Identification of Antioxidant Methyl Derivatives of <i>Ortho</i>-Carbonyl Hydroquinones That Reduce Caco-2 Cell Energetic Metabolism and Alpha-Glucosidase Activity

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dc.contributor.authorMonroy-Cardenas, Matias
dc.contributor.authorAlmarza, Cristopher
dc.contributor.authorValenzuela-Hormazabal, Paulina
dc.contributor.authorRamirez, David
dc.contributor.authorUrra, Felix A.
dc.contributor.authorMartinez-Cifuentes, Maximiliano
dc.contributor.authorAraya-Maturana, Ramiro
dc.date.accessioned2025-01-20T16:11:23Z
dc.date.available2025-01-20T16:11:23Z
dc.date.issued2024
dc.description.abstractalpha-glucosidase, a pharmacological target for type 2 diabetes mellitus (T2DM), is present in the intestinal brush border membrane and catalyzes the hydrolysis of sugar linkages during carbohydrate digestion. Since alpha-glucosidase inhibitors (AGIs) modulate intestinal metabolism, they may influence oxidative stress and glycolysis inhibition, potentially addressing intestinal dysfunction associated with T2DM. Herein, we report on a study of an ortho-carbonyl substituted hydroquinone series, whose members differ only in the number and position of methyl groups on a common scaffold, on radical-scavenging activities (ORAC assay) and correlate them with some parameters obtained by density functional theory (DFT) analysis. These compounds' effect on enzymatic activity, their molecular modeling on alpha-glucosidase, and their impact on the mitochondrial respiration and glycolysis of the intestinal Caco-2 cell line were evaluated. Three groups of compounds, according their effects on the Caco-2 cells metabolism, were characterized: group A (compounds 2, 3, 5, 8, 9, and 10) reduces the glycolysis, group B (compounds 1 and 6) reduces the basal mitochondrial oxygen consumption rate (OCR) and increases the extracellular acidification rate (ECAR), suggesting that it induces a metabolic remodeling toward glycolysis, and group C (compounds 4 and 7) increases the glycolysis lacking effect on OCR. Compounds 5 and 10 were more potent as alpha-glucosidase inhibitors (AGIs) than acarbose, a well-known AGI with clinical use. Moreover, compound 5 was an OCR/ECAR inhibitor, and compound 10 was a dual agent, increasing the proton leak-driven OCR and inhibiting the maximal electron transport flux. Additionally, menadione-induced ROS production was prevented by compound 5 in Caco-2 cells. These results reveal that slight structural variations in a hydroquinone scaffold led to diverse antioxidant capability, alpha-glucosidase inhibition, and the regulation of mitochondrial bioenergetics in Caco-2 cells, which may be useful in the design of new drugs for T2DM and metabolic syndrome.
dc.fuente.origenWOS
dc.identifier.doi10.3390/ijms25158334
dc.identifier.eissn1422-0067
dc.identifier.issn1661-6596
dc.identifier.urihttps://doi.org/10.3390/ijms25158334
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/90268
dc.identifier.wosidWOS:001287780900001
dc.issue.numero15
dc.language.isoen
dc.revistaInternational journal of molecular sciences
dc.rightsacceso restringido
dc.subjecthydroquinones
dc.subjectmethyl derivatives
dc.subjectantioxidants
dc.subjectdiabetes
dc.subjectDFT
dc.subjectdocking
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleIdentification of Antioxidant Methyl Derivatives of <i>Ortho</i>-Carbonyl Hydroquinones That Reduce Caco-2 Cell Energetic Metabolism and Alpha-Glucosidase Activity
dc.typeartículo
dc.volumen25
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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