Synthesis, structure, and biological aspects of cyclopeptides related to marine phakellistatins 7–9

Phakellistatins 7, 8 and 9, three cyclic decapeptides naturally occurring in marine sponges of the genus Phakellia and characterized by the distinctive presence of Pro–Pro tracts, pose a non-trivial synthetic challenge, despite only containing coded amino acid residues. Their chemical synthesis was approached using a combination of solid and solution-phase techniques. As expected, our synthetic efforts yielded, for each cyclopeptide, a mixture of geometric isomers, owing to their cis–trans isomerism at Pro peptide linkages. A further complication arose because their synthesis yielded, together with the desired monomeric cyclopeptides, cyclodimeric species. In the case of phakellistatin 7 (originally determined as cis-Pro2, cis-Pro8) our synthetic product was chemically and spectrally identical to the natural one, whereas none of the different isomeric products obtained for both phakellistatins 8 and 9 resulted to be fully equivalent (with respect to Pro geometries) to their natural counterparts. Finally, all synthetic cyclopeptides were submitted to biological assays and, as noted before for other members of the ‘proline rich’ family, synthetic compounds did not fully reproduce the biological properties (in terms of in vitro cytotoxicity against a panel of cancer cell lines) originally found for the natural products.