The synthesis and structure activity relationships of namalide, a marine natural product, are described. Namalide is a cyclic peptide whose macrocycle is formed by three amino acids with an exocyclic ureido phenylalanine moiety at its C-terminus. The configuration of namalide was established and analogs generated through Fmoc-based solid phase peptide synthesis. The synthetic version of natural namalide containing D-Lys and L-Ile was the most potent inhibitor of carboxypeptidase A with an IC50 value of 250 nM, where the linear version of it showed an18-fold reduction in activity. Analogs containing L-Lys or L-allo-Ile failed to inhibit carboxypeptidase A at the concentrations as high as 30 uM. Analog of Namalide that lacks the C-terminal exocyclic ureido Phe, and the namalide dimer were inactive. Namalide represents a new anabaenopeptin-type scaffold, and its protease inhibitory activity demonstrates that the 13-membered macrolactam can exhibit similar activity as the more common hexapeptides.

Namalide, a natural cyclic peptide and its analogs as carboxypeptidase A inhibitors

243rd National Meeting (2012)

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