BIOINSPIRED SEARCH AND DESIGN OF NEW CHEMICAL ENTITIES MODULATING THERAPEUTIC TARGETS (Q3149665): Difference between revisions
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(Created claim: summary (P836): THE OBJECTIVE OF THIS PROJECT IS THE DESIGN AND SYNTHESIS OF ORIGINAL PRODUCTS INSPIRED BY NATURE THAT ARE ABLE TO INTERACT SPECIFICALLY WITH KEY TARGETS OF INTEREST FOR THE TREATMENT OF THE MOST FREQUENT TYPES OF CANCER: JAK-STAT SIGNALING ROUTE AND SELECTIVE MODULATORS OF ESTROGEN RECEPTORS. FOR THIS WE WILL USE STRUCTURAL MOTIFS PRESENT IN NATURAL BIOACTIVE PRODUCTS OR ACCESS TO THEIR ANALOGS THROUGH THE USE OF EFFECTIVE AND STATE-OF-THE-ART...) |
(Changed label, description and/or aliases in en: translated_label) |
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BIOINSPIRED SEARCH AND DESIGN OF NEW CHEMICAL ENTITIES MODULATING THERAPEUTIC TARGETS | |||
Revision as of 14:35, 12 October 2021
Project Q3149665 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | BIOINSPIRED SEARCH AND DESIGN OF NEW CHEMICAL ENTITIES MODULATING THERAPEUTIC TARGETS |
Project Q3149665 in Spain |
Statements
185,130.0 Euro
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217,800.0 Euro
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85.0 percent
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1 January 2016
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31 December 2019
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UNIVERSIDAD DE LA LAGUNA
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28°29'8.77"N, 16°18'57.38"W
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38023
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EL OBJETIVO DE ESTE PROYECTO ES EL DISEÑO Y SINTESIS DE PRODUCTOS ORIGINALES INSPIRADOS EN LA NATURALEZA QUE SEAN CAPACES DE INTERACCIONAR ESPECIFICAMENTE CON DIANAS CLAVES DE INTERES PARA EL TRATAMIENTO DE LOS TIPOS DE CANCER MAS FRECUENTE: RUTA DE SEÑALIZACION JAK-STAT Y MODULADORES SELECTIVOS DE LOS RECEPTORES DE ESTROGENO. PARA ELLO UTILIZAREMOS MOTIVOS ESTRUCTURALES PRESENTES EN LOS PRODUCTOS NATURALES BIOACTIVOS O BIEN ACCEDEREMOS A ANALOGOS DE LOS MISMOS MEDIANTE EL USO DE ESTRATEGIAS EFICACES Y PUNTERAS COMO REACIONES DOMINO Y/O MULTICOMPONENTES, APROXIMACION DE SINTESIS ORIENTADA A LA DIVERSIDAD BASADA EN ESTRUCTURA PRIVILEGIADA (P-DOS) O LA APROXIMACION COMPLEJIDAD HACIA LA DIVERSIDAD (CTD). TAMBIEN SERAN ENSAYADOS PARA ESAS DIANAS PRODUCTOS OBTENIDOS DE FUENTES NATURALES YA QUE LA NATURALEZA PUEDE PROPORCIONAR VARIANTES DE ESTRUCTURAS A LAS CUALES NUESTRA INSPIRACION A LA HORA DE REALIZAR MODIFICACIONES QUIMICAS NO ES CAPAZ DE LLEGAR. ESPECIFICAMENTE SE SINTETIZARA PARA SU EVALUACION COMO INHIBIDORES DE STAT UNA VARIEDAD DE PRODUCTOS OBTENIDOS A PARTIR DE UN HIBRIDO NAFTOQUINONA-CUMARINA Y GLICOSIDOS DE FLAVONOIDES MODIFICADOS. COMO SERMS SE HAN DISEÑADO PIRROLIDONAS ALTAMENTE FUNCIONALIZADAS Y DERIVADOS DE AURONAS. TAMBIEN SERAN EVALUADOS FRENTE A ESAS DIANAS COMPLEJOS METALICOS A PARTIR DE LIGANDOS BIOACTIVOS BIDENDETADOS ASI COMO UNA QUIMIOTECA OBTENIDA A PARTIR DE DITERPENOS AROMATICOS. EN RELACION A LAS ACTIVIDADES BIOLOGICAS, SE EVALUARA LA EFICACIA Y TOXICIDAD DE ESTAS NUEVAS MOLECULAS. EN PRIMER LUGAR, SE UTILIZARA SISTEMAS DE BUSQUEDA A MEDIANA ESCALA BASADOS EN LINEAS CELULARES CON SISTEMAS REPORTEROS DE LUCIFERASA. ESTO PERMITIRA IDENTIFICAR CON RAPIDEZ A MODULADORES QUIMICOS QUE ACTUEN A CUALQUIER NIVEL DE LA CASCADA DE SEÑALIZACION DEPENDIENTE DE STAT O DE RE. LOS ENSAYOS E-SCREEN PERMITIRAN SELECCIONAR LOS PRODUCTOS CON ACTIVIDADES SERM. EN SEGUNDO LUGAR, SE EVALUARA LA CITOTOXICIDAD EN LINEAS DEPENDIENTES DE JAK2-STAT (HEL) O DE RE (T47D) Y EN LINFOCITOS PRIMARIOS. EN TERCER LUGAR, SE EVALUARA LA EFICACIA DE LAS MOLECULAS MAS ACTIVAS EN RELACION CON RESPUESTAS BIOLOGICAS CONCRETAS (PROLIFERACION, APOPTOSIS, MIGRACION, INVASION CELULAR, FORMACION DE COLONIAS, PRODUCCION DE FOSFATASA ALCALINA, CALCIFICACION). FINALMENTE, CON LAS MOLECULAS MAS ACTIVAS SE REALIZARAN ESTUDIOS MECANISTICOS DETALLADOS COMO SON: A) FOSFORILACION Y TRANSLOCACION NUCLEAR USANDO TECNICAS DE IMMUNOBLOTTING, GEMSA Y MICROSCOPIA, B) ACTIVIDAD QUINASA DE JAK2 IN VITRO Y ESPECIFICIDAD SOBRE OTRAS QUINASAS, C) APOPTOSIS Y CICLO CELULAR, D) BINDING AL RE, E) FARMACO-TOXICOGENOMICA PREDICTIVA IN VITRO, Y E) LAS EVALUACIONES BIOLOGICAS ORIENTADAS, APOYADAS EN LA MEJORA DEL DISEÑO QUIMICO, PERMITIRAN SELECCIONAR LA MOLECULA OPTIMA PARA EVALUAR SU EFICACIA Y TOXICIDAD IN VIVO._x000D_ EN BASE A LOS RESULTADOS DE ACTIVIDAD BIOLOGICA, PROVENIENTES DEL CRIBADO FRENTE A LAS DISTINTAS DIANAS TERAPEUTICAS, MEJORAREMOS LAS PROPIEDADES BIOLOGICAS Y/O FARMACOLOGICAS DE LAS MOLECULAS BIOACTIVAS POR MEDIO DE ESTUDIOS DE RELACION ESTRUCTURA-ACTIVIDAD (SAR) ASI COMO ESTUDIOS IN SILICO QUE FACILITARA EL DISEÑO RACIONAL DE NUEVAS ENTIDADES (Spanish)
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THE OBJECTIVE OF THIS PROJECT IS THE DESIGN AND SYNTHESIS OF ORIGINAL PRODUCTS INSPIRED BY NATURE THAT ARE ABLE TO INTERACT SPECIFICALLY WITH KEY TARGETS OF INTEREST FOR THE TREATMENT OF THE MOST FREQUENT TYPES OF CANCER: JAK-STAT SIGNALING ROUTE AND SELECTIVE MODULATORS OF ESTROGEN RECEPTORS. FOR THIS WE WILL USE STRUCTURAL MOTIFS PRESENT IN NATURAL BIOACTIVE PRODUCTS OR ACCESS TO THEIR ANALOGS THROUGH THE USE OF EFFECTIVE AND STATE-OF-THE-ART STRATEGIES SUCH AS DOMINO AND/OR MULTICOMPONENTS, SYNTHESIS APPROACH ORIENTED TO DIVERSITY BASED ON PRIVILEGED STRUCTURE (P-TWO) OR THE APPROACH COMPLEXITY TO DIVERSITY (CTD). THEY WILL ALSO BE TESTED FOR THESE TARGETS PRODUCTS OBTAINED FROM NATURAL SOURCES SINCE NATURE CAN PROVIDE VARIANTS OF STRUCTURES TO WHICH OUR INSPIRATION WHEN MAKING CHEMICAL MODIFICATIONS IS NOT ABLE TO REACH. SPECIFICALLY, A VARIETY OF PRODUCTS OBTAINED FROM A NAPHTHOQUINONE-COUMARIN HYBRID AND MODIFIED FLAVONOID GLYCOSIDES ARE SYNTHESISED FOR EVALUATION AS STAT INHIBITORS. AS SERMS, HIGHLY FUNCTIONAL PYRRHOLIDONS AND AURONE DERIVATIVES HAVE BEEN DESIGNED. THEY WILL ALSO BE EVALUATED AGAINST THESE METAL COMPLEX TARGETS FROM BIDENDETATE BIOACTIVE LIGANDS AS WELL AS A CHEMOTHEQUE OBTAINED FROM AROMATIC DITERPENES. IN RELATION TO BIOLOGICAL ACTIVITIES, THE EFFICACY AND TOXICITY OF THESE NEW MOLECULES WILL BE EVALUATED. FIRST, MEDIUM-SCALE SEARCH SYSTEMS BASED ON CELLULAR LINES WITH LUCIFERASE REPORTING SYSTEMS WILL BE USED. THIS WILL ALLOW THE RAPID IDENTIFICATION OF CHEMICAL MODULATORS OPERATING AT ANY LEVEL OF THE STAT OR D-DEPENDENT SIGNALING CASCADE. E-SCREEN TESTS WILL ALLOW THE SELECTION OF PRODUCTS WITH SERM ACTIVITIES. SECOND, CYTOTOXICITY WILL BE EVALUATED IN JAK2-STAT (HEL) OR RE (T47D)-DEPENDENT LINES AND PRIMARY LYMPHOCYTES. THIRD, THE EFFICACY OF THE MOST ACTIVE MOLECULES IN RELATION TO CONCRETE BIOLOGICAL RESPONSES (PROLIFERATION, APOPTOSIS, MIGRATION, CELLULAR INVASION, COLONY FORMATION, ALKALINE PHOSPHATASE PRODUCTION, CALCIFICATION) WILL BE EVALUATED. FINALLY, WITH THE MOST ACTIVE MOLECULES, DETAILED MECANISTIC STUDIES WILL BE CARRIED OUT, SUCH AS: (A) NUCLEAR phosphorylation and transfer of technology for immunnoBLOTTING, GEMSA and MICROSCOPY, (B) JAK2 KINASA ACTIVITY IN VITRO and SPECIFICITY ON OTHER CHINASAS, (C) APOPTOSIS and CELL CELL CYCLE, D) BINDING THE RE, E) PREDICTIVE PREDICTIVE pharmaco-TOXICOGENOMIC IN VITRO, AND E) ORIENTATE biological evaluations, supported by the improvement of the chemical design, will allow to select the optimal molecula to evaluate its efficacy and in-live Toxicity._x000D_ IN BASE TO THE BIOLOGICAL ACTIVITY RESULTS, products OF THE CRIBADO FENT TO DIANA TERAPEUTIC DYSTEMS, we will improve the biological PROPERTY AND/OR FARMACOLOGICAL OF bioactive molecules by means of STRUCTURE-ACTIVITY RELATED STUDIES (SAR) thus as IN-SILICO STUDIES that will facilitate the RACIONAL DESIGN OF NEW ENTITIES (English)
12 October 2021
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San Cristóbal de La Laguna
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Identifiers
SAF2015-65113-C2-1-R
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