267007-66-9Relevant articles and documents
The cyclo-β-tetrapeptide (β-HPhe-β-HThr-β-HLys-β-HTrp): Synthesis, NMR structure in methanol solution, and affinity for human somatostatin receptors
Gademann, Karl,Ernst, Martin,Seebach, Dieter,Hoyer, Daniel
, p. 16 - 33 (2007/10/03)
The known solid-state structure (Fig. 1, top) of cyclo(β-HAla)4 was used to model the structure of the title compound 1 as a prospective somatostatin mimic (Fig. 1, bottom). The synthesis started with the N-protected natural amino acids Boc-Phe-OH, Boc-Trp-OH, Boc-Lys(2-Cl-Z)-OH, and Boc-Thr(OBn)-OH, which were homologated to the corresponding β-amino-acid derivatives (Scheme 1) and coupled to the β-tetrapeptide Boc-β-HTrp-β-HPhe-β-HThr(OBn)-β-HLys(2-Cl-Z)-OMe (16); the (N-Me)-β-HThr-(N-Me)-β-HPhe analog 17 was also prepared. C- and N-terminal deprotection and cyclization through the pentafluorophenyl ester gave the insoluble β-tetrapeptide with protected Thr and Lys side chains (18). Solubilization and debenzylation could only be effected in LiCl-containing THF (ca. 10% yield; with ca. 55% recovery). HPLC Purification provided a sample of the title compound 1, the structure of which, as determined by NMR-spectroscopy (Fig. 2, left) was drastically different from the 'theoretical' model (Fig. 1). There is a transannular H-bond dividing the macrocyclic 16-membered ring, thus forming a ten- and a twelve-membered H-bonded ring, the former mimicking, or actually being superimposable on, an α-peptidic so-called β-turn. Still, the four side chains occupy equatorial positions on the ring, as planned, albeit with somewhat different geometry as compared to the 'original'. The cyclo-β-tetrapeptide has micromolar affinities to the human somatostatin receptors (hsst 1-5). Thus, we have demonstrated for the first time that it is possible to mimic a natural peptide hormone with a small β-peptide. Furthermore, we have discovered a simple way to construct the ubiquitous β-turn motif with β-peptides (which are known to be stable to mammalian peptidases).
