Since naturally occurring proteins and peptides are most often rapidly metabolized, synthetic peptide analogs are of increasing pharmacological interest.
As proteins and peptides are responsible for countless processes in living organisms, they are attractive lead compounds for development of drugs to treat a variety of diseases. A prime example is the administration of insulin to treat diabetes. However, naturally occurring proteins and peptides are often unfit as drugs for a number of reasons, including short half-lives in the body. It would thus be highly attractive to manufacture synthetic molecules that mimic the structure and function of proteins or peptides but with improved pharmacokinetic properties. This thesis presents progress in techniques designed for this purpose.
The activity and distinct selectivity of proteins and peptides are highly dependent on the accurate three-dimensional presentation of functional groups. Modulation of these properties is desired in development of pharmaceutical agents. However, due to proteolytic instability and poor cell permeability, peptides have traditionally been considered unsuitable as drug candidates. Synthetic peptide analogs are suggested as a tactic to bypass these undesired properties. Specifically, so-called peptidomimetics with the ability to mimic the structural elements in proteins are of interest.
A prominent type of peptidomimetics is α– peptoids (N-alkylglycines or simply peptoids) which are able to fold into helical and sheetlike arrangements. However, their backbone flexibility is increased due to presence of tertiary amides. In this project, backbone interactions that possibly account for stability of peptoid secondary structures were probed. Stereoelectronic modifications such as thioamidation and trifluoroacetylation were applied to a series of peptoid monomer model compounds. It was demonstrated that carbonylcarbonyl interactions could be probed in peptoids by trifluoroacetylation.
Synthesis of backbone-fluorinated oligopeptoids proved unsuccessful, but an intermediate was effectively utilized in the synthesis of fluorinated triazoles as amide bond surrogates via copper(I)-catalyzed azide-alkyne cycloaddition. The fluorine-containing triazole motifs were incorporated in both linear and cyclic peptide targets. In silico studies support this new fluorinated moiety as a viable bioisostere of the amide group.
Further, a small series of backbone-fluorinated α,β-hybrid and β,β–peptoid dimers were analyzed by NMR-spectroscopy, and the results complemented the conformational behaviour of their monomeric counterparts. Synthesis of backbone-fluorinated β–peptoid oligomers was commenced and initial strategies showed promising results for further investigation.