Peptide conformation: 48. Conformation and biological activity of proline containing cyclic retro‐analogues of somatostatin

Six cyclic retro‐analogues of the peptide hormone somatostatin have been synthesized using the solid phase technique. The peptides cyclo(‐Xaa¹‐Phe²‐Thr³‐Lys⁴‐Ybb⁵‐Phe⁶‐) and cyclo(‐Phe¹‐Xaa²‐Thr³‐Lys⁴‐Ybb⁵‐Phe⁶‐) with Xaa =d‐ or l‐Pro and Ybb =d‐ or l‐Trp were cyclized via the azide method. The conformations of the cyclic hexapeptides in DMSO‐d₆ solution were determined by a number of homo‐ and heteronuclear two‐dimensional n.m.r.‐techniques including 2D rotating frame NOE‐spectroscopy. Two‐step coherence transfers, ROE and chemical exchange, are observed for the first time in ROESY spectra. The backbone conformation of the all‐trans cyclopeptides consists of a β‐turn containing the Pro residue in the position i + 1. These retro‐analogues of somatostatin exhibit a high activity in the inhibition of cholate and phalloidin uptake by liver cells (cytoprotective effect); however, the hormonal activities of the natural hormone are completely suppressed. The constitutional and conformational requirements for the cytoprotective activity are discussed.