Síntesis de Nuevos Derivados Furiletilénicos y Modelación de Mecanismos de Acción de Compuestos con Actividad Antineoplásica Basado en la Metodología MARCH-INSIDE
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Fecha
2004-06-25
Autores
Saíz Urra, Liane
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Editor
Universidad Central "Marta Abreu" de las Villas
Resumen
Dada la similitud estructural entre el HMF y furfural, este último fue tomado como
patrón para diferentes reacciones del HMF, con vistas a intensificar el estudio de nuevos productos potencialmente bioactivos. Se desarrolló la condensación del furfural con ohidroxiacetofenona donde se obtiene la furfuriliden-o-hidroxiacetofenona con buenos rendimientos. De forma similar fue posible condensar la o-hidroxiacetofenona y pcloroacetofenona con HMF. No siendo así en el caso de la reacción del HMF y furfural
con o-cloroacetofenona, y del HMF con acetofenona, donde no fue posible aislar las
chalconas correspondientes.
Se llevó a cabo la condensación entre el HMF y el cianoacetato de etilo, cianoacetato de
metilo y la N-furfurilcianoacetamida para dar lugar a los productos de condensación
correspondientes. Los compuestos no mostraron actividad antibacteriana significativa
(IC50 > 100 ppm) para las cepas ensayadas.
De la interacción del G-1 con la Cisteína bajo diferentes condiciones de reacción, se pudo corroborar la acción de este aminoácido sobre la actividad de este producto bioactivo, pero no fue posible aislar los productos de reacción bajo las condiciones empleadas.
La esterificación del HMF con los aminoácidos tirosina y fenilalanina, bajo la activación
de los aminoácidos correspondientes tiene lugar, sin embargo estudios posteriores son necesarios para la adecuada separación de los productos de reacción.
Se abordó el desarrollo de modelos teóricos de predicción y clasificación de compuestos con determinados mecanismos de acción para las actividades antes expuestas a través del uso de la metodología MARCH-INSIDE, objetivo de la investigación del Grupo de Diseño de Fármacos del Centro de Bioactivos Químicos.
Se llevó a cabo el análisis de una serie de 344 compuestos anticancerígenos los cuales manifiestan su efecto por medio de 5 diferentes mecanismos de acción.
El Análisis Discriminante Lineal (STATISTICA 6.0) permitió arribar a un modelo con
buena calidad estadística sustentada en los parámetros establecidos para esta técnica. El modelo clasificó correctamente más del 70% de los casos estudiados en cada mecanismo de acción para un porcentaje global de buena clasificación del 87%. La separación aleatoria de la data en serie de entrenamiento y de predicción condujo a un porcentaje de buena clasificación global en todos los casos superiores al 80% así como parámetros estadísticos adecuados. La validación cruzada Leave-Group-Out arrojó buenos resultados y corroboró la robustez del modelo.
El screening virtual verificó la calidad del modelo, este ensayo virtual fue aplicado a
compuestos reportados en la literatura con los diferentes mecanismos de acción
involucrados en la realización del modelo pero no incluidos previamente en su
elaboración Esta evaluación asistida por computadora fue extendida al análisis de los
nuevos compuestos sintetizados a lo largo de este trabajo en el Centro de Bioactivos
Químicos.
Given the structural similarity between the HMF and furfural, this last one was taken as pattern for different reactions of the HMF, with a view of increasing the study of new potentially bioactives products. The condensation of furfural was developed with ohydroxyacetophenone where furfuriliden-or-hydroxyacetophenone was obtained with good yields. In a similar way it was possible to condense the o-hydroxyacetophenone and p-chloroacetophenone with HMF. Not being this way in the case of the reaction of the HMF and furfural with o-chloroacetophenone, and of the HMF with acetophenone, where it was not possible to isolate the corresponding chalcones. The condensation between the HMF and the ethyl 2-cyanoacetate and methyl 2- cyanacetate and N-furfuryl cyanacetamide was carried out, obtaining the corresponding reaction products. No significant biological activity was observed in all the obtained compounds against the tested strains (IC50>100 ppm). From the interaction of the G-1 with the Cisteína under different reaction conditions, we could confirm the action of this amino acid on the activity of this bioactive product, but it was not possible to isolate the reaction products under the experimental conditions. The esterificación of the HMF with the amino acids tyrosine and phenylalanine, took place under the activation of the corresponding amino acids, however further studies are necessary for the appropriate separation of the reaction products. The development of theoretical models of prediction and classification was approached in order to explain certain action mechanisms for the activities before exposed through the use of the MARCH-INSIDE methodology, goals of the investigation of the Group of Drug Design of the Centro de Bioactivos Químicos. The analysis of a series of 344 antibacterial and anticancer compounds which exert their effect by means of 5 different action mechanisms was carried out. The Analysis Lineal Discriminate (STATISTICA 6.0) yielded a classification model with good statistical parameters. The Model classified correctly more than 70% of all cases included in each group (mechanism) with an overall percentage of good classification of 87%. The data was split into training and test set yielding an overall percentage of good classification of more than 80% in all cases. Other Validation Techniques (Cross Validation Techniques and Virtual Screening) was applied to the model yielding suitable results. The Virtual Screening was extended to the newly synthesized compounds in this work.
Given the structural similarity between the HMF and furfural, this last one was taken as pattern for different reactions of the HMF, with a view of increasing the study of new potentially bioactives products. The condensation of furfural was developed with ohydroxyacetophenone where furfuriliden-or-hydroxyacetophenone was obtained with good yields. In a similar way it was possible to condense the o-hydroxyacetophenone and p-chloroacetophenone with HMF. Not being this way in the case of the reaction of the HMF and furfural with o-chloroacetophenone, and of the HMF with acetophenone, where it was not possible to isolate the corresponding chalcones. The condensation between the HMF and the ethyl 2-cyanoacetate and methyl 2- cyanacetate and N-furfuryl cyanacetamide was carried out, obtaining the corresponding reaction products. No significant biological activity was observed in all the obtained compounds against the tested strains (IC50>100 ppm). From the interaction of the G-1 with the Cisteína under different reaction conditions, we could confirm the action of this amino acid on the activity of this bioactive product, but it was not possible to isolate the reaction products under the experimental conditions. The esterificación of the HMF with the amino acids tyrosine and phenylalanine, took place under the activation of the corresponding amino acids, however further studies are necessary for the appropriate separation of the reaction products. The development of theoretical models of prediction and classification was approached in order to explain certain action mechanisms for the activities before exposed through the use of the MARCH-INSIDE methodology, goals of the investigation of the Group of Drug Design of the Centro de Bioactivos Químicos. The analysis of a series of 344 antibacterial and anticancer compounds which exert their effect by means of 5 different action mechanisms was carried out. The Analysis Lineal Discriminate (STATISTICA 6.0) yielded a classification model with good statistical parameters. The Model classified correctly more than 70% of all cases included in each group (mechanism) with an overall percentage of good classification of 87%. The data was split into training and test set yielding an overall percentage of good classification of more than 80% in all cases. Other Validation Techniques (Cross Validation Techniques and Virtual Screening) was applied to the model yielding suitable results. The Virtual Screening was extended to the newly synthesized compounds in this work.
Descripción
Palabras clave
Conversión Química, Diseño de Fármacos, Hidroximetilfurfural (HMF), Drug Design