RESUMEN
Inhibition of DYRK1A kinase, produced by chromosome 21 and consequently overproduced in trisomy 21 subjects, has been suggested as a therapeutic approach to treating the cognitive deficiencies observed in Down syndrome (DS). We now report the synthesis and potent DYRK1A inhibitory activities of fluoro derivatives of 3,5-di(polyhydroxyaryl)-7-azaindoles (F-DANDYs). One of these compounds (3-(4-fluorophenyl)-5-(3,4-dihydroxyphenyl)-1H-pyrrolo[2,3-b]pyridine, 5a) was selected for in vivo studies of cognitive rescuing effects in a standard mouse model of DS (Ts65Dn line). Using the Morris water maze task, Ts65Dn mice treated i.p. with 20 mg/kg of 5a performed significantly better than Ts65Dn mice treated with placebo, confirming the promnesiant effect of 5a in the trisomic mice. Overall, these results demonstrate for the first time that selective and competitive inhibition of DYRK1A kinase by the F-DANDY derivative 5a may provide a viable treatment strategy for combating the memory and learning deficiencies encountered in DS.
Asunto(s)
Síndrome de Down/psicología , Aprendizaje por Laberinto/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridinas/administración & dosificación , Animales , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Síndrome de Down/enzimología , Humanos , Inyecciones Intraperitoneales , Discapacidades para el Aprendizaje/tratamiento farmacológico , Trastornos de la Memoria/tratamiento farmacológico , Ratones , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/química , Piridinas/farmacología , Quinasas DyrKRESUMEN
A comprehensive conformational analysis of both 2,3-difluorobutane diastereomers is presented based on density functional theory calculations in vacuum and in solution, as well as NMR experiments in solution. While for 1,2-difluoroethane the fluorine gauche effect is clearly the dominant effect determining its conformation, it was found that for 2,3-difluorobutane there is a complex interplay of several effects, which are of similar magnitude but often of opposite sign. As a result, unexpected deviations in dihedral angles, relative conformational energies and populations are observed which cannot be rationalised only by chemical intuition. Furthermore, it was found that it is important to consider the free energies of the various conformers, as these lead to qualitatively different results both in vacuum and in solvent, when compared to calculations based only on the electronic energies. In contrast to expectations, it was found that vicinal syn-difluoride introduction in the butane and by extension, longer hydrocarbon chains, is not expected to lead to an effective stabilisation of the linear conformation. Our findings have implications for the use of the vicinal difluoride motif for conformational control.
Asunto(s)
Butanos/química , Flúor/química , Alcanos/química , Halogenación , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , EstereoisomerismoRESUMEN
A series of 3,5-diaryl-1H-pyrrolo[2,3-b]pyridines were synthesized and evaluated for inhibition of DYRKIA kinase in vitro. Derivatives having hydroxy groups on the aryl moieties (2c, 2j-l) demonstrated high inhibitory potencies with Kis in the low nanomolar range. Their methoxy analogues were up to 100 times less active. Docking studies at the ATP binding site suggested that these compounds bind tightly to this site via a network of multiple H-bonds with the peptide backbone. None of the active compounds were cytotoxic to KB cells at 10(-6) M. Kinase profiling revealed that compound 2j showed 2-fold selectivity for DYRK1A with respect to DYRK2 and DYRK3.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Indoles/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridinas/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Enlace de Hidrógeno , Indoles/farmacología , Células KB , Simulación del Acoplamiento Molecular , Piridinas/farmacología , Quinasas DyrKRESUMEN
The 2-azido analogue of 2'-deoxyuridine was prepared in three steps from 2'-deoxy-2-thiouridine. The sulfur atom of the 2-thio nucleoside was methylated and then displaced by hydrazine to furnish the corresponding 2-hydrazino derivative. After diazotization, the 2-azido compound that exists as its tetrazolo tautomer was obtained. Upon UV irradiation in aqueous solution, the title compound led to isocytosine.
Asunto(s)
Desoxirribosa/análogos & derivados , Desoxirribosa/química , Desoxirribosa/síntesis química , Procesos Fotoquímicos , Tetrazoles/química , Azidas/química , Isomerismo , Rayos UltravioletaRESUMEN
Previously reported syntheses of the photoaffinity label 5-azido-2'-deoxyuridine are rather inefficient and involve the tedious preparation of a 5-nitro intermediate. To overcome these inconveniences, we have developed a new approach from the commercially available 5-bromo-2'-deoxyuridine nucleoside. Our synthetic route makes use of a benzylamination reduction sequence. Using this strategy, the 5-azido-2'-deoxyuridine photolabel is prepared in three steps and quantitative yields.
Asunto(s)
Azidas/síntesis química , Desoxiuridina/análogos & derivados , Etiquetas de Fotoafinidad/síntesis química , Azidas/química , Bencilaminas/química , Bromodesoxiuridina/química , Desoxiuridina/síntesis química , Desoxiuridina/química , Modelos Químicos , Oxidación-Reducción , Etiquetas de Fotoafinidad/químicaRESUMEN
UV irradiation of 5-azido-2'-deoxyuridine in water provides up to seven products. All likely result from a pivotal azirene, formed by the intramolecular rearrangement of the initially formed nitrene, that undergoes nucleophilic addition at its C5 position. This study strongly suggests that only nucleophilic amino acid residues in close proximity are cross-linkable in photolabeling experiments by using the 5-azidouracil photophore.