Synthesis of Nonreducible Bicyclic Analogues of Somatostatin

Article abstract of DOI:10.1021/ja00541a025

The bis-carba analogues (Ib and Ic) of cyclo-(formula) (Ia) and cyclo-(formula) were prepared by a combination of solid-phase and solution peptide synthesis methods.Tactics involving three types of amino-protecting groups and two types of carboxyl protection were applied.The 20-membered ring portion formed in high yield under standard peptide cyclization conditions, using the azide method.The 16-membered ring portion formed well only with catalysis of the azide acylation reaction by N-hydroxybenzotriazole.The analogues are more resistant to hydrolysis catalyzed by trypsin but do not show increased duration of action for inhibition of growth hormone release relative to the disulfide.Disulfide reduction in vivo does not appear to be the rate-limiting step for inactivation of the sulfur containing bicyclic somatostin analogues.