ORG Seminar: Phil Dawson - Scripps

Organic Chemistry Applied to Biological Macromolecules – In and Out of Water

Abstract: Biological macromolecules are hydrophilic rich polymers containing numerous chemically reactive functional groups. Chemical manipulation of these polymers typically requires chemistry that is tailored for compatibility with aqueous buffers and that are highly chemoselective. The development and application of these chemoselective ligation strategies for the chemical synthesis of proteins and peptide macrocycles will be discussed.  For other applications, such as the generation of DNA Encoded Libraries, the hydrophilic, unprotected nature of the DNA tag severely limits the repertoire of compatible chemical reactions. Rather than pursuing the optimization of individual synthetic organic reactions for water compatibility, we reasoned that a general strategy for transferring DNA-substrates into organic solvents could significantly expand the structural diversity explored by DEL. Reversible absorption of macromolecules to a solid support (RASS) has facilitated peptide and protein modification, enabling the use of anhydrous solvents and multistep synthetic procedures. This RASS strategy was adapted for DEL through a. Adsorption of DNA headpiece substrates to polystyrene based, quaternary ammonium resin facilitates transfer to organic solvents such as DMA, THF, and CH₂Cl₂. This expanded scope of reaction conditions compatible with DEL library generation and for the efficient generation of oligonucleotide-conjugates.