Chemistry Department Seminar, Sheila R. Haynes, Xavier University, Nov. 21, 1:30, Logan 100

Synthesis of α,α-Dialkylated Amino Acid-Rich Peptides | November 18, 2003

Peptides and peptide analogs are central to the understanding of biological and biochemical phenomena as well as in the development of pharmaceutical agents. In this research, a homologous series of 9-mer peptide analogs and their acetylated versions, which were design to be bioactive, amphipathic, 310-helices, were successfully prepared using a combination of solution and solid phase synthetic techniques. The peptides were each composed of 78 % α, α-dialkylated amino acids (ααAAs) [one 4-aminopiperidine-4-carboxylic acid (Api) and six aminoisobutyric acid (Aib)]. The synthesis of peptides containing multiple ααAAs is inherently complicated due to severe steric hindrance caused by tetrasubstitution at the α-carbon. The strategic incorporation of the novel dimer, Fmoc-Aib-Aib-OH, along with the in situ coupling reagent, PyAOP, played significant roles in the improved coupling and overall yields of the de novo designed peptides. The helical preference (α vs. 310) of each peptide in six different solvent environments was investigated as well as each peptide’s antimicrobial activity and cytotoxicity. The 310-helical, amphipathic design was observed best for the acetylated 9-mer peptides. Most of the peptides exhibited moderate activity against E. coli and minor activity against S. aureus. The non-acetylated peptides (concentrations  100 M) and the acetylated peptides (concentrations  200 M) did not exhibit any significant cytotoxocity to normal macrophages.