Patrick Wheeler

Use of Phenylacetyl Disulfide (PADS) in the Synthesis of Oligodeoxyribonucleotide Phosphorothioates

Abstract Oligodeoxyribonucleotide phosphorothioates, where one of the nonbridging oxygen of the internucleotide phosphate is formally replaced by a sulfur atom, are the first class to undergo human clinical trials. Ongoing phosphorothioate clinical trials against several disease targets has necessitated manufacture of very large quantities of oligonucleotide active pharmaceutical ingredient (API). Clinical trial and future market demands have stimulated effort towards developing cost efficient large scale synthesis of these complex bio-molecules. This effort has culminated in the routine synthesis of 20-mer oligodeoxyribonucleotide phosphorothioates at 150 mmole scale using only 1.75-fold molar excess of amidites in less than 8 h total synthesis time.

2′- and 3′- Biotin Conjugated Nucleoside Building Blocks: Synthesis of Biotinylated Oligonucleotides

Abstract The vitamin biotin plays a significant role in biological assays based on its unusually high affinity [KD=10−15M] to streptavidin and avidin. This assay can be used for monitoring cellular trafficking of antisense oligonucleotides using hiotin conjugation. In addition to the above diagnostic application, biotin conjugation to macromolecules could be used as a vitamin-mediated delivery system for macromolecules into cells. Complexation of avidin to hiotin-oligonucleotides (phosphodiesters or PNA) have been used to enhance the uptake of oligonucleotides1. Appropiiate placement of biotin in oligonucleotides could also provide increased nuclease resistance.