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Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism
Published on: July 28, 2017
Ribo-timidinas 2',4'-carbocíclicas de cinco y seis miembros con conformación bloqueada: síntesis, estructura y
Puneet Srivastava1, Jharna Barman, Wimal Pathmasiri
1Department of Bioorganic Chemistry, Biomedical Center, Uppsala University, Uppsala, Sweden.
Journal of the American Chemical Society
|June 8, 2007
Resumen
Los nuevos análogos carbocíclicos del ácido nucleico bloqueado (LNA) y el ENA mejoran la estabilidad de los oligonucleótidos antisenso y el potencial terapéutico. Estos oligonucleótidos modificados muestran una mejor resistencia a la nucleasa y propiedades farmacocinéticas para el desarrollo potencial de fármacos.
Área de la Ciencia:
- Química Medicinal La Química Medicinal es el campo de la Química Medicinal.
- Química del ácido nucleico Química del ácido nucleico
- Terapéutica terapéutica de los oligonucleótidos
Sus antecedentes:
- Los oligonucleótidos antisense (AON) son agentes terapéuticos prometedores, pero a menudo sufren de baja estabilidad y farmacocinética.
- Las modificaciones de ácido nucleico bloqueado (LNA) yエNA mejoran las propiedades de AON, pero son deseables más mejoras.
Objetivo del estudio:
- Para sintetizar nuevos análogos carbocíclicos de LNA (carbocíclico-LNA-T) yエNA (carbocíclico-ENA-T).
- Evaluar el impacto de estas modificaciones en las propiedades de los oligonucleótidos antisense (AON).
Principales métodos:
- Síntesis de carbocíclico-LNA-T y carbocíclico-ENA-T utilizando reacciones de ciclización radical.
- Incorporación de nucleósidos modificados en AONs.
- Confirmación estructural mediante la espectroscopia de RMN (HMBC, TOCSY, COSY, NOE).
- Evaluación de la estabilidad dúplex (Tm), las tasas de escisión de RNasa H y la estabilidad de la nucleasa en el suero sanguíneo.
Principales resultados:
- El carbocíclico-LNA-T y el carbocíclico-ENA-T fueron sintetizados en altos rendimientos.
- Las AON modificadas mostraron temperaturas de fusión duplex mejoradas (Tm) en comparación con las AON nativas.
- La incorporación única de carbocíclico-LNA o carbocíclico-ENA aumentó significativamente la estabilidad de la nucleasa en el suero sanguíneo (>48 horas).
- Las tasas de escisión de la RNasa H fueron comparables a las de las AON nativas y otras AON modificadas.
Conclusiones:
- Las modificaciones carbocíclicas-LNA y carbocíclicas-ENA imparten una notable resistencia y estabilidad a la nucleasa a las AON.
- Estas modificaciones ofrecen propiedades farmacocinéticas mejoradas, potencialmente reduciendo las dosis requeridas.
- El carbocíclico-LNA-T y el carbocíclico-ENA-T son candidatos prometedores para agentes terapéuticos antisentido debido a su estabilidad y eficacia.
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