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

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datacite.creatorMonroy Cárdenas, Matías Esteban
datacite.creatorAlmarza Chávez, Cristopher
datacite.creatorValenzuela Hormazábal, Paulina
datacite.creatorRamírez, David
datacite.creatorUrra, Félix A.
datacite.creatorMartínez Cifuentes, Maximiliano
datacite.creatorAraya Maturana, Ramiro Juan
datacite.date.issued2024
datacite.identifierDOI
datacite.identifier.doi10.3390/ijms25158334
datacite.identifier.issn1422-0067
datacite.identifier.orcid0009-0005-3694-5086
datacite.identifier.orcid0009-0009-8861-806X
datacite.identifier.orcid0009-0008-6110-1573
datacite.identifier.orcid0000-0003-0002-1189
datacite.identifier.orcid0000-0003-2959-3164
datacite.identifier.orcid0000-0002-5082-9146
datacite.identifier.wosidWOS:001287780900001
datacite.rightsAcceso abierto
datacite.subjectHydroquinones
datacite.subjectMethyl derivatives
datacite.subjectAntioxidants
datacite.subjectDiabetes
datacite.subjectDFT
datacite.subjectDocking
datacite.titleIdentification of Antioxidant Methyl Derivatives of Ortho-Carbonyl Hydroquinones That Reduce Caco-2 Cell Energetic Metabolism and Alpha-Glucosidase Activity
dc.date.accessioned2024-11-19T13:27:19Z
dc.date.available2024-11-19T13:27:19Z
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.description.pages17 p.
dc.identifier.folio3240227
dc.identifier.folio1241547
dc.identifier.folio1221874
dc.identifier.folio1220656
dc.identifier.folioACT210097
dc.identifier.folioEQM220164
dc.identifier.folioUM-03/22
dc.identifier.folio2023000771INV
dc.identifier.urihttps://repositorio.utalca.cl/repositorio/handle/1950/14551
dc.languageInglés
dc.publisherMdpi
dc.relation.urihttps://www.mdpi.com/1422-0067/25/15/8334
dc.sourceInternational Journal of Molecular Sciences
oaire.citationTitleInternational Journal of Molecular Sciences
oaire.fundingReferenceThis research was funded by Fondecyt grant number 3240227, 1241547, 1221874, 1220656;ANID Anillo grant number ACT210097; FONDEQUIP grant number EQM220164; VID-UChile grantnumber UM-03/22 and VRID-UDEC grant number 2023000771INV
oaire.licenseConditionhttps://creativecommons.org/licenses/by/4.0/
oaire.licenseCondition.urihttps://creativecommons.org/licenses/by/4.0/
oaire.resourceTypeArtículo de Revista
oaire.versionVersión Publicada
utalca.catalogadorPAG
utalca.facultadUniversidad de Talca (Chile). Instituto de Química de Recursos Naturales.
utalca.facultadUniversidad de Talca (Chile). Interdisciplinary group on Mitochondrial Targeting and Bioenergetics.
utalca.idcargapag191124
utalca.indexArtículo indexado en Web of Science
utalca.indexArtículo indexado en Scopus
utalca.informaciondegeneroHombre y Mujer
utalca.odsSalud y bienestar
utalca.odsIndustria, innovación e infraestructura
utalca.odsProducción y consumo responsables
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