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Rutas sumamente concisas hacia las epothilonas: la síntesis total y evaluación de la epothilona 490
Kaustav Biswas1, Hong Lin, Jon T Njardarson
1Bioorganic Chemistry, Preclinical Pharmacology Core Facility and Analytical Pharmacology Core Facility, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA.
Journal of the American Chemical Society
|August 15, 2002
Resumen
Este estudio presenta una nueva síntesis estereospecífica de epothilones utilizando metástasis de olefinas de cierre de anillo (RCM). El nuevo protocolo de reducción de RCM genera de manera eficiente el marco epothilone para el desarrollo de fármacos antitumorales y la síntesis de análogos.
Área de la Ciencia:
- Química orgánica es la química orgánica.
- Química Medicinal La Química Medicinal es un campo de estudio de la química medicinal.
- Biología Química Biología química.
Sus antecedentes:
- Las epotilonas son una clase de agentes antitumorales prometedores.
- Las síntesis anteriores de epothilones utilizando la metátesis de olefinas de cierre de anillo (RCM) carecían de estereocontrol.
- La epothilona 490 (3) provocó una reevaluación de la RCM para la síntesis de epothilona.
Objetivo del estudio:
- Desarrollar una síntesis de laboratorio concisa, modular y estereoselectiva de epothilones.
- Establecer un nuevo protocolo de reducción de RCM para la generación eficiente del marco epothilone.
- Explorar la síntesis de nuevos análogos de epothilona para estudios de la relación estructura-actividad (SAR).
Principales métodos:
- Metátesis de olefinas estereospecíficas de cierre de anillo (RCM) para formar el anillo macrólido.
- Las condiciones aldólicas mediadas por titanio quiral para la introducción tardía del alcohol C3-S.
- Reducción selectiva de diimida de la olefina recién formada.
- Funcionalización de la nueva olefina para la síntesis analógica.
Principales resultados:
- Se logró un rendimiento del 64% de la E-olefina deseada mediante la realización de RCM como el paso sintético final.
- La reducción selectiva de diimida produjo 12,13-desoxiyepotilona B, un candidato clínico.
- La nueva ruta facilitó la construcción de nuevos análogos para el cribado de citotoxicidad y afinidad de microtúbulos.
- Epothilone 490 mostró un bajo rendimiento in vivo en xenografts debido a una farmacocinética desfavorable, pero es prometedor para el uso humano basado en criterios farmacocinéticos.
Conclusiones:
- Se ha desarrollado con éxito una nueva síntesis estereoselectiva de epotilonas basada en RCM.
- El protocolo de reducción de RCM proporciona una ruta eficiente a los análogos de epothilone y al candidato clínico 12,13-desoxyepothilone B.
- Mientras que la epothilona 490 exhibió una pobre eficacia in vivo en modelos preclínicos, su perfil farmacocinético sugiere un potencial valor terapéutico en humanos.
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