Synthesis, structural aspects and bioactivity of the marine cyclopeptide hymenamide C

Head-to-tail proline containing cyclopeptide hymenamide C [cyclo(Leu-Trp-Pro3-Phe-Gly-Pro6-Glu); 1], isolated from a marine sponge and for which a preliminary immunomodulating activity was reported, was efficiently synthesized by a three-dimensional orthogonal solid-phase strategy (Fmoc/tBu/Allyl) via anchoring the ω-carboxyl function of the glutamic acid to the solid support (PAC–PEG–PS). The linear precursor was entirely assembled and subsequently cyclized on resin, yielding a major product identical to the natural hymenamide C and a minor one, a geometric isomer of hymenamide C (2), differing for the geometry of peptide linkages at Pro residues. Both the ‘proline-rich’ cyclopeptides were submitted to a multiparametric in vitro screening on immune cells in order to acquire additional information on their biological activity. Indeed, compounds 1 and 2 were shown to exert inhibitory effect on human neutrophil elastase degranulation release at micromolar concentration.