new tridentate phosphine ligand for metal catalysis, 4-(bis(2-(diphenylphosphanyl)phenyl)phosphanyl)-N,N-dimethylaniline (Me2N-TP), that allows us to convert an ortho C-H bond to a C-CH3 bond in aromatics and heteroaromatics bearing simple carbonyl groups under mild oxidative conditions. The reaction is powerful enough to methylate all four ortho C-H bonds in benzophenone. The reaction tolerates a variety of functional groups, such as boronic ester, halide, sulfide, heterocycles, and enolizable ketones.

The molecular chaperone Hsp70 promotes the proteolytic removal of oxidatively damaged proteins by the proteasome

One hallmark of aging is the accumulation of protein aggregates, promoted by the unfolding of oxidized proteins. Unraveling the mechanism by which oxidized proteins are degraded may provide a basis to delay the early onset of features, such as protein aggregate formation, that contribute to the aging phenotype. In order to prevent aggregation of oxidized proteins, cells recur to the 20S proteasome, an efficient turnover proteolysis complex. It has previously been shown that upon oxidative stress the 26S proteasome, another form, dissociates into the 20S form. A critical player implicated in its dissociation is the Heat Shock Protein 70 (Hsp70), which promotes an increase in free 20S proteasome and, therefore, an increased capability to degrade oxidized proteins. The aim of this study was to test whether or not Hsp70 is involved in cooperating with the 20S proteasome for a selective degradation of oxidatively damaged proteins. Our results demonstrate that Hsp70 expression is induced in HT22 cells as a result of mild oxidative stress conditions. Furthermore, Hsp70 prevents the accumulation of oxidized proteins and directly promotes their degradation by the 20S proteasome. In contrast the expression of the Heat shock cognate protein 70 (Hsc70) was not changed in recovery after oxidative stress and Hsc70 has no influence on the removal of oxidatively damaged proteins. We were able to demonstrate in HT22 cells, in brain homogenates from 129/SV mice and in vitro, that there is an increased interaction of Hsp70 with oxidized proteins, but also with the 20S proteasome, indicating a role of Hsp70 in mediating the interaction of oxidized proteins with the 20S proteasome. Thus, our data clearly implicate an involvement of Hsp70 oxidatively damaged protein degradation by the 20S proteasome.

Reaction of benzyl alcohols, isatoic anhydride, and primary amines mediated by I2/K2CO3 in water: a new and green approach for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones

An efficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones proceeding via a three-component reaction between benzyl alcohols, isatoic anhydride, and primary amines in the presence of iodine and potassium carbonate is reported. This protocol allows the straightforward preparation of the titled products using readily available benzyl alcohols instead of unstable aldehydes under mild oxidative conditions.

High density lipoprotein efficiently accepts surface but not internal oxidised lipids from oxidised low density lipoprotein

ObjectiveOxidised low density lipoprotein (oxLDL) contributes to atherosclerosis, whereas high density lipoprotein (HDL) is known to be atheroprotective due, at least in part, to its ability to remove oxidised lipids from oxLDL. The molecular details of the lipid transfer process are not fully understood. We aimed to identify major oxidised lipid species of oxLDL and investigate their transfer upon co-incubation with HDL with varying levels of oxidation. Approach and resultsA total of 14 major species of oxidised phosphatidylcholine and oxidised cholesteryl ester from oxLDL were identified using an untargeted mass spectrometry approach. HDL obtained from pooled plasma of normolipidemic subjects (N=5) was oxidised under mild and heavy oxidative conditions. Non-oxidised (native) HDL and oxidised HDL were co-incubated with oxLDL, re-isolated and lipidomic analysis was performed. Lipoprotein surface lipids, oxidised phosphatidylcholines and oxidised cholesterols (7-ketocholesterol and 7β-hydroxycholesterol), but not internal oxidised cholesteryl esters, were effectively transferred to native HDL. Saturated and monounsaturated lyso-phosphatidylcholines were also transferred from the oxLDL to native HDL. These processes were attenuated when HDL was oxidised under mild and heavy oxidative conditions. The impaired capacities were accompanied by an increase in a ratio of sphingomyelin to phosphatidylcholine and a reduction in phosphatidylserine content in oxidised HDL, both of which are potentially important regulators of the oxidised lipid transfer capacity of HDL. ConclusionsOur study has revealed the differential transfer efficiency of surface and internal oxidised lipids from oxLDL and their acceptance onto HDL. These capacities were modulated when HDL was itself oxidised.

A mild and efficient CH2-extrusion reaction for the enantiospecific synthesis of highly configurationally stable Tröger bases.

A novel CH2 -extrusion reaction leading to the transformation of ethano-Tröger bases into disubstituted methano derivatives is reported (yields up to 93 %). Under mild and metal-free oxidative conditions, a loss of CH2 and a ring contraction are provoked. Despite two bond cleavages at stereogenic nitrogen and carbon centers and a temporary rupture of the bicyclic structure, a very high enantiospecificity (es≥98 %) is observed for this unusual reaction.

ChemInform Abstract: Iron‐Catalyzed C(sp2)—H Bond Functionalization with Organoboron Compounds.

We report here that an iron-catalyzed directed C–H functionalization reaction allows the coupling of a variety of aromatic, heteroaromatic, and olefinic substrates with alkenyl and aryl boron compounds under mild oxidative conditions. We rationalize these results by the involvement of an organoiron(III) reactive intermediate that is responsible for the C–H bond-activation process. A zinc salt is crucial to promote the transfer of the organic group from the boron atom to the iron(III) atom.

Fe-catalyzed double cross-dehydrogenative coupling of 1,3-dicarbonyl compounds and arylmethanes.

Fe-catalyzed tandem cross-dehydrogenative coupling of the methyl group in arylmethanes with 1,3-dicarbonyl compounds has been developed. The reaction affords one new C(sp(3))-C(sp(2)) bond and one new C(sp(3))-C(sp(3)) bond in a one-pot protocol. Further study suggests that this reaction might start with a Friedel-Crafts-type reaction (cross-dehydrogenative arylation) followed by cross-dehydrogenative coupling with an activated methylene group under mild oxidative conditions.

Rhodium(III)-catalyzed oxidative alkenylation of 1,3-dithiane-protected arenecarbaldehydes via regioselective C-H bond cleavage.

A Rh(III)-catalyzed direct alkenylation of 2-aryl-1,3-dithiane derivatives with alkenes has been developed. The 1,3-dithiane group can serve as an effective directing group for the exclusively monoselective alkenylation under mild oxidative conditions. The directing group is readily removable after the coupling event.

On a sugary-relationship between caspases and lamins

On a sugary-relationship between caspases and lamins

Interstrand cross-link and bioconjugate formation in RNA from a modified nucleotide.

RNA oligonucleotides containing a phenyl selenide derivative of 5-methyluridine were chemically synthesized by solid-phase synthesis. The phenyl selenide is rapidly converted to an electrophilic, allylic phenyl seleneate under mild oxidative conditions. The phenyl seleneate yields interstrand cross-links when part of a duplex and is useful for synthesizing oligonucleotide conjugates. Formation of the latter is illustrated by reaction of an oligonucleotide containing the phenyl selenide with amino acids in the presence of mild oxidant. The products formed are analogous to those observed in tRNA that are believed to be formed posttranslationally via a biosynthetic intermediate that is chemically homologous to the phenyl seleneate.

Iron-catalyzed C(sp(2))-H bond functionalization with organoboron compounds.

We report here that an iron-catalyzed directed C-H functionalization reaction allows the coupling of a variety of aromatic, heteroaromatic, and olefinic substrates with alkenyl and aryl boron compounds under mild oxidative conditions. We rationalize these results by the involvement of an organoiron(III) reactive intermediate that is responsible for the C-H bond-activation process. A zinc salt is crucial to promote the transfer of the organic group from the boron atom to the iron(III) atom.

Reversible amyloid fiber formation in the N terminus of androgen receptor.

Most of the biological effects of androgen hormones are mediated through an intracellular transcription factor, the androgen receptor (AR). This protein presents a long disordered N-terminal domain (NTD), known to aggregates into amyloid fibers.1 This aggregation property is usually associated with the presence of a poly-glutamine tract (polyQ), known to be involved in several pathologies.2 The NTD has gain interest recently because potential anti-prostate-cancer molecules could target this domain.3 Here, we characterize a conserved region of the NTD (distal from polyQ); it promotes the formation of amyloid fibers under mild oxidative conditions. Unlike most fibrils, which are irreversibly aggregated, the free peptides can be restored from the fibril by the addition of a reducing agent.

The Synthesis of α‐Azidoesters and Geminal Triazides

Three simple methods for the synthesis of geminal triazides are described: Starting from 1) 3-oxocarboxylic acids, 2) iodomethyl ketones, or 3) terminal olefins, a range of triazidomethyl ketones can be constructed under mild oxidative reaction conditions by the use of IBX-SO3 K, a sulfonylated derivative of 2-iodoxybenzoic acid (IBX), and NaN3 as an azide source. This is the first report of representatives of this novel class of triazide compounds: Despite their high nitrogen content, the geminal triazides are easy to handle, even when preparative-scale syntheses are performed. (Caution: These procedures still require protective measures!) The triazides are now broadly available for further studies regarding their properties and reactivity. Furthermore, we show how the method can be used to provide α-azidoesters, which are potential building blocks for amino acids.

Proteome-wide profiling of carbonylated proteins and carbonylation sites in HeLa cells under mild oxidative stress conditions

A number of oxidative protein modifications have been well characterized during the past decade. Presumably, reversible oxidative posttranslational modifications (PTMs) play a significant role in redox signaling pathways, whereas irreversible modifications including reactive protein carbonyl groups are harmful, as their levels are typically increased during aging and in certain diseases. Despite compelling evidence linking protein carbonylation to numerous disorders, the underlying molecular mechanisms at the proteome remain to be identified. Recent advancements in analysis of PTMs by mass spectrometry provided new insights into the mechanisms of protein carbonylation, such as protein susceptibility and exact modification sites, but only for a limited number of proteins. Here we report the first proteome-wide study of carbonylated proteins including modification sites in HeLa cells for mild oxidative stress conditions. The analysis relied on our recent strategy utilizing mass spectrometry-based enrichment of carbonylated peptides after DNPH derivatization. Thus a total of 210 carbonylated proteins containing 643 carbonylation sites were consistently identified in three replicates. Most carbonylation sites (284, 44.2%) resulted from oxidation of lysine residues (aminoadipic semialdehyde). Additionally, 121 arginine (18.8%), 121 threonine (18.8%), and 117 proline residues (18.2%) were oxidized to reactive carbonyls. The sequence motifs were significantly enriched for lysine and arginine residues near carbonylation sites (±10 residues). Gene Ontology analysis revealed that 80% of the carbonylated proteins originated from organelles, 50% enrichment of which was demonstrated for the nucleus. Moreover, functional interactions between carbonylated proteins of kinetochore/spindle machinery and centrosome organization were significantly enriched. One-third of the 210 carbonylated proteins identified here are regulated during apoptosis.

Cloning, Expression, and Characterization of a Methionine Sulfoxide Reductase B Gene from Nicotiana tabacum

Reactive oxygen species (ROS) are generated during normal aerobic metabolism and in plants exposed to environmental stress. Methionine (Met) residues are particularly sensitive to ROS-mediated oxidation, leading to the formation of methionine sulfoxide (MetSO) under mild oxidative conditions. Methionine sulfoxide reductase (MSR) repairs oxidized Met and protects plants from oxidative damage. Herein, we identified a tobacco (Nicotiana tabacum) MSRB gene, referred to as NtMSRB3. Analysis of the sequence showed that the NtMSRB3 protein had four typical motifs in a SelR domain, which is known as the catalytic region of MSRBs. NtMSRB3 specifically reduced the R epimer of MetSO and converted either free MetSO or Dabsyl-MetSO in the presence of dithiothreitol. Escherichia coli cells harboring NtMSRB3 displayed relative high viability under H₂O₂ stress. Subcellular localization of NtMSRB3 revealed that it was a plastid-targeted protein. Furthermore, the semi-quantitative reverse transcription polymerase chain reaction assay showed that NtMSRB3 was upregulated apparently by abscisic acid, salt, cold, and methyl viologen stress within 24 h of treatment.

Iron-Catalyzed Oxidative Tandem Reactions with TEMPO Oxoammonium Salts: Synthesis of Dihydroquinazolines and Quinolines

A straightforward iron-catalyzed divergent oxidative tandem synthesis of dihydroquinazolines and quinolines from N-alkylanilines using a TEMPO oxoammonium salt as a mild and nontoxic oxidant has been developed. Fe(OTf)2 was the Lewis acid catalyst of choice for the formation of dihydroquinazolines, whereas FeCl3 led to better results for the synthesis of quinolines. This divergent approach implies that, for both syntheses, direct oxidative functionalization of a α-C(sp(3))-H bond of the N-alkylanilines occurs, leading to C-N bond formation or C-C bond formation upon homocondensation or reaction with simple olefins, respectively. Cyclization followed by a final oxidation generates these classes of interesting bioactive heterocycles in one synthetic transformation. Additionally, the one-pot multicomponent synthesis of quinolines from anilines, aldehydes, and olefins has also been successfully developed under these mild oxidative conditions.

ChemInform Abstract: A Cooperative Catalytic System of Platinum/Iridium Alloyed Nanoclusters and a Dimeric Catechol Derivative: An Efficient Synthesis of Quinazolines Through a Sequential Aerobic Oxidative Process.

AbstractA new polymer‐supported catalyst system consisting of platinum/iridium alloyed nanoclusters and spiro‐bisindane ligand THSI is used for the facile preparation of fused quinazoline derivatives under mild aerobic oxidative conditions.

Highly enantioselective organocatalytic α-selenylation of aldehydes using hypervalent iodine compounds

The highly enantioselective organocatalytic α-selenylation reaction of aldehydes using a hypervalent iodine compound as an oxidative agent from commercially available phenyl diselenide under mild oxidative conditions is described. This transformation affords α-selenyl aldehydes in good yields and with excellent enantioselectivities. By using hypervalent iodine compounds, it opens up a suitable and alternative way for the preparation of biologically active building blocks such as β-hydroxy alcohols, α-amino acids, and α-hydroxy esters.

Synthesis of Indoles by Copper-Catalyzed Heteroannulation of o-Aminophenylboronic Acid Pinacol Esters with β-Keto Esters

Copper-catalyzed coupling of ortho-aminophenylboronic acid pinacol esters with β-ketoesters afforded, under mild base-free oxidative conditions, 2,3-disubstituted indoles featuring a key Chan-Lam type carbon-carbon bond forming reaction.

A Cooperative Catalytic System of Platinum/Iridium Alloyed Nanoclusters and a Dimeric Catechol Derivative: An Efficient Synthesis of Quinazolines Through a Sequential Aerobic Oxidative Process

AbstractA cooperative catalytic system of heterogeneous polymer‐supported bi‐metallic platinum/iridium (Pt/Ir) alloyed nanoclusters and 5,5′,6,6′‐tetrahydroxy‐3,3,3′,3′‐tetramethyl‐1,1′‐spiro‐bisindane (TTSBI) enabled the facile preparation of quinazoline derivatives with low catalyst loadings and broad substrate scope under mild aerobic oxidative conditions. The ability to perform the reaction in gram‐scale and under open‐air conditions highlights the synthetic application of this cooperative catalytic system.