Electrophilic Aldehydes Research Articles

The biochemistry of the carcinogenic alcohol metabolite acetaldehyde

Acetaldehyde (AcH) is the first metabolite of ethanol and is proposed to be responsible for the genotoxic effects of alcohol consumption. As an electrophilic aldehyde, AcH can form multiple adducts with DNA and other biomolecules, leading to function-altering and potentially toxic and carcinogenic effects. In this review, we describe sources of AcH in humans, including AcH biosynthesis mechanisms, and outline the structures, properties and functions of AcH-derived adducts with biomolecules. We also describe human AcH detoxification mechanisms and discuss ongoing challenges in the field.

Direct ketone synthesis from primary alcohols and alkenes enabled by a dual photo/cobalt catalysis

Catalytic methods to couple alcohol and alkene feedstocks are highly valuable in synthetic chemistry. The direct oxidative coupling of primary alcohols and alkenes offers a streamlined approach to ketone synthesis. Currently, available methods are based on transition metal-catalyzed alkene hydroacylation, which involves the generation of an electrophilic aldehyde intermediate from primary alcohol dehydrogenation. These methods generally require high reaction temperatures and a high loading of precious metal catalysts and are predominantly effective for branch-selective reactions with electron-rich alkenes. Herein, we designed a dual photo/cobalt-catalytic method to manipulate the reactivity of nucleophilic ketyl radicals for the synthesis of ketones from primary alcohols and alkenes in complementary reactivity and selectivity. This protocol exhibits exceptional scope across both primary alcohols and alkenes with high chemo- and regio-selectivity under mild reaction conditions. Mechanism investigations reveal the essential role of cobalt catalysis in enabling efficient catalysis and broad substrate scope.

Role of reactive carbonyls and superoxide radicals in protein damage by cigarette smoke extracts: Comparison of Heat-not-Burn e-cigarettes to conventional cigarettes

Oxidative protein damage involving carbonylation of respiratory tract proteins typically accompanies exposure to tobacco smoke. Such damage can arise via multiple mechanisms, including direct amino acid oxidation by reactive oxygen species or protein adduction by electrophilic aldehydes. This study investigated the relative importance of these pathways during exposure of a model protein to fresh cigarette emission extracts. Briefly, protein carbonyl adducts were estimated in bovine serum albumin following incubation in buffered solutions with whole cigarette emissions extracts prepared from either a single 1R6F research cigarette or a single “Heat-not-Burn” e-cigarette. Although both extracts caused concentration-dependent protein carbonylation, conventional cigarette extracts produced higher adduct yields than e-cigarette extracts. Superoxide radical generation by conventional and e-cigarette emissions was assessed by monitoring nitro blue tetrazolium reduction and was considerably lower in extracts made from “Heat-Not-Burn” e-cigarettes. The superoxide dismutase/catalase mimic EUK-134 strongly suppressed radical production by whole smoke extracts from conventional cigarettes, however, it did not diminish protein carbonyl adduction when incubating smoke extracts with the model protein. In contrast, edaravone, a neuroprotective drug with strong carbonyl-trapping properties, strongly suppressed protein damage without inhibiting superoxide formation. Although these findings require extension to appropriate cell-based and in vivo systems, they suggest reactive aldehydes in tobacco smoke make greater contributions to oxidative protein damage than smoke phase radicals.

Quantitative Determination of Water in Organic Liquids by Ambient Mass Spectrometry

AbstractThis study uses a rapid tandem mass‐spectrometry method to determine water content in complex organic solutions. Emphasis is placed on trace‐water analysis by a fast and accurate alternative to the Karl–Fischer method. In this new method, water is captured by a charge‐labeled molecular probe. Water binds strongly with high specificity to the strongly electrophilic aldehyde site in a charge‐labelled molecule (N‐methylpyridinium); competitive binding by other analytes is effectively discriminated against in the mass‐measurement step. Quantitative determinations are made over a wide concentration range, 0.001 % (10 ppm) to 99 %, with better than 10 % relative standard deviation, along with short (1 min) analysis times using small sample volumes (several μL). Applications include water measurement in simple organic solvents, for example, deuterated solvents, as well as in complex mixtures, for example, organic reaction mixtures. Additionally, this method allows for water monitoring in levitated droplets. Mechanistic investigations into the impact of water on important chemical processes in organic synthesis and environmental science are reported.

Quantitative Determination of Water in Organic Liquids by Ambient Mass Spectrometry.

This study uses a rapid tandem mass-spectrometry method to determine water content in complex organic solutions. Emphasis is placed on trace-water analysis by a fast and accurate alternative to the Karl-Fischer method. In this new method, water is captured by a charge-labeled molecular probe. Water binds strongly with high specificity to the strongly electrophilic aldehyde site in a charge-labelled molecule (N-methylpyridinium); competitive binding by other analytes is effectively discriminated against in the mass-measurement step. Quantitative determinations are made over a wide concentration range, 0.001 % (10 ppm) to 99 %, with better than 10 % relative standard deviation, along with short (1 min) analysis times using small sample volumes (several μL). Applications include water measurement in simple organic solvents, for example, deuterated solvents, as well as in complex mixtures, for example, organic reaction mixtures. Additionally, this method allows for water monitoring in levitated droplets. Mechanistic investigations into the impact of water on important chemical processes in organic synthesis and environmental science are reported.

Aminoalcohol Synthesis through Nonprecious Metal Catalysis: Enantioselective Cu-Catalyzed Reductive Coupling of Aldehydes and Allenamides.

Herein, we report the development of a Cu-catalyzed aminoallylation of aldehyde electrophiles through reductive coupling by circumventing the problematic competitive reduction of the aldehyde electrophile by a CuH catalyst. This leads to a highly diastereo- and enantioselective process for the synthesis of chiral 1,2-aminoalcohols containing secondary alcohol substitution. Cleavage of the N substituents on the reaction products was performed, allowing access to the other diastereomer of the aminoalcohol, which was investigated in the context of a synthesis of eligulstat.

Mitigating a Bioactivation Liability with an Azetidine-Based Inhibitor of Diacylglycerol Acyltransferase 2 (DGAT2) En Route to the Discovery of the Clinical Candidate Ervogastat.

We recently disclosed SAR studies on systemically acting, amide-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) that addressed metabolic liabilities with the liver-targeted DGAT2 inhibitor PF-06427878. Despite strategic placement of a nitrogen atom in the dialkoxyaromatic ring in PF-06427878 to evade oxidative O-dearylation, metabolic intrinsic clearance remained high due to extensive piperidine ring oxidation as exemplified with compound 1. Piperidine ring modifications through alternate N-linked heterocyclic ring/spacer combination led to azetidine 2 that demonstrated lower intrinsic clearance. However, 2 underwent a facile cytochrome P450 (CYP)-mediated α-carbon oxidation followed by azetidine ring scission, resulting in the formation of ketone (M2) and aldehyde (M6) as stable metabolites in NADPH-supplemented human liver microsomes. Inclusion of GSH or semicarbazide in microsomal incubations led to the formation of Cys-Gly-thiazolidine (M3), Cys-thiazolidine (M5), and semicarbazone (M7) conjugates, which were derived from reaction of the nucleophilic trapping agents with aldehyde M6. Metabolites M2 and M5 were biosynthesized from NADPH- and l-cysteine-fortified human liver microsomal incubations with 2, and proposed metabolite structures were verified using one- and two-dimensional NMR spectroscopy. Replacement of the azetidine substituent with a pyridine ring furnished 8, which mitigated the formation of the electrophilic aldehyde metabolite, and was a more potent DGAT2 inhibitor than 2. Further structural refinements in 8, specifically introducing amide bond substituents with greater metabolic stability, led to the discovery of PF-06865571 (ervogastat) that is currently in phase 2 clinical trials for the treatment of nonalcoholic steatohepatitis.

Differential Contributions of Distinct Free Radical Peroxidation Mechanisms to the Induction of Ferroptosis.

Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Lipid peroxidation can propagate through either the hydrogen-atom transfer (HAT) or peroxyl radical addition (PRA) mechanism. However, the contribution of the PRA mechanism to the induction of ferroptosis has not been studied. In this study, we aim to elucidate the relationship between the reactivity and mechanisms of lipid peroxidation and ferroptosis induction. We found that while some peroxidation-reactive lipids, such as 7-dehydrocholesterol, vitamins D3 and A, and coenzyme Q10, suppress ferroptosis, both nonconjugated and conjugated PUFAs enhanced cell death induced by RSL3, a ferroptosis inducer. Importantly, we found that conjugated PUFAs, including conjugated linolenic acid (CLA 18:3) and conjugated linoleic acid (CLA 18:2), can induce or potentiate ferroptosis much more potently than nonconjugated PUFAs. We next sought to elucidate the mechanism underlying the different ferroptosis-inducing potency of conjugated and nonconjugated PUFAs. Lipidomics revealed that conjugated and nonconjugated PUFAs are incorporated into distinct cellular lipid species. The different peroxidation mechanisms predict the formation of higher levels of reactive electrophilic aldehydes from conjugated PUFAs than nonconjugated PUFAs, which was confirmed by aldehyde-trapping and mass spectrometry. RNA sequencing revealed that protein processing in the endoplasmic reticulum and proteasome are among the most significantly upregulated pathways in cells treated with CLA 18:3, suggesting increased ER stress and activation of unfolded protein response. These results suggest that protein damage by lipid electrophiles is a key step in ferroptosis.

Biochemical control of the mitochondrial protein MitoNEET by biological thiols and lipid-derived electrophiles

MitoNEET is a mitochondrial [2Fe-2S]-containing protein known for its involvement in cellular metabolism, iron regulation, and oxidative stress. The protein has been associated with diseases ranging from diabetes to Parkinson's disease, prompting the development of compounds designed to target mitoNEET selectively. Unfortunately, drug development is limited due to a lack of mechanistic understanding of how mitoNEET integrates into pathophysiological processes, and biological compounds that govern mitoNEET function are still ill-defined. We demonstrate an oxygen-dependent reaction with biological thiols catalyzed by mitoNEET. Specifically, we observed that mitoNEET converts L-cysteine to cystine. Finally, we showed that reduced glutathione (L-GSH) regulates the reactivity of two lipid-derived biomarkers of oxidative stress, 4-HNE and 4-ONE, towards mitoNEET. We found that exposure to L-GSH before treatment with either of the electrophilic aldehydes prevents the formation of a covalently linked mitoNEET dimer. Meanwhile, adding L-GSH after electrophile treatment recovers mitoNEET from the 4-HNE induced modification but not from the modification induced by 4-ONE. These results indicate a possible role for mitoNEET in thiol-mediated oxidative stress and may facilitate the development of drugs designed to modulate mitoNEET activity to improve pathophysiological states.

Iridium-, Ruthenium-, and Nickel-Catalyzed C-C Couplings of Methanol, Formaldehyde, and Ethanol with π-Unsaturated Pronucleophiles via Hydrogen Transfer.

In this Perspective, the use of methanol and ethanol as C1 and C2 feedstocks in metal-catalyzed C-C couplings to π-unsaturated pronucleophiles via hydrogen auto-transfer is surveyed. In these processes, alcohol oxidation to form an aldehyde electrophile is balanced by reduction of an π-unsaturated hydrocarbon to form a transient organometallic nucleophile. Mechanistically related reductive couplings of paraformaldehyde mediated by alcohol reductants or formic acid also are described. These processes encompass the first catalytic enantioselective C-C couplings of methanol and ethanol and, more broadly, illustrate how the native reducing ability of alcohols enable the departure from premetalated reagents in carbonyl addition.

Lipid-Derived Aldehydes: New Key Mediators of Plant Growth and Stress Responses.

Aldehydes, derivatives of lipids, are ubiquitously produced through non-enzymatic and enzymatic pathways in higher plants and participate in many physiological and biological processes. Increasing evidence demonstrates that aldehydes are involved in plants response to many abiotic stresses, such as light, drought, heat and nutrient deficiency. In plant cells, endogenously triggered or exogenously applied high concentrations of aldehydes can damage proteins and nucleic acid, disturb redox homeostasis, and consequently inhibit plant growth; therefore, they are considered cytotoxins. Aldehyde levels are also used as biomarkers to evaluate the health status of plants. Further genetic research shows that several enzymes have strong capacities to detoxify these electrophilic aldehydes. Small molecules, such as carnosine and glutathione, also exhibit the ability to scavenge aldehydes, effectively promoting plant growth. Recently, increasing evidence has shown that certain aldehydes at certain concentrations can upregulate survival genes, activate antioxidant responses, increase defense against pathogens and stimulate plant growth. This review summarizes recent studies of lipid-derived aldehydes in higher plants, mainly focusing on the generation pathway, toxic effects, and detoxification strategies. In addition, the signaling effects of aldehydes in plants are also discussed.

Electrophilic Aldehyde 4-Hydroxy-2-Nonenal Mediated Signaling and Mitochondrial Dysfunction.

Reactive oxygen species (ROS), a by-product of aerobic life, are highly reactive molecules with unpaired electrons. The excess of ROS leads to oxidative stress, instigating the peroxidation of polyunsaturated fatty acids (PUFA) in the lipid membrane through a free radical chain reaction and the formation of the most bioactive aldehyde, known as 4-hydroxynonenal (4-HNE). 4-HNE functions as a signaling molecule and toxic product and acts mainly by forming covalent adducts with nucleophilic functional groups in proteins, nucleic acids, and lipids. The mitochondria have been implicated as a site for 4-HNE generation and adduction. Several studies clarified how 4-HNE affects the mitochondria's functions, including bioenergetics, calcium homeostasis, and mitochondrial dynamics. Our research group has shown that 4-HNE activates mitochondria apoptosis-inducing factor (AIFM2) translocation and facilitates apoptosis in mice and human heart tissue during anti-cancer treatment. Recently, we demonstrated that a deficiency of SOD2 in the conditional-specific cardiac knockout mouse increases ROS, and subsequent production of 4-HNE inside mitochondria leads to the adduction of several mitochondrial respiratory chain complex proteins. Moreover, we highlighted the physiological functions of HNE and discussed their relevance in human pathophysiology and current discoveries concerning 4-HNE effects on mitochondria.

Diarylprolinol as an Effective Organocatalyst in Asymmetric Cross-Aldol Reactions of Two Different Aldehydes.

The aldol reaction is one of the most important carbon-carbon bond-forming reactions in organic chemistry. Asymmetric direct cross-aldol reaction of two different aldehydes has been regarded as a difficult reaction because of the side reactions such as self-aldol reaction and over reaction. We found that trifluoromethyl-substituted diarylprolinol, α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol (1), is an effective organocatalyst that promotes several cross-aldol reactions of aldehydes with excellent diastereo- and enantioselectivities. Acetaldehyde can be employed as a suitable nucleophilic aldehyde. Successful electrophilic aldehydes are ethyl glyoxylate, chloroacetaldehyde, dichloroacetaldehyde, chloral, α-alkyl-α-oxo aldehyde, trifluoroacetaldehyde, glyoxal, alkenyl aldehyde, alkynyl aldehyde, and formaldehyde. Some of the aldehydes are commercially available as a polymer solution, an aqueous solution, or in the hydrated form. They can be used directly in the asymmetric aldol reaction as a commercially available form, which is a synthetic advantage. Given that the obtained aldol products possess several functional groups along with a formyl moiety, they are synthetically useful chiral building blocks.

Diarylprolinol with Trifluoromethyl Substituents and Diphenylprolinol‐Derived Perfluoroalkanesulfonamide as Organocatalysts in the Cross‐Aldol Reaction of Aldehydes

AbstractThe asymmetric cross‐aldol reaction of two different aldehydes is a synthetically relevant reaction. Diarylprolinol catalyst with trifluoromethyl substituents and sulfonamide catalyst derived from diphenylprolinol are organocatalysts for the cross‐aldol reaction. The reactivity and stereoselectivity of these two catalysts were compared in the asymmetric cross‐aldol reactions of propanal and acetaldehyde as nucleophilic aldehydes and several electrophilic aldehydes. Depending on the electrophilic aldehydes, the preferable catalyst differs. By the proper selection of these two catalysts, potentially synthetically useful chiral building blocks can be synthesized with diastereoselectivities of anti:syn=2.6:1∼>20:1 and enantioselectivities of 60∼>98% ee.magnified image

NHC‐Organocatalysed Hydroacylation of Unactivated or Weakly Activated C−C Multiple Bonds and Ketones

AbstractN‐Heterocyclic Carbenes (NHCs) are versatile organocatalysts owing to their umpolung capability – i. e. the catalytic transformation of electrophilic aldehydes into nucleophilic species. Profoundly, aldehyde umpolungs were exploited in Benzoin and Stetter reactions, whereas hydroacylation of unactivated carbon‐carbon multiple bonds (alkenes and alkynes) are challenging and highly desired. Normally, catalytic hydroacylation of alkenes was achieved by transition metal catalysts based on rhodium, cobalt, nickel, ruthenium, and iridium. However, the metal‐catalyzed strategy is accompanied by undesired side reactions, such as decarbonylation of aldehydes, and thus demands installation of directing group in the aldehydes. In contrast, NHCs overcome these downsides and utilize the umpolung strategy beyond the Benzoin and Stetter reactions to implement catalytic hydroacylation of unpolarised and unactivated carbon‐carbon multiple bonds (alkenes and alkynes) under mild reaction conditions with step‐ and atom‐economy. In addition, this unconventional transformation is extended to catalytic asymmetric catalysis. This highlight covers the progress and practicality of NHC‐catalyzed hydroacylation of alkenes, alkynes, arynes, and ketones to access biologically relevant organics. Both inter‐and intramolecular hydroacylation reactions in combination with Stetter were presented and key mechanistic pathways were discussed.

Curcumin functionalized TiO2 modified bentonite clay nanostructure for colorimetric Aflatoxin B1 detection in peanut and corn

This work reports an analytical technique to determine Aflatoxin B1 (AFB1) in food samples using electrostatic interaction with curcumin (Cur) functionalized TiO2 NPs supported on layered structured bentoniteclay(Ti(Cur)O2Bent). TiO2Bent synthesized by thermal decomposition method, obtained crystallite size of 32.4 nm by XRD and SEM uniform morphology of TiO2NPs on the bentonite surface. The optical band gap decreased with intercalation of TiO2 NPs in the interlayers of bentonite than bare TiO2 NPs and showed presence of alumina-silicate in composite by FT-IR for improved ion-exchange properties. Cur form a chelated complex with TiO2Bent due to extended conjugation of the dye at 1,3 diketone moiety as shown by C13 NMR studies. TiO2Bent improved Cur capability to form electrostatic bond with unsaturated aldehyde electrophiles of AFB1 at pH 9.54. This was evidenced by FT-IR at 1647 cm−1 and sp. hybridization by C13 NMR studies for CO bond in AFs. The hypsochromic modification in color of the dye from red (505 nm) to yellow (403 nm) was recorded by UV–Vis in AFB1 spiked peanut (1–5 ppb) and corn (1–20 ppb). Absorption at maximum intensity of ~434 nm in the linear concentration of AFB1 obtained limit of detection (LOD) (3σ) as 1.4 ppb and 0.38 ppb for peanut and corn respectively. Hence, this rapid sensing developed by the green chemicals synthesis of NPs reagent could be developed into paper-based sensor for onsite detection of AFB1 in food sector.

AS CLÁSSICAS HIDRAZONAS COMO REVELADORES DE IMPRESSÕES DIGITAIS: UMA PROPOSTA DE QUÍMICA ORGÂNICA EXPERIMENTAL

CLASSIC HYDRAZONES AS FINGERMARK DEVELOPERS: AN EXPERIMENTAL ORGANIC CHEMISTRY PROPOSAL. Fingermark dusting powders are an important tool of forensic practitioners, being a first-choice process for most crime scene investigators. The development of new products is of utmost importance for forensic science. Hydrazones comprise compounds derived from ketones or aldehydes in reaction with hydrazines. These reactions are widely studied in organic chemistry because of the versatility of these compounds in organic synthesis. The study of these reactions leads to the understanding of the nucleophilicity of hydrazines, as well as the electrophilicity of aldehydes and ketones. The present work presents one proposal of experimental organic chemistry, aiming at a new application of this classic class of organic substances in forensic chemistry, specifically as a developer of latent fingermarks due to the variations of the color of the compounds, with spectra ranging in a range from 250 to 500 nm. These compounds were identified by Infrared Spectroscopy, Ultraviolet-Visible Spectroscopy and Mass Spectrometry. The development on glass surfaces demonstrated the potential application of these compounds in everyday life situations.

Diastereo-, Enantio-, and Z-Selective α,δ-Difunctionalization of Electron-Deficient Dienes Initiated by Rh-Catalyzed Conjugate Addition.

Metal-catalyzed enantioselective conjugate additions are highly reliable methods for stereoselective synthesis; however, multicomponent reactions that are initiated by conjugate arylation of acyclic π-systems are rare. These reactions generally proceed with poor diastereoselectivity while requiring basic, moisture sensitive organometallic nucleophiles. Here, we show that Rh-catalysts supported by a tetrafluorobenzobarrelene ligand (Ph-tfb) enable the enantio-, diastereo-, and Z-selective α,δ-difunctionalization of electron-deficient 1,3-dienes with organoboronic acid nucleophiles and aldehyde electrophiles to generate Z-homoallylic alcohols with three stereocenters. The reaction accommodates diene substrates activated by ester, amide, ketone, or aromatic groups and can be used to couple aryl, alkenyl, or alkyl aldehydes. Diastereoselective functionalization of the Z-olefin unit in the addition products allows for the generation of compounds with five stereocenters in high dr and ee. Mechanistic studies suggest aldehyde allylrhodation is the rate-determining step, and unlike reactions of analogous Rh-enolates, the Rh-allyl species generated by δ-arylation undergoes aldehyde trapping rather than protonolysis, even when water is present as a cosolvent. These findings should have broader implications in the use of privileged metal-catalyzed conjugate addition reactions as entry points toward the preparation of acyclic molecules containing nonadjacent stereocenters.

Oxi-HA/ADH Hydrogels: A Novel Approach in Tissue Engineering and Regenerative Medicine

Hyaluronic acid (HA) is a natural polyelectrolyte abundant in mammalian connective tissues, such as cartilage and skin. Both endogenous and exogenous HA produced by fermentation have similar physicochemical, rheological, and biological properties, leading to medical and dermo-cosmetic products. Chemical modifications such as cross-linking or conjugation in target groups of the HA molecule improve its properties and in vivo stability, expanding its applications. Currently, HA-based scaffolds and matrices are of great interest in tissue engineering and regenerative medicine. However, the partial oxidation of the proximal hydroxyl groups in HA to electrophilic aldehydes mediated by periodate is still rarely investigated. The introduced aldehyde groups in the HA backbone allow spontaneous cross-linking with adipic dihydrazide (ADH), thermosensitivity, and noncytotoxicity to the hydrogels, which are advantageous for medical applications. This review provides an overview of the physicochemical properties of HA and its usual chemical modifications to better understand oxi-HA/ADH hydrogels, their functional properties modulated by the oxidation degree and ADH concentration, and the current clinical research. Finally, it discusses the development of biomaterials based on oxi-HA/ADH as a novel approach in tissue engineering and regenerative medicine.

Development of fluorescent-labeled trapping reagents based on cysteine to detect soft and hard electrophilic reactive metabolites

Trapping assays are conducted at lead optimization stages to detect reactive metabolites (RMs) that can contribute to drug toxicity. The commonly used dansyl glutathione (dGSH) provides a sensitive analysis owing to the fluorescent label, however, it captures only soft electrophilic RMs. TRs for hard electrophilic RMs, few of which are labeled fluorescently, can detect hard electrophilic aldehydes only by forming unstable imine derivatives. In this study, we aimed to develop novel fluorescently labeled TRs that detect both soft and hard electrophilic RMs and form stable ring structures with aldehydes. We designed four dansylated TRs based on cysteine, which has both soft and hard nucleophilic groups. To evaluate the reactivity of the TRs, we incubated them with several substrates and found that one of the TRs (CysGlu-Dan) detected all the soft and hard electrophilic RMs. We also examined the inhibition potential of each TR for seven major CYPs involved in drug metabolism and found that CysGlu-Dan showed an inhibitory profile similar to that of dGSH. In conclusion, CysGlu-Dan can be used to evaluate the risk of RMs in drug discovery.