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Síntesis total de Rameswaralide utilizando una estrategia retrosintética dirigida por farmacoforos

Nathanyal J Truax¹, Safiat Ayinde², Jun O Liu²

¹Department of Chemistry & Biochemistry, Baylor University, 101 Bagby Avenue, Waco, Texas 76710, United States.

Journal of the American Chemical Society

|September 27, 2022

Resumen

La primera síntesis total de rameswaralida se logró utilizando una estrategia dirigida por farmacóforos. Este enfoque permitió el desarrollo de la relación estructura-actividad e identificó un intermediario clave con una potente actividad anticancerígena.

Área de la Ciencia:

Química orgánica
Química medicinal
Productos naturales Química

Sus antecedentes:

Los cembranoides son una clase de productos naturales con actividades biológicas potenciales.
Rameswaralide es un cembranoide que se encuentra en los corales blandos.
El desarrollo de rutas sintéticas eficientes para productos naturales complejos es crucial para su evaluación biológica.

Objetivo del estudio:

Para lograr la primera síntesis total de rameswaralida.
Desarrollar un perfil de relación estructura-actividad (SAR) durante la síntesis.
Explorar nuevas estrategias sintéticas para la construcción de sistemas policíclicos complejos.

Principales métodos:

Análisis retrosintético dirigido por farmacoforos.
La lactonización de Diels-Alder y la resolución cinética para la síntesis enantioselectiva.
Desarrollo de estrategias de anulación del anillo D, incluida la ciclización radical fotocatalizada y la adición de Michael.

Principales resultados:

El éxito de la síntesis total de rameswaralida.
Identificación de un intermediario epoxi α-bromo ciclohepteno tricíclico con una citotoxicidad selectiva contra las células de cáncer de colon HCT-116.
Descubrimiento de una transposición del estado de oxidación que permite una fácil introducción de la fracción α-metileno butirolactona.

Conclusiones:

La estrategia sintética desarrollada es efectiva para acceder a estructuras cembranoides complejas.
Los análogos de β-ceto éster intermedios y bicíclicos identificados son prometedores como farmacóforos para futuras investigaciones.
Este trabajo proporciona una base para explorar SAR y desarrollar nuevos agentes anticancerígenos.

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