Synthesis and Characterization of Octapeptide Somatostatin Analogues with Backbone Cyclization: Comparison of Different Strategies,Biological Activities and Enzymatic Stabilities

Somatostatin octapeptide analogues of the general sequence DPhe⁵‐Phe ⁶‐Tyr⁷‐DTrp⁸‐Lys⁹‐Val¹⁰‐Ph ¹¹‐Thr¹²‐NH₂ containing two types of backbone cyclization have been synthesized by the solid phase methodology. Backbone cyclization in these peptides was achieved via N‐modified phenylalanines in position 6 and 11. The N‐modified amino acids were incorporated as dipeptide building units which have been prepared in solution prior to the solid phase synthesis. Two dipeptide units of structure a) Fmoc‐aa ₁ ψCO—N((CH₂)_n‐X)]Phe—OH or b) Fmoc‐aa₁ ψCH₂—N(COlpar;CH₂)_n‐X)]Phe—OH have been introduced into the peptide sequence. Different resins and linkers were examined for an optimized peptide assembly and monitoring. The synthesized somatostatin analogues are highly resistant against enzymatic degradation as determined in vitro by incubation with rat liver homogenate. The biological activity was determined in binding experiments to the somatostatin receptors expressed in CHO‐ or BON‐1 cells. Most analogues show moderate activity without differentiation between the receptor subtypes.