Un abordaje conceptual y metodológico de la correlación de la estructura química y actividad biológica de tres compuestos anticancerígenos y algunos derivados

dc.contributorOcampo-Cardona, Rogelio
dc.contributorGrupo de Química Teórica y Bioinformática - QTB (Categoría B)
dc.creatorChacón P., Julián Camilo
dc.date2022-09-26T13:15:34Z
dc.date2022-09-26T13:15:34Z
dc.date2022-09-23
dc.date.accessioned2023-09-06T18:33:05Z
dc.date.available2023-09-06T18:33:05Z
dc.identifierhttps://repositorio.ucaldas.edu.co/handle/ucaldas/18090
dc.identifierUniversidad de Caldas
dc.identifierRepositorio Institucional Universidad de Caldas
dc.identifierhttps://repositorio.ucaldas.edu.co/
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8699094
dc.descriptionIlustraciones, gráficas
dc.descriptionspa:Los estudios de correlación estructura química actividad biológica conocidos por sus siglas en inglés como SAR, son métodos sistemáticos que permiten analizar compuestos candidatos a fármacos anticancerígenos y sus efectos fisiológicos en líneas celulares de cáncer. También, permiten evaluar las tendencias citotóxicas de compuestos en el laboratorio, diseñar o modificar fármacos, realizar estudios farmacocinéticos y de interacción del receptor de algunas drogas. Todo esto abordado desde las áreas de la química, biología y estadística; utilizando descriptores moleculares, resultados de ensayo in vivo e in vitro y métodos quimiométricos que permiten evaluar y determinar cuál es el compuesto óptimo para ser candidato a fármaco anticancerígeno. Este trabajo aborda el acopio y análisis documental, con enfoque principalmente conceptual alrededor de la pregunta ¿en qué consiste una correlación entre la estructura química y la actividad biológica, y su aplicación a algunos compuestos anticancerígenos del tipo taxano (paclitaxel), líquidos iónicos imidazólicos y sales de amonio cuaternaria? Se explica qué es un estudio de correlación estructura actividad, su posible abordaje metodológico investigativo, y en qué datos in vitro se apoya un estudio SAR. Uno de los tratamientos para combatir el cáncer es el uso de fármacos, estos interactúan con una diana específica en la célula cancerígena ocasionando que se inicien procesos apoptóticos, uno de los más utilizados es el paclitaxel (o taxol) el cual interactúa con la β-tubulina afectando la dinámica de los microtúbulos lo que genera una formación anormal del huso mitótico que desencadena en la muerte celular. Por otra parte, los candidatos a fármacos como los líquidos iónicos de imidazolio pueden inducir citotoxicidad mediante estrés oxidativo aumentando las especies reactivas de oxígeno intracelular (ROS) y disminuyendo las actividades enzimáticas antioxidantes. De manera análoga, algunos fármacos que en su estructura tienen la presencia de sales de amonio cuaternario pueden generar inhibición de especies reactivas de oxígeno intracelular o alterar la función normal de proteínas como MPAK y la Hsp90, lo cual da comienzo a los procesos de apoptosis. Con respecto a los estudios SAR del paclitaxel, se demuestra que todas las modificaciones que se realicen en las posiciones C-13, C-4, la posición en el anillo benzoílo del C-2, el anillo oxetano y la fenilisoserina en el C-13 están relacionadas con la pérdida, reducción o aumento de su actividad anticancerígena, además, para que el taxol interactúe con la β-tubulina se indica que debe adoptar una conformación T-taxol. De otra parte, en los LIs de imidazolio se resalta que la aromaticidad del compuesto, el aumento de los carbonos en la cadena lateral y el aumento de la polaridad, pueden contribuir a la actividad anticancerígena. Adicionalmente, las sales de amonio cuaternario se utilizan para generar mayor solubilidad, biodisponibilidad y protección en el fármaco del cual hacen parte. Pero no se argumenta que la presencia de éstas pueda estar relacionada con una actividad anticancerígena.
dc.descriptioneng:Chemical structure biological activity correlation studies, known by its acronym in English as SAR, are systematic methods that allow the analysis of candidate compounds for anticancer drugs and their physiological effects on cancer cell lines. Also, they allow evaluating the cytotoxic tendencies of compounds in the laboratory, designing or modifying drugs, carrying out pharmacokinetic and receptor interaction studies of some drugs. All this approached from the areas of chemistry, biology and statistics; using molecular descriptors, in vivo and in vitro test results and chemometric methods that allow evaluating and determining which is the optimal compound to be an anticancer drug candidate. This work deals with the collection and documentary analysis, with a mainly conceptual approach around the question: what does a correlation between chemical structure and biological activity consist of, and its application to some anticancer compounds of the taxane type (paclitaxel), imidazole ionic liquids and quaternary ammonium salts? It explains what a structure-activity correlation study is, its possible investigative methodological approach, and what in vitro data supports a SAR study. One of the treatments to combat cancer is the use of drugs, these interact with a specific target in the cancer cell causing apoptotic processes to start, one of the most used is paclitaxel (or taxol) which interacts with β- tubulin affecting the dynamics of microtubules which generates an abnormal formation of the mitotic spindle that triggers cell death. On the other hand, drug candidates such as imidazolium ionic liquids can induce cytotoxicity through oxidative stress by increasing intracellular reactive oxygen species (ROS) and decreasing antioxidant enzyme activities. Similarly, some drugs that contain quaternary ammonium salts in their structure can inhibit intracellular reactive oxygen species or alter the normal function of proteins such as MPAK and Hsp90, which initiates apoptotic processes. With respect to the SAR studies of paclitaxel, it is shown that all modifications made at the C-13, C-4 positions, the benzoyl ring position at C-2, the oxetane ring and the phenylisoserine at C- 13 are related to the loss, reduction or increase of its anticancer activity, in addition, for taxol to interact with β-tubulin it is indicated that it must adopt a T-taxol conformation. On the other hand, in imidazolium LIs it is highlighted that the aromaticity of the compound, the increase in carbons in the side chain and the increase in polarity, can contribute to anticancer activity. Additionally, quaternary ammonium salts are used to generate greater solubility, bioavailability and protection in the drug of which they are part. But it is not argued that the presence of these may be related to anticancer activity.
dc.descriptionLista de siglas o abreviaturas / 1. Resumen / 2. Planteamiento del problema / 3. Justificación / 4. Objetivos / 4.1 General / 4.2 Específicos / 5. Metodología / 5.1 Generalidades / 5.2 Metodología específica por subtemas / 5.2.1 Subtema sobre estudios de relación estructura actividad (SAR) / 5.2.2 Subtema sobre estudios de relación estructura actividad de taxol en cáncer / 5.2.3 Subtema sobre estudios de relación estructura actividad de líquidos iónicos de imidazolio en cáncer / 5.2.4 Subtema sobre estudios de relación estructura actividad de sales de amonio cuaternario en cáncer / 6. Resultados y discusión / 6.1 Estudios de relación estructura actividad (SAR) / 6.1.1 ¿Por qué realizar un estudio SAR? / 6.1.2 Algunas investigaciones que constituyen la historia de SAR / 6.1.3 Generalidades de los estudios SAR / 6.1.3.1 Caracterización de compuestos químicos para los estudios SAR / La estructura molecular y propiedades fisicoquímicas / Descriptores unidimensionales (1D) / Descriptores bidimensionales (2D) / Descriptores tridimensionales (3D) / 6.1.3.2 Determinación de la actividad biológica de los compuestos anticancerígenos / Ensayo de reducción MTT / Ensayo de unión a microtúbulos / 6.1.3.3 Algunos métodos quimiométricos utilizados para los estudios SAR / Análisis de componentes principales / K-vecino más cercano / Árbol de decisión (Decision Tree) / 5 Bosque aleatorio (Random Forest) / 6.1.3.2 Software para estudios SAR / 6.2 El cáncer como área de estudio / 6.3 Estudios de relación estructura actividad de taxol en cáncer / 6.3.1 Generalidades / 6.3.2 Los taxanos y su actividad anticancerígena / 6.3.3 El taxol (paclitaxel) y algunos estudios de relación estructura actividad (SAR) / 6.3.3.1 Efecto de las modificaciones en los anillos del paclitaxel sobre su actividad anticancerígena / 6.3.3.2 Modificaciones en la cadena lateral C-13 y su remoción en el paclitaxel / 6.3.3.3 Estudios SAR del paclitaxel en la actualidad / 6.4 Estudios de relación estructura actividad de líquidos iónicos de imidazolio en cáncer / 6.4.1 Algunas generalidades sobre líquidos iónicos de imidazolio / 6.4.2 Líquido iónico de imidazolio y su actividad anticancerígena / 6.4.3 Líquidos iónicos de imidazolio y algunos estudios de relación estructura actividad (SAR) en cáncer / 6.4.3.1 Efecto de la variación en la cadena lateral del imidazolio en la actividad anticancerígena / 6.4.3.2 Efecto de la variación del anión del imidazolio en la actividad anticancerígena / 6.4.3.3 Técnicas para los estudios SAR en LIs de imidazolio / 6.5 Estudios de relación estructura actividad SAR de sales de amonio cuaternario en cáncer / 6.5.1 Generalidades / 6.5.2 Sales de amonio cuaternario y su actividad anticancerígena / 6.5.3 Sales de amonio cuaternario y algunos estudios de relación estructura actividad (SAR) / 6.5.3.1 Derivados de quitosano de amonio cuaternario / 6.5.3.2 Derivados de diosgenina amonio cuaternario / 6.5.3.3 Derivados de quinuclidina de geldanamicina amonio cuaternario / 7. Conclusiones / 8. Bibliografía
dc.descriptionMaestría
dc.descriptionMagister en Química
dc.descriptionSales de amonio cuaternario
dc.formatapplication/pdf
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dc.languageeng
dc.languagespa
dc.publisherFacultad de Ciencias Exactas y Naturales
dc.publisherManizales
dc.publisherMaestría en Química
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dc.rightsinfo:eu-repo/semantics/openAccess
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rightshttp://purl.org/coar/access_right/c_abf2
dc.subjectSales de amonio cuaternario
dc.subjectSAR
dc.subjectEstudios de relación estructura actividad
dc.subjectLíquidos iónicos de imidazolio
dc.subjectPaclitaxel
dc.subjectTaxol
dc.subjectQuímica
dc.subjectAnálisis químico
dc.titleUn abordaje conceptual y metodológico de la correlación de la estructura química y actividad biológica de tres compuestos anticancerígenos y algunos derivados
dc.typeTrabajo de grado - Maestría
dc.typehttp://purl.org/coar/resource_type/c_bdcc
dc.typeText
dc.typeinfo:eu-repo/semantics/masterThesis
dc.typeinfo:eu-repo/semantics/publishedVersion


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