Preparation of oligodeoxyribonucleoside phosphorodithioates by a triester method

Area of Science:

• Oligonucleotide Chemistry
• Medicinal Chemistry
• Biotechnology

Background:

• The synthesis of modified oligonucleotides is crucial for developing novel therapeutics and research tools.
• Phosphorothioate linkages are common in antisense oligonucleotides but can have associated toxicities.
• Developing methods for synthesizing phosphorodithioate linkages offers an alternative with potentially different properties.

Purpose of the Study:

• To extend a known method for thymidine phosphorodithioate dimer synthesis.
• To enable the preparation of oligo-2 -deoxyribonucleotide phosphorodithioates containing all four bases.
• To achieve large-scale synthesis with high purity and minimal impurities.

Main Methods:

• Extension of a thymidine phosphorodithioate dimer preparation method.
• Utilizing a dithiophosphorylating agent (RSP(S)(ODhbt)2) for linkage introduction.
• Block synthesis in solution for oligonucleotides up to octamers.

Main Results:

• Successful preparation of oligo-2 -deoxyribonucleotide phosphorodithioates with all four bases.
• Method is suitable for large-scale synthesis.
• High purity phosphorodithioates obtained with minimal phosphorothioate impurities (detection limit 0.5-1%).

Conclusions:

• The developed method provides a robust route to pure oligodeoxyribonucleoside phosphorodithioates.
• Phosphorothioate linkages are avoided unless exposed to prolonged ammonia treatment.
• This advancement facilitates the production of modified oligonucleotides for various applications.