PhD Oral Exam - Christopher Liczner, Chemistry

When studying for a doctoral degree (PhD), candidates submit a thesis that provides a critical review of the current state of knowledge of the thesis subject as well as the student’s own contributions to the subject. The distinguishing criterion of doctoral graduate research is a significant and original contribution to knowledge.

Once accepted, the candidate presents the thesis orally. This oral exam is open to the public.

Abstract

Oligonucleotides have found applications in intracellular therapeutics and diagnostics. This can be attributed, in part, to their ability to self-assemble, 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 discovered 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.