A versatile post-synthetic method on a solid support for the synthesis of RNA containing reduction-responsive...

Area of Science:

• Oligonucleotide chemistry
• Medicinal chemistry
• Bioconjugation

Background:

• Oligoribonucleotides (RNAs) are crucial in biological processes but susceptible to degradation.
• Developing stable RNA analogs is essential for therapeutic applications, such as small interfering RNA (siRNA).
• Existing RNA modification strategies may lack efficiency or versatility.

Purpose of the Study:

• To develop a novel post-synthetic method for introducing disulfide-containing modifications at the 2'-hydroxyl (2'-OH) position of RNA.
• To synthesize diverse 2'-O-alkyldithiomethyl RNA analogs.
• To evaluate the stability and deprotection characteristics of the modified RNAs.

Main Methods:

• A solid-support based synthesis was employed.
• Thiol disulfide exchange reactions were utilized between alkyldisulfanyl-pyridine derivatives and 2'-O-acetylthiomethyl RNA.
• Butylamine was used as a catalyst in the reaction.

Main Results:

• A range of 2'-O-alkyldithiomethyl RNA modifications were successfully synthesized.
• These RNA modifications demonstrated significantly enhanced resistance to nucleases.
• The disulfide modifications were readily cleaved using glutathione, enabling facile deprotection.

Conclusions:

• The developed method provides efficient access to diverse disulfide-modified RNAs.
• The modifications confer nuclease resistance and are cleavable, making them suitable for prodrug strategies.
• This approach holds potential for the development of advanced siRNA prodrugs with improved stability and delivery.