Extended retro‐inverso analogs of somatostatin

An extended retro‐inverso modification was introduced at the central six residues of the somatostatin molecule, the region of internal enzymatic degradations. The synthesis of the analog [Ala4,g‐Phe6‐r‐D‐Phe7‐r‐D‐Trp8‐r‐D‐Lys9‐r‐D‐Thr10‐m‐R,S‐Phe11]‐somatostatin required a unique strategy accommodating the unusual structure. Side‐chain protection based on the t‐butyl group in combination with Fmoc and Nps α‐amino protection was employed. The key component containing the gem‐diaminoalkyl residue was generated by an iodobenzene bistrifluoroacetate‐mediated reaction. The separation of diastereomers of the cyclic tetradecapeptide in highly pure form was accomplished by high‐performance liguid chromatography on a semipreparative scale. The analogs exhibited very low potency in the growth hormone inhibition test in vitro. This is interpreted as the consequence of the complex structural changes created by the extended retro‐inverso modification.