Abstract

Oligonucleotides have found applications as intracellular therapeutics and diagnostic agents. This can be attributed, in part, to their ability to self-assemble into higher order structures, ease of synthesis, highly specific target binding and large number of sites available for modification. These modifications can be introduced in a site-selective and automated manner by solid-phase synthesis employing phosphoramidite chemistry, as well as through post-synthetic reactions. Since natural oligonucleotides suffer from intrinsic drawbacks, such as nuclease degradation, poor cellular uptake and unfavorable targeting, great efforts have gone towards modifying their sugar-phosphate backbone and/or generating oligonucleotide conjugates to improve their properties and expand their utility. Thus, adding to the toolbox of methodologies available to generate oligonucleotide conjugates, especially in a practical and sustainable fashion, is of the highest importance and the main focus of this thesis. To this end, we first developed a modular, robust and photo-activated upconverting nanoparticle delivery platform for therapeutic oligonucleotides. Photocleavable and alkyne containing phosphoramidites, synthesized in a greener way, were used to assemble these oligonucleotide conjugates. Secondly, we demonstrated that a 5'-diselenide oligonucleotide could be used to post-synthetically generate a large library of conjugates in a relatively rapid, chemoselective and high yielding manner, utilizing diselenide-selenoester ligation and alkylation chemistries. Finally, a new Pd-catalyzed cross-coupling reaction was developed for the synthesis of biphenyls that is both practical and green. Progress is currently being made to use this chemistry, dubbed the “deselenative cross-coupling”, to synthesize emissive nucleobase analogues and as such, fluorescent oligonucleotide conjugates.