Synthesis of highly functionalized alkene dipeptide isosteres and its application to the structure-activity relationship study on bioactive peptides

Abstract

Peptide bonds are one of the essential contributors to overall structure and functions of bioactive peptides. The partial double-bond character derived from the resonance structure restricts the free rotation of the carbon-nitrogen bond and stabilizes the planar conformations. Additionally, the ability to form hydrogen bonds allows the stabilization of characteristic secondary structures such as α-helix and β-turn as well as the association with the receptors. Alkene dipeptide isosteres, based on the concept of ω-dihedral angle planarity, have been used as amide bond equivalents, which serve as mechanistic probes lacking amide polarity. We have developed a facile methodology for the stereoselective synthesis of highly functional dipeptide isosteres. The key reaction is the alkylation of δ-aminated α, β-enoates having an appropriate leaving group at the γposition. Organocopper-mediated anti-SN2' alkylation of α, β-enoates afforded multi-substituted olefin-containing isosteres. One-pot reduction-transmetalation-alkylation of γ, γ difluoro-α, β-enoates provided fluoroalkene dipeptide isosteres. Reduction of these substrates with organocuprate, SmI2, or Pd/PhSiH3/Et 3N system gave Xaa-Gly-type mimetics. Similar methods were also utilized for the preparation of cis-peptide bond mimetics. The resulting isosteres and the key intermediates were studied in structure-activity relationship of bioactive peptides including integrin αvβ3 antagonist, chemokine receptor CXCR 4 antagonist, puberty-related GPR 54 agonist, and peptide transporter PEPT 1 substrate.