Poster Presentation 6th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2017

Solid phase synthesis of celogentin C (#52)

Varsha Thombare 1 , Craig Hutton 1
  1. University of Melbourne, Parkville, VIC, Australia

Cyclic and polycyclic peptides have emerged as valuable pharmaceutical templates due to their resistance to chemical or enzymatic hydrolysis and high selectivity. Especially bicyclic peptides found in nature exhibit a macrocyclic structure that is further constrained by an intramolecular linkage connecting two side chains of the peptide. Celogentin C is one of such bicyclic peptides which possess potent antimitotic activty1. The celogentin family peptides are characterized by a central tryptophan residue, cross-linked from the C2-position of the indole ring to the N1-position of the imidazole ring of a histidine residue. Further, the β-carbon of leucine is crosslinked to the C6-position of the tryptophan indole to form the second ring. Due to these unusual cross links between the side chains of leucine-tryptophan-histidine, the chemical synthesis of the celogentin family of peptides is very tedious, labour intensive and low yielding2-3. The main challenge in the synthesis of celogentin C is the formation of the two key cross-links between tryptophan-histidine and tryptophan-leucine. We report efforts toward synthesis of celogentin C on solid support, including oxidative coupling, Larock indole synthesis, Suzuki coupling and silylation reactions on solid phase.

Reference:

1 Christina Leung, T. W.; Williams, D. H.; C J Barna, J.; Foti, S.; B.Oelrichs, P., Structural studies on the peptide moroidin from laportea moroides. Tetrahedron 1986, 42 (12), 3333-3348.

2 Suzuki, H.; Morita, H.; Iwasaki, S.; Kobayashi, J. i., New antimitotic bicyclic peptides, celogentins D–H, and J, from the seeds of Celosia argentea. Tetrahedron 2003, 59 (28), 5307-531

3 Ma, B.; Banerjee, B.; Litvinov, D. N.; He, L.; Castle, S. L., Total Synthesis of the Antimitotic Bicyclic Peptide Celogentin C. Journal of the American Chemical Society 2010, 132 (3), 1159-1171.