Synthesis, biological activities and conformational studies of somatostatin analogs

We review our recent studies on synthesis conformational analysis and biolo gical 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 cycl ic 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 comp ounds 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 s omatostatin) with Xaa=Phe or Nal, Xcc=Phe or Nal and Nxbb=Nphe (N-benzylgly cine), (R)-beta -MeNphe ([N-(R)alpha -methylbenzyl] glycine), (S)-beta -MeN phe ([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=al lo-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 residu es in positions 10 and 12. These changes enabled us to investigate the infl uence of the stereochemistry within these residues on conformation and bind ing affinity. The compounds with (S)-configuration at the C-alpha of residu e 10 exhibit binding to the hsst receptors and adopt conformations containi ng a type II' beta -turn spanning residues D-Trp and Lys while those compou nds with (R)-configuration at the C-alpha of residue 10 are inactive and ad opt different backbone conformations. (C) 2000 Elsevier Science Ltd. All ri ghts reserved.