10.1021/ol202767k
The research explores the development of amino-triazolodiazepine (Ata) scaffolds as potential replacements for histidine residues in bioactive peptides. The study aims to validate the Ata moiety as a histidine mimic by incorporating it into the angiotensin IV (AT IV) peptide sequence and evaluating its biological activity through inhibitory enzyme assays. Two synthetic routes were employed to construct the Ata scaffolds: an intermolecular ruthenium-catalyzed cycloaddition followed by lactamization, and an intramolecular thermal Huisgen cycloaddition. Key chemicals used in the synthesis include Boc-protected serine, Fmoc-protected N-propargyl amine, and various N-propargyl substituted amino acid methyl esters. The intermolecular route was found to be more effective for synthesizing dipeptide mimetics, yielding higher overall yields and better enantiopurity compared to the intramolecular approach. The Ata-Gly dipeptidomimetic was successfully incorporated into the AT IV sequence, and the resulting analog demonstrated equipotency with the native peptide in inhibiting insulin regulated aminopeptidase (IRAP) and aminopeptidase-N (AP-N) activity. This study concludes that the Ata scaffold is a viable histidine mimic, offering potential for enhancing receptor selectivity, ligand potency, metabolic stability, and membrane permeation in peptide-based drug design.
