A tricyclic template derived from (2S,4R)-4-hydroxyproline for the synthesis of protein loop mimetics

Article abstract of DOI:10.1002/hlca.19960790817

A tricyclic diketopiperazine, formally derived by coupling (2S,4S)-4-aminoproline (Pro(NH₂)) and (2S,4R)-4-(carboxymethyl)proline (Pro(CH₂COOH)), is synthesized starting from readily available (2S,4R)-4-hydroxyproline. The resulting tricyclic template has carboxy and amino groups to which a peptide chain may be attached. The Fmoc-protected template 5 is incorporated into the cyclic molecule cyclo(-Ala¹-Asn²-Pro³-Asn⁴-Ala⁵-Ala⁶ Pro(NH₂)⁷ = Pro(CH₂COOH)⁸ ) (6) where Pro(NH₂)⁷ = Pro(CH₂COOH)⁸ represents the template, using solid-phase peptide synthesis with cyclization in solution. The molecule is shown by NMR and dynamic simulated annealing methods to adopt a preferred conformation in aqueous solution, which includes an extended backbone at the residues Asn²-Pro³-Asn⁴, and a type-Iβ-turn at Asn⁴-Ala⁵-Ala⁶ Pro(NH₂)⁷. These studies show that this novel template may be used in the synthesis of cyclic peptide and protein mimetics having defined secondary structure in aqueous environments.