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Agonistas de los receptores de estrógenos basados en diazocina: estabilización de la forma activa dentro del receptor

Julia Ewert¹, Linda Heintze², Mireia Jordà-Redondo³

¹Otto-Diels-Institute of Organic Chemistry, Christian-Albrechts-University of Kiel, 24098 Kiel, Germany.

Journal of the American Chemical Society

|August 11, 2022

Resumen

Este estudio introduce nuevos fármacos fotointercambiables que se activan con luz violeta y se desactivan con luz verde. Estos compuestos demuestran una alta especificidad del objetivo, minimizando los efectos secundarios y el impacto ambiental.

Área de la Ciencia:

Química medicinal
Farmacología
La fotoquímica

Sus antecedentes:

La fotofarmacología ofrece un control preciso de la actividad del fármaco utilizando la luz.
Los medicamentos actuales con conmutación de luz a menudo usan azobenzeno, pero este estudio explora un nuevo andamio.
La especificidad del objetivo es crucial para minimizar los efectos secundarios, especialmente para los compuestos que alteran el sistema endocrino.

Objetivo del estudio:

Diseñar y sintetizar nuevos compuestos con propiedades similares a las de los fármacos.
Investigar la actividad farmacológica y el comportamiento sensible a la luz de los nuevos derivados de la diazocina.
Explorar el potencial de los fármacos activados por la luz para mejorar la especificidad del objetivo y reducir el impacto ambiental.

Principales métodos:

Estudios de acoplamiento computacional para evaluar la similitud estructural con el 17β-estradiol.
Síntesis química de siete derivados de la dihidroxi diazocina.
Prueba del gen receptor de estrógeno para evaluar la actividad biológica y la sensibilidad a la luz.

Principales resultados:

Los estudios de acoplamiento mostraron una gran similitud estructural entre el estrógeno natural y los isómeros *E* de las diazocinas sintetizadas.
Cuatro derivados sintetizados de la diazocina exhibieron actividad estrogénica dependiente de la luz, intercambiable con luz violeta y verde.
El isómero *E* activo de un compuesto mostró una rápida isomerización en agua pero una actividad prolongada dentro del receptor de estrógeno, lo que sugiere una influencia del complejo ligando-receptor.

Conclusiones:

Las diazocinas desarrolladas representan una nueva clase prometedora de fármacos fotointercambiables.
La rápida isomerización tras la liberación del receptor mejora la especificidad del objetivo y reduce las posibles alteraciones endocrinas.
Esta estrategia ofrece un enfoque valioso para desarrollar terapias más seguras y efectivas, en particular para afecciones relacionadas con el sistema endocrino.

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