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Síntesis total y asignación estructural completa de la yaku'amida A
Takefumi Kuranaga1, Yusuke Sesoko, Komei Sakata
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Journal of the American Chemical Society
|March 19, 2013
Resumen
Los investigadores sintetizaron el yaku yaku.
Área de la Ciencia:
- Productos naturales del mar química productos naturales del mar química
- La síntesis orgánica es la síntesis orgánica.
- Química medicinal es la química de los medicamentos.
Sus antecedentes:
- Yaku'amide A es una potente citotoxina aislada de una esponja marina.
- Su estructura completa, incluida la estereoquímica C4, era previamente indeterminada.
- La molécula presenta inusuales residuos de aminoácidos deshidro.
Objetivo del estudio:
- Para lograr la primera síntesis total de yaku'amida A. A.
- Para asignar definitivamente la C4 estereoquímica de la yaku'amida A. A.
- Desarrollar nuevas metodologías sintéticas para la construcción de péptidos altamente insaturados.
Principales métodos:
- Reacciones de acoplamiento cruzado mediadas por cobre para la síntesis de ácido deshidroamino selectivo E/Z.
- Elongamiento del péptido paso a paso a partir de un intermediario tetrapeptido.
- Espectroscopia de Resonancia Magnética Nuclear (RMN) para la asignación estereoquímica.
- Ensayos biológicos utilizando células de leucemia de ratón P388.
Principales resultados:
- Éxito en la síntesis total de yaku'amida A y su epímero C4.
- Completa la asignación estereoquímica de la yaku'amida A natural como el epímero C4S.
- Demostración de citotoxicidades comparables entre los epímeros C4.
- Desarrollo de métodos eficientes para el ensamblaje de péptidos que contienen ácido deshidroamino.
Conclusiones:
- Las estrategias sintéticas permiten el acceso a los análogos de yaku'amida A.
- Las metodologías establecidas facilitan estudios adicionales sobre las relaciones estructura-actividad.
- Ahora es posible comprender el papel de la conformación del aminoácido deshidro en la citotoxicidad.
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