Dicarbonyl Electrophiles Research Articles

Electrophilic reactive aldehydes as a therapeutic target in colorectal cancer prevention and treatment.

Colorectal cancer (CRC) is a major health problem worldwide. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation and form covalent adducts with amine-containing macromolecules. We have shown high levels of adducts of isoLGs in colonic epithelial cells of patients with CRC. We thus investigated the role of these reactive aldehydes in colorectal cancer development. We found that 2-hydroxybenzylamine (2-HOBA), a natural compound derived from buckwheat seeds that acts as a potent scavenger of electrophiles, is bioavailable in the colon of mice after supplementation in the drinking water and does not affect the colonic microbiome. 2-HOBA reduced the level of isoLG adducts to lysine as well as tumorigenesis in models of colitis-associated carcinogenesis and of sporadic CRC driven by specific deletion of the adenomatous polyposis coli gene in colonic epithelial cells. In parallel, we found that oncogenic NRF2 activation and signaling were decreased in the colon of 2-HOBA-treated mice. Additionally, the growth of xenografted human HCT116 CRC cells in nude mice was significantly attenuated by 2-HOBA supplementation. In conclusion, 2-HOBA represents a promising natural compound for the prevention and treatment of CRC.

The nutraceutical electrophile scavenger 2-hydroxybenzylamine (2-HOBA) attenuates gastric cancer development caused by Helicobacter pylori

Stomach cancer is a leading cause of cancer death. Helicobacter pylori is a bacterial gastric pathogen that is the primary risk factor for carcinogenesis, associated with its induction of inflammation and DNA damage. Dicarbonyl electrophiles are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. 2-hydroxybenzylamine (2-HOBA) is a natural compound derived from buckwheat seeds and acts as a potent scavenger of reactive aldehydes. Our goal was to investigate the effect of 2-HOBA on the pathogenesis of H. pylori infection. We used transgenic FVB/N insulin-gastrin (INS-GAS) mice as a model of gastric cancer. First, we found that 2-HOBA is bioavailable in the gastric tissues of these mice after supplementation in the drinking water. Moreover, 2-HOBA reduced the development of gastritis in H. pylori-infected INS-GAS mice without affecting the bacterial colonization level in the stomach. Further, we show that the development of gastric dysplasia and carcinoma was significantly reduced by 2-HOBA. Concomitantly, DNA damage were also inhibited by 2-HOBA treatment in H. pylori-infected mice. In parallel, DNA damage was inhibited by 2-HOBA in H. pylori-infected gastric epithelial cells in vitro. In conclusion, 2-HOBA, which has been shown to be safe in human clinical trials, represents a promising nutritional compound for the chemoprevention of the more severe effects of H. pylori infection.

Dicarbonyl Electrophiles Mediate Inflammation-Induced Gastrointestinal Carcinogenesis

Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. Thus, we sought to determine the role of dicarbonyl electrophiles in inflammation-associated carcinogenesis. The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, in human gastric organoids, and in patients with colitis and colitis-associated carcinoma (CAC). The effect on cancer development of a potent scavenger of dicarbonyl electrophiles, 5-ethyl-2-hydroxybenzylamine (EtHOBA), was determined in transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils as models of H pylori-induced carcinogenesis and in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium as a model of CAC. The effect of EtHOBA on mutations in gastric epithelial cells of H pylori-infected INS-GAS mice was assessed by whole-exome sequencing. We show increased isoLG adducts in gastric epithelial cell nuclei in patients with gastritis and intestinal metaplasia and in human gastric organoids infected with H pylori. EtHOBA inhibited gastric carcinoma in infected INS-GAS mice and gerbils and attenuated isoLG adducts, DNA damage, and somatic mutation frequency. Additionally, isoLG adducts were elevated in tissues from patients with colitis, colitis-associated dysplasia, and CAC as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. In this model, EtHOBA significantly reduced adduct formation, tumorigenesis, and dysplasia severity. Dicarbonyl electrophiles represent a link between inflammation and somatic genomic alterations and are thus key targets for cancer chemoprevention.

First-in-human study assessing safety, tolerability, and pharmacokinetics of 2-hydroxybenzylamine acetate, a selective dicarbonyl electrophile scavenger, in healthy volunteers

Background2-Hydroxybenzylamine (2-HOBA) is a selective scavenger of dicarbonyl electrophiles that protects proteins and lipids from being modified by these electrophiles. It is currently being developed for use as a nutritional supplement to help maintain good health and protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline associated with Mild Cognitive Impairment and Alzheimer’s disease.MethodsIn this first-in-human study, the safety, tolerability, and pharmacokinetics of six ascending single oral doses of 2-HOBA acetate were tested in eighteen healthy human volunteers.ResultsReported adverse events were mild and considered unlikely to be related to 2-HOBA. There were no clinically significant changes in vital signs, ECG recordings, or clinical laboratory parameters. 2-HOBA was fairly rapidly absorbed, with a tmax of 1–2 h, and eliminated, with a t1/2 of approximately 2 h. Both tmax and t1/2 were independent of dose level, while Cmax and AUC increased proportionally with dose level.Conclusions2-HOBA acetate was safe and well-tolerated at doses up to 825 mg in healthy human volunteers, positioning it as a good candidate for continued development as a nutritional supplement.Trial registrationThis study is registered at ClinicalTrials.gov (NCT03176940).

40 - Post-translational modification of ApoA-1 in metabolic syndrome

The increased cardiovascular morbidity and mortality associated with low cholesterol content of HDL is not improved by interventions that increase HDL cholesterol, suggesting that the vascular pathology results from dysfunction of the HDL apoproteins. In conditions associated with low HDL cholesterol, such as metabolic syndrome, increased oxidative stress leads to lipid peroxidation and formation of highly reactive dicarbonyl electrophiles, including malondialdehyde (MDA), isolevuglandins and 4-oxo-nonenal, that covalently react with the e-amine of lysines. Modification of ApoA-1 by MDA is known to disrupt reverse cholesterol transport. We measured the level of the lysine- MDA-lysine crosslinks in the HDL proteins of patients with metabolic syndrome with LC/tandem mass spectrometry utilizing a 13C-labelled internal standard and found an increased level of this lysine modification in comparison with healthy volunteers (metabolic syndrome, 5.5 ± 0.3 ng/mg protein; healthy subjects, 4.4 ± 0.2 ng/mg protein; P = 0.041). To address ApoA-1 more specifically, we characterized the relative reactivity of lysine sites on HDL- associated ApoA-1 and found that several lysines (aa 12, 23, 59 and 238/239) were preferentially modified by MDA. The probability that, in addition to MDA-K crosslinks, there are many other modifications of ApoA-1 lysines by carbonyl electrophiles was investigated by determining the loss of unmodified peptides that contained a lysine sensitive to carbonyl adduction. In metabolic syndrome, we found that the ratio of unmodified peptide 11-23 (K12) to an ApoA-1 peptide without a lysine was markedly reduced (0.44 ± 0.13 vs healthy controls 2.26 ± 0.32; P = 0.0005) indicating a global modification of this peptide by 80%. The proportion of unmodified 227-238 (K238) was reduced by 56% in ApoA-1 from metabolic syndrome patients (p = 0.0005). This represents a profound degree of post-translational modification of the molecule that regulates the function of HDL.

ChemInform Abstract: Synthesis of Cyclic Bis(trimethylsilyl) Enol Ethers and Their [3 + 4] and [3 + 5] Annulation Reactions with Dicarbonyl Electrophiles. Access to Highly Functionalized Tricyclic Ethers Possessing trans Intrabridgehead Stereochemistry.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of Cyclic Bis(trimethysilyl) Enol Ethers and Their [3 + 4] and [3 + 5] Annulation Reactions with Dicarbonyl Electrophiles. Access to Highly Functionalized Tricyclic Ethers Possessing Trans Intrabridgehead Stereochemistry

The synthesis of cyclic bis(trimethylsilyl) enol ethers from cycloalkanone carboxylates is described. The [3 + 4] and [3 + 5] annulation reactions of these bis(dinucleophilic) synthons with various 1,4- and 1,5-dicarbonyl electrophiles leads to the formation of tricyclic keto ethers with good regio- and stereochemical control. An interesting trans intrabridgehead stereochemistry is observed when using bis(trimethylsilyl) enol ethers derived from nine- to 12-membered ring β-keto esters.

ChemInform Abstract: Chelation and Nonchelation Control in the (3 + 4) and (3 + 5) Annulation Reactions of Benzyloxy‐Substituted Dicarbonyl Electrophiles with Bis(trimethylsilyl) Enol Ethers.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: (3 + 4) and (3 + 5) Annulation Reactions of α‐(Phenylthio) Dicarbonyl Electrophiles with Bis(trimethylsilyl) Enol Ethers: Synthesis of Highly Functionalized Medium Ring Carbocycles.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Chelation and Nonchelation Control in the [3 + 4] and [3 + 5] Annulation Reactions of Benzyloxy-Substituted Dicarbonyl Electrophiles with Bis(trimethylsilyl) Enol Ethers

Chelation and Nonchelation Control in the [3 + 4] and [3 + 5] Annulation Reactions of Benzyloxy-Substituted Dicarbonyl Electrophiles with Bis(trimethylsilyl) Enol Ethers

3 + 4] and [3 + 5] Annulation Reactions of .alpha.-(Phenylthio)Dicarbonyl Electrophiles with Bis(trimethylsilyl) Enol Ethers: Synthesis of Highly Functionalized Medium Ring Carbocycles

3 + 4] and [3 + 5] Annulation Reactions of .alpha.-(Phenylthio)Dicarbonyl Electrophiles with Bis(trimethylsilyl) Enol Ethers: Synthesis of Highly Functionalized Medium Ring Carbocycles