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Design and syntheses of nonnatural amino acids and their incorporation into somatostatin and RGD analogs


The peptide hormone somatostatin has been the focus of ongoing research in our laboratories. In an effort to constrain the tetrapeptide pharmacophore of somatostatin in a rigid type II' beta-turn, we synthesized the 4,6- substituted dibenzofuran amino acid, 4-(2-aminoethyl)-6-(2 -carboxyethyl)-dibenzofuran (DBFaa). Two sets of dipeptides, Z-Lys(Boc)-Thr(t-But)-OH and H-Phe-D-Trp(Boc)- OMe, and Z-Lys(Boc)-Val-OH and H-Tyr(t-But)-D-Trp(Boc)-OMe were synthesized and then coupled to the dibenzofuran amino acid scaffold to provide c[Phe-D-Trp-Lys-Thr-DBFaa] and c[Tyr-D-Trp-Lys-Val-DBFaa]. 2D-NMR spectroscopy of both compounds provided ROEs which supported the presence of a type II' beta-turn spanning the D-Trp-Lys residues. The binding affinities of both scaffolded somatostatin analogs were evaluated for potency and selectivity for each subtype of the hsst receptors in binding assays. Neither compound showed any affinity for hsst1 or hsst4. The c[Phe-D-Trp-Lys-Thr-DBFaa] compound was slightly selective for hsst2 (2 [mu]M) over hsst3 (4.2 [mu]M) and hsst5 (3.5 [mu]M). The c[Tyr-D-Trp-Lys-Val-DBFaa] analog did not display any affinity for hsst5, but was selective for hsst2 (2.2 [mu]M) over hsst3 (5.5 [mu][M). In an effort to incorporate analogs of naturally occurring tryptophan into somatostatin compounds, we designed and synthesized eight unnatural nitrogen-containing, fused 5,6 -heterocyclic, aromatic alpha-amino acids. The target compounds include Z-D-1H-benzimidazole-yl alanine, Z-D-1H- and Z-D-2H-benzotriazole-yl alanine, Z-D-1H-indazole-yl alanine, Z-D-9H- and Z-D-7H-purine-yl alanine, and Z-D-3H- and Z-D-1H-(4-azabenzimidazole-yl) alanine. The key step of the syntheses of the amino acids involved the nucleophilic displacement of the tosylate of Garner's alcohol, which enabled us obtain the desired D-amino acids in good yields. Three of the amino acids, Z-D-1H- benzimidazole-yl alanine, Z-D-1H-benzotriazole-yl alanine, and Z-D-1H-indazole-yl alanine were incorporated into the pentapeptide, H-Lys(Boc)-Thr(t-But)-Phe-Pro-Phe, cyclized, and were obtained cleanly and in good yields. Another area of research in our laboratories involved the synthesis of RGD-containing integrin ligands. We designed and synthesized a family of unnatural thioether amino acids; Fmoc-S-(t-butoxycarbonylmethyl)-cysteine, Fmoc-S-(t- butoxycarbonylethyl)-cysteine, Fmoc-S-(t- butoxycarbonylmethyl)-homocysteine, and Fmoc-S-(t- butoxycarbonylethyl)-homocysteine. These compounds were designed to replace the mercaptopropionic acid-cysteine disulfide bridge of the integrin alpha v beta 3-specific compound c[(Mpa)RGDD(tBuG)C]-NH2. The syntheses of the thioether building blocks were scalable and produced the desired products in good yields. Of the series, the peptide c[NH-Arg-Gly-Asp-Asp-(tBuG)-(S-Ac-C)]-NH2 demonstrated potent affinity for the [beta]3 and [alpha]5[beta]1 receptors while having reduced affinity for integrin [alpha]IIb[beta]3

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