Kessler H, Klein M, Wagner K
Institute for Organic Chemistry, Johann Wolfgang Goethe University, Frankfurt, West Germany.
Int J Pept Protein Res. 1988 May;31(5):481-98.
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 beta-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.
已采用固相技术合成了六种肽激素生长抑素的环状反向类似物。肽环（-Xaa1-Phe2-Thr3-Lys4-Ybb5-Phe6-）和环（-Phe1-Xaa2-Thr3-Lys4-Ybb5-Phe6-），其中Xaa = D-或L-脯氨酸，Ybb = D-或L-色氨酸，通过叠氮化物法环化。通过包括二维旋转框架NOE光谱在内的多种同核和异核二维核磁共振技术，确定了环状六肽在DMSO-d6溶液中的构象。在ROESY光谱中首次观察到两步相干转移、ROE和化学交换。全反式环肽的主链构象由在i + 1位置含有脯氨酸残基的β-转角组成。这些生长抑素的反向类似物在抑制肝细胞摄取胆酸盐和鬼笔环肽方面表现出高活性（细胞保护作用）；然而，天然激素的激素活性被完全抑制。讨论了细胞保护活性的结构和构象要求。
