NEW METALOFARMACOS DESIGNED TO INCREASE SELECTIVITY IN CANCER TREATMENTS. USE OF PHOTOTHERAPY AND VEHICULISATION WITH LIGANDS AIMED AT TUMORS. (Q3145224)
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Project Q3145224 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | NEW METALOFARMACOS DESIGNED TO INCREASE SELECTIVITY IN CANCER TREATMENTS. USE OF PHOTOTHERAPY AND VEHICULISATION WITH LIGANDS AIMED AT TUMORS. |
Project Q3145224 in Spain |
Statements
86,539.2 Euro
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108,174.0 Euro
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80.0 percent
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1 January 2019
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31 December 2021
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UNIVERSIDAD DE CASTILLA-LA MANCHA
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38°57'35.10"N, 3°52'58.26"W
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13034
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EN ESTE PROYECTO SE PREPARAN NUEVOS METALOFARMACOS CON SELECTIVIDAD Y EFICACIA EN EL TRATAMIENTO DEL CANCER. HOY EN DIA, LOS TRATAMIENTOS QUIMIOTERAPEUTICOS OCASIONAN SEVEROS EFECTOS SECUNDARIOS Y RESISTENCIA. EL PROYECTO TIENE COMO OBJETIVO DISEÑAR Y DESARROLLAR MEDICAMENTOS QUE PUEDAN CONTRIBUIR A SUPERAR ESTOS PROBLEMAS A TRAVES DE DOS ESTRATEGIAS COMPLEMENTARIAS. EN PRIMER LUGAR, SE PREPARAN COMPLEJOS METALICOS PARA FOTOQUIMIOTERAPIA QUE SE ACTIVARAN CON IRRADIACION CON LUZ LO QUE PERMITE UN CONTROL ESPACIO-TEMPORAL DE LA ACTIVIDAD DEL FARMACO. EN SEGUNDO LUGAR, LOS LIGANDOS DE LOS COMPLEJOS MAS ACTIVOS SE FUNCIONALIZARAN CON EL FIN DE PERMITIR LA PREPARACION DE BIOCONJUGADOS CON PEPTIDOS QUE SE DIRIJAN A RECEPTORES SOBREEXPRESADOS EN LAS CELULAS CANCEROSAS. ESTOS BIOCONJUGADOS SE PREPARARAN MEDIANTE TECNICAS DE ACOPLAMIENTO TIPO CLICK Y POSEERAN GRUPOS FUNCIONALES ESCINDIBLES, SENSIBLES AL PH ACIDO DE LOS LISOSOMAS, PARA LIBERAR EL FARMACO DENTRO DE LAS CELULAS. SE SINTETIZARAN VARIAS FAMILIAS DE COMPLEJOS DE IR (III) O RU (II) DE LOS TIPOS [IR(C^N)2(N'^N'')]N+ (N = 0, 1) O [RU(N^N)2(N'^N'')]N+ (N = 1, 2) (C^N = LIGANDOS CICLOMETALADOS, N'^N'' = LIGANDOS BIDENTADOS N-DADORES) PARA SU USO EN TERAPIA FOTODINAMICA (PDT). LOS LIGANDOS N'^N'' SE HAN SELECCIONADO CONSIDERANDO PROPIEDADES FOTOQUIMICAS FAVORABLES DE COMPLEJOS YA PUBLICADOS: DESLOCALIZACION ELECTRONICA QUE ENSANCHE LAS BANDAS DE ABSORCION O CON UN DESPLAZAMIENTO BATOCROMICO (PARA FACILITAR LA EXCITACION EN LA VENTANA TERAPEUTICA CON MAYOR PENETRACION TISULAR), O EL BALANCE ENTRE HIDRO Y LIPOFILIA. ADEMAS, SE DISEÑARAN COMPLEJOS DE IR CON COLAS LIPOFILICAS PARA INSERTARSE EN LA MEMBRANA CELULAR DE MANERA QUE LA IRRADIACION PUEDA OXIDAR LOS FOSFOLIPIDOS Y DAÑARLA. TAMBIEN HEMOS PLANEADO PREPARAR COMPLEJOS DE RU (II) DE TIPO [RU(N^N^N)(N'^N'')L]2+ COMO POTENCIALES AGENTES DE QUIMIOTERAPIA FOTOACTIVADA (PACT). LOS LIGANDOS L SERAN CONOCIDOS INHIBIDORES DE LA GLUCOLISIS, QUE SE LIBERARAN SELECTIVAMENTE DESPUES DE LA IRRADIACION, RESTRINGIENDO LA GLUCOLISIS EN CELULAS CANCEROSAS. TAMBIEN SE ENSAYARA UNA ESTRATEGIA PACT SIN PRECEDENTES, BASADA EN LA UNION DE FRAGMENTOS [CP'RU]+ (CP' = CICLOPENTADIENILO) A LOS LIGANDOS CON DESLOCALIZACION ELECTRONICA TIPO POLIPIRIDINA YA COORDINADOS, CON EL OBJETIVO DE QUE LA FOTOACTIVACION PROMUEVA LA PERDIDA DE [CP'RU]+ ACTIVANDO EL COMPLEJO FRENTE AL ADN. EL CARACTER HIDROFILICO Y LIPOFILICO TAMBIEN SE MODULARA CON LOS ANIONES. TAMBIEN SE LLEVARAN A CABO ESTUDIOS COMPUTACIONALES PARA ANALIZAR LA INTERACCION DE LOS MEJORES FARMACOS CON BIOMOLECULAS COMO EL ADN Y PROTEINAS MODELO. LOS ESTUDIOS BIOLOGICOS CON LOS METALOFARMACOS Y CON LOS CONJUGADOS SE ABORDARAN EN EL SUBPROYECTO COORDINADO 2. (Spanish)
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THIS PROJECT HAS BEEN CONCEIVED TO PREPARE NEW METALLO-DRUGS THAT COULD ACT WITH SELECTIVITY AND EFFICIENCY IN THE CANCER TREATMENT. NOWADAYS, THE CHEMOTHERAPEUTIC TREATMENTS SUFFER FROM SEVERE SIDE EFFECTS AND RESISTANCE. THE PROJECT IS AIMED TO DESIGN AND DEVELOP DRUGS THAT COULD CONTRIBUTE TO OVERCOME THESE PROBLEMS THROUGH TWO COMPLEMENTARY STRATEGIES. FIRSTLY, WE INTEND TO SYNTHESIZE METAL COMPLEXES AS POTENTIAL PHOTOCHEMOTHERAPY AGENTS THAT WILL BE ACTIVATED UPON IRRADIATION WITH LIGHT TO GET SPATIO-TEMPORAL CONTROL ON THE DRUG ACTIVITY. SECONDLY, THE LIGANDS OF THE MOST ACTIVE COMPLEXES WILL BE FUNCTIONALIZED IN ORDER TO ALLOW THE PREPARATION OF METALLO-BIOCONJUGATES WITH PEPTIDES THAT TARGET RECEPTORS OVEREXPRESSED IN THE CANCER CELLS. THESE CONJUGATES WILL BE PREPARED BY CLICK-TYPE COUPLING TECHNIQUES AND WILL HAVE CLEAVABLE FUNCTIONAL GROUPS, SENSITIVE TO THE ACID PH OF THE LYSOSOMES, TO RELEASE THE DRUG INSIDE THE CELLS. SEVERAL FAMILIES OF IR(III) OR RU(II) COMPLEXES OF THE TYPES [IR(C^N)2(N'^N'')]N+ (N = 0,1) OR [RU(N^N)2(N'^N'')]N+ (N = 1,2) (C^N = CYCLOMETALLATED LIGANDS, N'^N'' = BIDENTATE N-DONOR LIGANDS) WILL BE SYNTHESIZED TO BE USED IN PHOTODYNAMIC THERAPY (PDT). THE N'^N'' LIGANDS HAVE BEEN SELECTED CONSIDERING THE POSITIVE EFFECTS IN COMPLEXES REPORTED PREVIOUSLY, ELECTRON DELOCALIZATION OR ASYMMETRY TO GET A SHIFTING OR BROADENING IN THE ABSORPTION BANDS TOWARDS LONGER WAVELENGTHS (TO FACILITATE THE EXCITATION IN THE THERAPEUTIC WINDOW WHICH SHOWS HIGHER TISSUE PENETRATION), OR THE BALANCE BETWEEN HYDRO AND LIPOPHILICITY. MOREOVER, IR COMPLEXES WITH LIPOPHILIC TAILS WILL BE DESIGNED TO BE INSERTED INTO THE CELL MEMBRANE SO THAT IRRADIATION CAN OXIDIZE PHOSPHOLIPIDS AND DAMAGE THE MEMBRANE. THEN, WE HAVE PLANNED TO PREPARE RU(II) COMPLEXES OF TYPE [RU(N^N^N)(N'^N'')L]2+ AS POTENTIAL PHOTO-ACTIVATED CHEMOTHERAPY (PACT) AGENTS. WE HAVE SELECTED DIFFERENT INHIBITORS OF GLYCOLYSIS AS THE MONODENTATE LIGANDS (L), WHICH SHOULD BE SELECTIVELY RELEASED UPON IRRADIATION TO RESTRAIN THE GLYCOLYTIC PROCESS ON WHICH CANCER CELLS ARE DEPENDENT. AN UNPRECEDENTED PACT STRATEGY BASED IN THE COORDINATION OF [CP'RU]+ (CP' = CYCLOPENTADIENYL) FRAGMENTS TO ELECTRON DELOCALIZED AROMATIC LIGANDS OF POLYPYRIDYL METAL COMPLEXES WILL ALSO BE ASSAYED IN THE HOPE THAT THE PHOTOACTIVATED LOSS OF [CP'RU]+ WILL ALLOW THE INTERCALATION OF THE POLYPYRIDYL SPECIES INTO DNA. THE HYDRO AND LIPOPHILIC CHARACTER WILL BE ALSO MODULATED WITH THE ANIONS. COMPUTATIONAL STUDIES WILL ALSO BE CARRIED OUT TO ANALYSE THE INTERACTION OF THE BEST DRUGS WITH BIOMOLECULES SUCH AS DNA AND MODEL PROTEINS. THE BIOLOGICAL STUDIES WITH THE METAL-PHARMACEUTICALS AND WITH THE CONJUGATES WILL BE ADDRESSED IN THE COORDINATED SUB-PROJECT 2. (English)
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Ciudad Real
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Identifiers
RTI2018-100709-B-C21
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