Synthesis and Pharmacological Evaluation of an Analogue of the Peptide Hormone Oxytocin That Contains a Mimetic of an Inverse γ-Turn

Abstract

Oxytocin is a neurohypophyseal peptide hormone that induces labor and lactation in mammals. An inverse gamma-turn mimetic corresponding to the tripeptide Ile-Val-Asn has been synthesized and incorporated instead of residues 3-5 of oxytocin to probe the hypothesis that a gamma-turn involving these residues is found in the receptor bound conformation of oxytocin. In the turn mimetic, residues i and i + 1 are connected by a psi[CH(2)O] isostere while a covalent methylene bridge replaces the hydrogen bond that is often found between residues i and i + 2 in gamma-turns. The turn mimetic was assembled from three types of building blocks: an azido epoxide, an alpha-bromo acid, and a protected beta-amino alcohol. The oxytocin analogue did not induce contractions of the uterus nor did it inhibit oxytocin-induced contractions. It is suggested that the loss of bioactivity is mainly due to the presence of a psi[CH(2)O] isostere instead of an amide bond between residues i and i + 1 in the turn mimetic.

Synthesis and Screening of Stereochemically Diverse Combinatorial Libraries of Peptide Tertiary Amides

“…While the use of this reagent can be problematic in peptide synthesis due to racemization at the α-carbon, this was not anticipated to be an issue in PTA synthesis via the sub-monomer route because amino acid racemization involves formation of an intermediate oxazalone that cannot form in this class of molecules (Goodman and Levine, 1964; Yuan et al, 2002). To confirm this, R and S bromopropionic acid were condensed with a chiral amine ((S)-(−)-1-Phenylethylamine) under these conditions.…”

crystal structure analyses of azasulfuryltripeptides reveal potential for γ‐turn mimicry†

“…Stabilization of the γ–turn geometry appears to arise from the combination of lone pair‐lone pair repulsion between the adjacent nitrogen of the hydrazine, and the conformational preferences of the sulfamide . In contrast to γ–mimics based on covalent constraint, to the best of our knowledge, the azasulfuryltripeptides presented herein represent the first examples of stabilization of a γ–turn conformation by electronic interactions of neighboring heteroatoms. Of particular note, introduction of azasulfurylglycine for glycine in the Pro‐Gly motif altered the commonly preferred type II β–turn geometry in favor of a γ–turn conformation.…”

“…Furthermore, they were found to adopt dihedral angles about the aminosulfamide residue that were similar to the central amino acid in a γ‐turn secondary structure. γ–Turn conformations have been recognized to be important for the biological activity of various peptides, particularly ligands of G‐protein‐coupled receptors . In spite of their importance in various recognition events, relatively few examples of γ–turn mimics have been reported; most involving conformational constraint by structural linkages such as benzodiazepine, pyrrolodiazepine, diazepine, morpholin‐3‐one, 4‐aminoproline, 2‐alkyl‐2‐carboxyazetidine, 4‐alkyamino‐3‐cyano‐azabicyclo[3.2.1.…”

Peptidomimetics and their Applications in Antifungal Drug Design

“…Some examples from the vast literature [86] in the field are peptidomimetics of vasopressin [99], oxytocin [100], LHRH [101], somatostatin and angiotensin II [102,103]. Type-III mimetics represent the idyllic peptidomimetics in that they possess novel templates which, though appearing unrelated to the original peptides, contain the necessary groups positioned on a novel nonpeptide scaffold to serve as topographical mimetics [104,105].…”