Synthesis and Characterization o f Nucleoside Analogues and their Incorporation into PNA Monomers and Oligopeptides

The synthesis o f peptide nucleic acid (PNA) is o f interest for their binding to nucleic acids and their potential for gene-based diagnostics and therapy. This thesis describes the synthesis of Fmoc/Boc protected PNA monomers for thymine (T), 2,6-diaminopurine (DAP), and 2-aminopurine (2AP). The oligomerization and selectivity over mismatches in DNA were studied with 2AP showing a higher selectivity for T over DAP (11.5 °C vs 6 °C). Inclusion of 2AP allowed fluorometric monitoring o f the denaturation o f PNA:DNA hybrid duplexes.. The synthesis o f sin azide-containing PNA monomer was completed and successfully incorporated into PNA. A solid phase copper azide-alkyne cycloaddition was performed in , quantitative yield. The synthesis of alkynes to be incorporated into the PNA is described. The syntheses of the monomers described will make unusual PNAs more accessible, allowing the study o f their unique propertie

Novel Conjugation Strategies Using the Diels-Alder Reaction

The development of new functional materials requires reliable conjugation chemistry for coupling molecular fragments under mild reaction conditions. The Diels–Alder (DA) reaction has been used in organic synthesis extensively over the past 90 years, but only recently has its ability to form fast and stable linkages been explored. New developments in small molecule DA reactivity have led to advances in protecting group chemistry and conjugation strategies. During my graduate studies, we developed novel diene-linkers, attached them onto antibodies, and conjugated maleimide-drugs to form DA antibody–drug conjugates. While exploring these adducts, we were able to exploit the lower retro-DA temperature of endo furan–maleimide adducts towards a new protecting group for maleimides in polymer synthesis. We also developed norbornadiene-containing polymers as a new “protected” form of cyclopentadiene that can be unmasked at room temperature with readily available reagents. These three conjugation strategies have enabled facile preparation of functional materials with more stable bonds and greater architectural complexity