Synthesis, biological activities and conformational studies of somatostatin analogs

We review our recent studies on synthesis conformational analysis and biological activity of a series of analogs of the cyclic hexapeptide L-363,301 c-[Phe(11)-Pro(6)-Phe(7)-D-Trp(8)-Lys(9)-Thr(10)] and of analogs of the cyclic octapeptide D-Phe(5)-c[Cys(6)-Phe(7)-D-Trp(8)-Lys(9)-Thr(10)Cys(11)]-Thr(12)-ol (sandostatin(R), octreotide). The proline residue in L-363,301 was substituted with N-alkylated glycine residues resulting in a series of compounds with the general structure c-[Xaa(11)-Nxbb(6)-Xcc(7)-D-Trp(8)-Lys(9)-Thr(10)] (the numbering refers to the positions of the residues in native somatostatin) with Xaa=Phe or Nal, Xcc=Phe or Nal and Nxbb=Nphe (N-benzylglycine), (R)-beta -MeNphe ([N-(R)alpha -methylbenzyl] glycine), (S)-beta -MeNphe ([N-(S)alpha -methylbenzyl]glycine), Nnal [N-(naphthylmethyl)glycine], Nasp [N-(2-carboxyethyl)glycine], Nlys [N-(4-aminobutyl)glycine], Ndab [N-(2-aminoethyl)glycine]. These compounds were used to investigate the effect of different substitutions within the bridging region of L-363,301 and our studies resulted in compounds that exhibit increased selectivity toward the hsst2 receptor compared to the parent compound. The sandostatin analogs D-Phe(5)-c[Cys(6)-Phe(7)-D-Trp(8)-Lys(9)-Thr(10)-Cys(11)]-Thr(12)-NH2 (Xaa=allo-Thr, D-allo-Thr, D-beta Hyv (D-beta -hydroxyvaline), L-beta Hyv (L-beta -hydroxyvaline), D-Thr and Xbb=Thr or Xaa=Thr and Xbb=allo-Thr, D-allo-Thr, L-beta Hyv, D-Thr) contain subtle stereochemical changes in the Thr residues in positions 10 and 12. These changes enabled us to investigate the influence of the stereochemistry within these residues on conformation and binding affinity. The compounds with (S)-configuration at the C-alpha of residue 10 exhibit binding to the hsst receptors and adopt conformations containing a type II' beta -turn spanning residues D-Trp and Lys while those compounds with (R)-configuration at the C-alpha of residue 10 are inactive and adopt different backbone conformations. (C) 2000 Elsevier Science Ltd. All rights reserved.