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Grupo 2-benzamidoetil--un nuevo tipo de grupo protector de fosfato para la síntesis de oligonucleótidos
1Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2292 Faraday Ave., Carlsbad, California 92009, USA. aguzaev@isisph.com
Journal of the American Chemical Society
|July 18, 2001
Resumen
Los nuevos grupos protectores de fosforamidita para la síntesis de oligonucleótidos ofrecen tasas de desprotección ajustables, con algunas eliminadas en minutos. Esto permite una síntesis eficiente de oligonucleótidos naturales y modificados sin dañar los ácidos nucleicos.
Área de la Ciencia:
- Química orgánica es la química orgánica.
- Química del ácido nucleico Química del ácido nucleico
- Química sintética de la química sintética.
Sus antecedentes:
- La síntesis eficiente de oligonucleótidos requiere estrategias de grupo de protección robustas.
- Los grupos protectores de fosforamidita existentes exhiben estabilidad variable y cinética de desprotección.
- Se necesitan nuevos grupos protectores para optimizar la síntesis de oligonucleótidos.
Objetivo del estudio:
- Para sintetizar y evaluar los nuevos 5'-O-(4,4'-dimetoxitritilo) timidina fosforamiditas con protección P(III).
- Investigar la cinética y el mecanismo de desprotección de estos nuevos grupos protectores.
- Evaluar la utilidad de estos bloques de construcción en la síntesis de oligonucleótidos y sus análogos.
Principales métodos:
- Síntesis de 11 nuevas fosforamiditas protegidas con 2-benzamidoetanol.
- Incorporación de estas fosforamiditas en oligonucleótidos sintéticos de 20 mer y análogos de fosforotioato.
- Estudios cinéticos de la desprotección utilizando hidróxido de amonio concentrado a diferentes temperaturas.
- Investigación mecanicista del proceso de desprotección utilizando un modelo de fosfotriéster.
Principales resultados:
- Los tiempos de desprotección variaron de 25 minutos a 48 horas dependiendo del patrón de sustitución del grupo protector.
- Los grupos 2-[N-isopropil-N-(4-metoxibenzoil) amino]etil (H) y omega-{thionobenzoylamino) alquilo (I y K) mostraron la eliminación más rápida.
- Se sintetizaron nuevos reactivos fosforiladores y bloques de construcción de fosforamidita y se aplicaron con éxito en la síntesis de oligonucleótidos.
- El mecanismo de desprotección reveló la formación independiente del pH de un intermediario de catión de 2-oxazolinio estable que no reacciona con el oligonucleótido.
Conclusiones:
- Se desarrolló una estrategia versátil para proteger los grupos de fosfodiéster internucleósido.
- Los nuevos grupos protectores ofrecen tasas de desprotección ajustables, lo que permite una síntesis eficiente de oligonucleótidos.
- Esta metodología tiene potencial para aplicaciones en química orgánica sintética que involucra compuestos de fósforo (III) y (V).
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