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La biocatálisis en el diseño de fármacos: las aminasas reductoras de ingeniería (RedAms) se utilizan para acceder a

Arnau Rué Casamajo¹, Yuqi Yu¹, Christian Schnepel²

¹Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom.

Journal of the American Chemical Society

|October 2, 2023

Resumen

Un nuevo proceso biocatalítico que utiliza una aminasa reductora de ingeniería (RedAm) proporciona un bloque de construcción de amina quiral específico para el descubrimiento de fármacos. Este método produce eficientemente un isómero deseado, crucial para el desarrollo de nuevas terapias.

Área de la Ciencia:

Química orgánica
Biocatálisis
Química medicinal

Sus antecedentes:

Los nuevos bloques de construcción son esenciales para descubrir nuevas terapias de moléculas pequeñas.
Las moléculas quirales complejas son valiosas para expandir las bibliotecas de compuestos, pero son difíciles de sintetizar.
El acceso eficiente a estereoisómeros específicos es fundamental en el desarrollo de fármacos.

Objetivo del estudio:

Desarrollar un método biocatalítico para producir un diastereómero específico de un bloque de construcción de aminas quirales.
Diseñar una aminasa reductora (RedAm) para mejorar la estereoselectividad.
Demostrar la utilidad a escala preparativa del biocatalizador diseñado.

Principales métodos:

La mutagénesis guiada por estructura se empleó para diseñar una aminasa reductora (RedAm).
El RedAm diseñado (IR-09 W204R) catalizó la conversión de una cetona racémica en un isómero de amina quiral específico.
Se utilizó la dealilación catalizada por paladio para obtener el producto final de amina primaria.

Principales resultados:

El RedAm modificado produjo el isómero (S,S,S) con una conversión del 45% y un exceso enantiomérico del 95% (ee).
El paso subsiguiente de delilación produjo la amina primaria objetivo en un rendimiento del 73%.
El proceso biocatalítico se demostró con éxito a escala preparatoria.

Conclusiones:

Los biocatalizadores diseñados, como el RedAm desarrollado, ofrecen rutas eficientes para bloques de construcción quirales complejos.
Este enfoque facilita la síntesis de productos intermedios valiosos para el descubrimiento de fármacos.
El RedAm diseñado sirve como base para un mayor desarrollo y optimización del proceso.

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