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 DPhe(5)-Phe(6)-T yr(7)-DTrp(8)-Lys(9)-Val(10)-Phe(11)-Thr(12)-NH2 containing two types of ba ckbone cyclization have been synthesized by the solid phase methodology. Ba ckbone cyclization in these peptides was achieved via N-modified phenylalan ines 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) psi [ CO-N((CH2)(n)- X)]Phe-OH or b) Fmoc-aa(1) psi [CH2-N(CO(CH2)(n)-X)]Phe-OH h ave been introduced into the peptide sequence. Different resins and linkers were examined for an optimized peptide assembly and monitoring. The synthe sized somatostatin analogues are highly resistant against enzymatic degrada tion as determined in vitro by incubation with rat liver homogenate. The bi ological activity was determined in binding experiments to the somatostatin receptors expressed in CHO- or BON-1 cells. Most analogues show moderate a ctivity without differentiation between the receptor subtypes.