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dc.rights.licenseAtribución-NoComercial 4.0 Internacional
dc.contributor.advisorCuca Suárez, Luis Enrique
dc.contributor.authorPlazas González, Erika Andrea
dc.date.accessioned2020-07-23T21:19:36Z
dc.date.available2020-07-23T21:19:36Z
dc.date.issued2020-07-22
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/77833
dc.description.abstractLos trastornos neurodegenerativos multifactoriales, como la enfermedad de Alzheimer (EA), son un problema creciente de salud pública mundial debido al aumento de su incidencia y la baja efectividad de los tratamientos actuales. Dado que la farmacoterapia basada en un blanco molecular ha sido insuficiente en el descubrimiento de agentes para el tratamiento o cura de enfermedades complejas, el enfoque multi-diana se ha posicionado como una de las estrategias más promisorias en la búsqueda de nuevos candidatos a fármacos. En el presente trabajo se realizó una búsqueda racional de alcaloides isoquinolínicos con potencial inhibitorio frente a colinesterasas en especies del género Zanthoxylum; y la determinación de la actividad multi-diana frente a mecanismos claves asociados a la patogénesis de la EA, como el agotamiento de neurotransmisores, la agregación de beta-amiloide (Aβ1-42) y el estrés oxidativo. Inicialmente, se realizó un perfilado metabolómico (LC-MS) de extractos alcaloidales de especies del género Zanthoxylum (Rutaceae), con el fin de identificar posibles alcaloides inhibidores de colinesterasas, priorizar los extractos más promisorios y hacer la selección de una especie para continuar con el aislamiento bio-dirigido de los metabolitos de interés. Para este propósito, se analizaron 41 extractos alcaloidales de nueve especies de Zanthoxylum por HPLC-UV-HRMS y se determinó la actividad inhibitoria frente a colinesterasas (AChE/BChE). Haciendo uso de un análisis bioquimiométrico, se seleccionaron 11 alcaloides biomarcadores, los cuales fueron identificados tentativamente por dereplicación manual. Los extractos con mayor actividad inhibitoria frente a las enzimas (Z. schreberi y Z. monophylum) mostraron alta presencia de dos biomarcadores identificados tentativamente como berberina y queleritrina, los cuales han sido ampliamente reportados como inhibidores de colinesterasas y monoamino oxidasas. Por lo tanto, se realizó un estudio químico dirigido del extracto de corteza de Z. schreberi en búsqueda de berberina y queleritrina, a fin de validar los resultados del modelo estadístico y hacer la priorización de los extractos con mayor potencial inhibitorio y baja presencia de estos alcaloides. Los resultados del estudio bio-dirigido de Z. schreberi permitieron confirmar la predicción realizada por el modelo bioquimiométrico y hacer la selección de la especie Z. rigidum para continuar con la búsqueda racional de alcaloides inhibidores de colinesterasas con potencial multi-diana. Por medio del estudio bio-dirigido del extracto de raíz de Z. rigidum se aislaron ocho alcaloides isoquinolínicos y uno quinolónico, a los cuales se les evaluó la actividad inhibitoria frente a colinesterasas (AChE y BChE), monoamino oxidasas (MAO-A y B) y en la agregación de Aβ1-42. En el estudio preliminar de actividad biológica se encontró que dos alcaloides benzofenantridínicos, nitidina (EP4) y avicina (EP12), presentaron el mayor potencial inhibitorio frente a todos blancos moleculares, por lo cual fueron seleccionados para continuar con la caracterización multi-diana. Estas benzofenantridinas poseen actividad inhibitoria frente a la dupla de colinesterasas con valores de IC50 en el rango micromolar, siendo más activos frente a AChE. En el análisis cinético con las colinesterasas los dos alcaloides mostraron mecanismos de inhibición mixta y contantes (Ki) menores a 1 µM. La avicina presentó mayor potencial inhibitorio de las colinesterasas con valores de Ki de 0,063 µM (EeAChE), 0,511 µM (HrAChE) y 0,123 µM (EqBChE). Asimismo, avicina y nitidina poseen actividad antiagregante de Aβ1–42 con IC50 de 5,6 y 1,9 µM, respectivamente. Adicionalmente, los dos alcaloides presentaron inhibición selectiva de la monoamino oxidasa A, con valores de IC50 menores a 2 µM e índices de selectividad superiores a 100. En el estudio cinético con MAO A los dos compuestos mostraron mecanismo de inhibición mixta y constantes de inhibición (Ki) en el rango nanomolar. Estos resultados sugieren que las benzofenantridinas avicina (EP12) y nitidina (EP4) poseen un alto potencial multi-diana, por lo tanto, representan un importante punto de partida en la búsqueda y desarrollo de moléculas con potencial terapéutico para la enfermedad de Alzheimer.
dc.description.abstractMultifactorial neurodegenerative disorders such as Alzheimer's disease (AD) are considered a growing public health problem due the rising incidence and low effectiveness of current treatment. Since pharmacotherapy based on a single target has been insufficient for drug development in complex diseases, the emerging multi-target approach is a promising strategy in the search of new anti-AD drug candidates. Herein the rational search and isolation of anti-cholinergic isoquinoline alkaloids from Zanthoxylum genus and the multi-target activity on key mechanisms associated with AD’s pathogenesis, i.e. cholinergic and monoaminergic depletion, β-amyloid (Aβ) aggregation, and oxidative stress were investigated. Initially, a LC-MS-based metabolomic approach of Zanthoxylum species was performed to identify potential anti-cholinesterase alkaloids predictors, rank the most promising extracts and selected one to carry out bio-directed isolation of potential bioactive alkaloids. 41 alkaloid extracts of nine Zanthoxylum species were analyzed by HPLC-UV-HRMS and inhibitory activity against cholinesterase (AChE/BChE). 11 alkaloid biomarkers were selected using a biochemometric analysis, and tentatively identified by manual dereplication approach. The most active extracts against cholinesterase (Z. schreberi and Z. monophylum) showed higher concentration of two biomarkers tentatively identified as berberine and chelerythrine, which have been reported as cholinesterase and monoamine oxidase inhibitors. Thus, a targeted isolation of berberine and chelerythrine from the bark extract of Z. schreberi was performed, in order to validate the results of the statistical model and select those extracts with the highest inhibitory activity and lowest concentration of these biomarkers. The findings in bio-guided isolation of Z. schreberi support the biochemometric model prediction and allowed us to select the species Z. rigidum to continue the rational search of anticholinesterase-multimodal alkaloids. Alkaloid isolation from root extract of Zanthoxylum rigidum was carried out using multi-step chromatography and monitoring by TLC-bioautography against acetylcholinesterase (AChE) giving eight purified isoquinoline and one quinolone alkaloids. Isolated compounds were tested for inhibitory activity against cholinesterase (AChE and BChE), monoamine oxidase (MAO-A and B) and Aβ aggregation. Our study revealed two benzophenanthridine alkaloids, nitidine (EP4) and avicine (EP12), as the most promising multi-target candidates. Both benzophenanthridines presented dual cholinesterase inhibition with IC50 values in micromolar range, being more active against AChE than BChE. Kinetic analysis with cholinesterase showed both compounds are reversible-mixed inhibitors, where avicine presented highest potency with Ki values of 0.063 µM (EeAChE), 0.511 µM (HrAChE) and 0.123 µM (EqBChE). Likewise, avicine and nitidine presented moderate Aβ1–42 anti-aggregation activity with IC50 values of 5.6 y 1.9 µM, respectively. In addition, both benzophenanthridines are MAO-A selective inhibitors, with IC50 values lower than 2 µM and selective index higher than 100. In the kinetic analysis with MAO A both alkaloids showed mixed-type inhibition and Ki values in the nanomolar range. Our findings suggest that avicine and nitidine are promising natural compounds and multifunctional candidates, representing a suitable starting point for the development of new therapeutic agents for Alzheimer’s disease.
dc.description.sponsorshipColciencias
dc.format.extent207
dc.format.mimetypeapplication/pdf
dc.language.isospa
dc.rightsDerechos reservados - Universidad Nacional de Colombia
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subject.ddc610 - Medicina y salud::615 - Farmacología y terapéutica
dc.titleBúsqueda racional de alcaloides isoquinolínicos del género Zanthoxylum (Rutaceae) como posibles agentes multifuncionales para el tratamiento del Alzheimer
dc.typeOtro
dc.rights.spaAcceso abierto
authorProfile.contributor.emaileaplazasg@unal.edu.co
dc.description.additionalLínea de Investigación: Bioprospección en agentes terapéuticos
dc.type.driverinfo:eu-repo/semantics/other
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dc.publisher.programBogotá - Ciencias - Doctorado en Ciencias - Química
dc.contributor.researchgroupGrupo de Investigación en Química de Productos Naturales Vegetales Bioactivos
dc.description.degreelevelDoctorado
dc.publisher.departmentDepartamento de Química
dc.publisher.branchUniversidad Nacional de Colombia - Sede Bogotá
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dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.subject.proposalBenzophenanthridines
dc.subject.proposalBenzofenantridinas
dc.subject.proposalMetabolómica
dc.subject.proposalMetabolomics
dc.subject.proposalAnálisis estadístico multivariado
dc.subject.proposalMultivariate statistical analyses
dc.subject.proposalEnzyme inhibitors
dc.subject.proposalInhibidores enzimáticos
dc.subject.proposalCholinesterase
dc.subject.proposalColinesterasas
dc.subject.proposalMonoamino oxidasas
dc.subject.proposalMonoamine oxidase
dc.subject.proposalβ-Amyloid
dc.subject.proposalβ-amiloide
dc.type.coarhttp://purl.org/coar/resource_type/c_1843
dc.type.coarversionhttp://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.contentText
oaire.accessrightshttp://purl.org/coar/access_right/c_abf2
authorProfile.contributor.genderFemenino


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