SSTR1‐ and SSTR3‐Selective Somatostatin Analogues

Abstract

We prepared the two enantiomers of 3-(3'-quinolyl)-alanine (Qla, 1) in multigram scale by asymmetric hydrogenation. These amino acids, protected as Fmoc derivatives, were then used in the solid-phase synthesis of two new somatostatin 14 (SRIF-14) analogues 8 a and 8 b, tetradecapeptides in which the tryptophan residue (Trp8) is replaced by one of the two enantiomers of 3-(3'-quinolyl)-alanine (Qla8) and therefore lack the N--H bond in residue 8. The selectivity of these new analogues for the somatostatin receptors, SSTR1-5, was measured. Substitution with L-Qla8 yielded peptide 8 a, which was highly selective for SSTR1 and SSTR3, with an affinity similar to that of SRIF-14. Substitution by D-Qla gave the relatively selective analogue 8 b, which showed high affinity for SSTR3 and significant affinity for SSTR1, SSTR2 and SSTR5. The biological results demonstrate that bulky and electronically poor aromatic amino acids at position 8 are compatible with strong activity with SSTR1 and SSTR3. Remarkably, these high affinity levels were achieved with peptides in which the conformational mobility was increased with respect to that of SRIF-14. This observation suggests that conformational rigidity is not required, and might be detrimental to the interaction with receptors SSTR1 and SSTR3. The absence of an indole N proton in Qla8 might also contribute to the increased flexibility observed in these analogues.

Peptide Receptor Targeting in Cancer: The Somatostatin Paradigm

“…Although less-represented sst3 agonists and antagonists have been also synthesized: BIM-23056 is a sst3 agonist with antagonist activity for sst5, analogs with replacement of the tryptophan residue by one of the two enantiomers of 3-(3′-quinolyl)-alanine binds sst1 and 3 [82], while BN81658, is a selective sst3 antagonist [83]. …”

Fine‐tuning the π–π Aromatic Interactions in Peptides: Somatostatin Analogues Containing Mesityl Alanine

“…[*] P. Martín-Gago, Dr. R. Ramón Given recent advances in peptide chemistry which have greatly facilitated synthesis of large cyclic peptides, we reasoned that we could introduce point modifications into the 14-residue scaffold to fine-tune rigidity, specificity, and stability to produce new analogues that are structurally much closer to the natural hormone than the octapeptides. In previous studies, [16] we explored the substitution of Trp8 with 3-(3'-quinolyl) alanine (Qla, both enantiomers), and found that the corresponding analogues exhibit more conformational variability than does somatostatin itself. Remarkably, these analogues were selective for SSTR1 and SSTR3 receptors.…”

MaxPHOS Ligand: PH/NH Tautomerism and Rhodium‐ Catalyzed Asymmetric Hydrogenations

“…In some cases, for these substrates, switching the solvent from MeOH to THF enhanced reaction selectivity (Table 3, entry 9). Finally, hydrogenation of dehydroamino acid substrate containing a 3′‐quinolyl side chain proceeded with complete selectivity (Table 3, entry 13) 21…”