Solid-phase synthesis of stereoregulated oligodeoxyribonucleoside phosphorothioates.
Natsuhisa Oka1, Mika Yamamoto, Terutoshi Sato
1Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan.
Nucleic Acids Symposium Series (2004)
|December 8, 2006
Summary
This study presents an efficient solid-phase synthesis for stereocontrolled oligodeoxyribonucleoside phosphorothioates. The optimized oxazaphospholidine method yields P-stereoregulated DNA oligomers with high diastereopurity.
Area of Science:
- Chemical synthesis
- Oligonucleotide chemistry
- Medicinal chemistry
Background:
- Oligodeoxyribonucleoside phosphorothioates are crucial in antisense and siRNA therapies.
- Solid-phase synthesis is a common method for producing these molecules.
- Controlling stereochemistry at the phosphorus atom is essential for biological activity.
Purpose of the Study:
- To develop an efficient and stereocontrolled solid-phase synthesis of oligodeoxyribonucleoside phosphorothioates.
- To optimize the oxazaphospholidine method for improved synthesis outcomes.
- To achieve high diastereopurity in the final phosphorothioate DNA oligomers.
Main Methods:
- Solid-phase synthesis utilizing the oxazaphospholidine method.
- Investigation and optimization of capping and sulfurizing reagents and conditions.
- Deprotection of internucleotidic linkages under basic conditions.
Main Results:
- An efficient stereocontrolled synthesis of oligodeoxyribonucleoside phosphorothioates was achieved.
- Optimization of capping and sulfurizing steps resolved issues with chiral auxiliary removal.
- P-stereoregulated phosphorothioate DNA oligomers were obtained with excellent diastereopurity.
Conclusions:
- The optimized oxazaphospholidine method provides an efficient route to stereocontrolled phosphorothioate DNA synthesis.
- This method overcomes challenges associated with conventional phosphorothioate DNA synthesis.
- The resulting high-purity P-stereoregulated oligomers are valuable for therapeutic applications.
