Synthesis and Conformational Studies of Peptidomimetics Containing a New Bifunctional Diketopiperazine Scaffold Acting as a β-Hairpin Inducer

• Published in: Journal of organic chemistry Vol. 73; no. 2; pp. 652 - 660
• Main Authors: Ressurreição, Ana Sofia M, Bordessa, Andrea, Civera, Monica, Belvisi, Laura, Gennari, Cesare, Piarulli, Umberto
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 18.01.2008; Amer Chemical Soc
• Subjects: Biomimetics - methods; Chemistry; Chemistry, Organic; Computer Simulation; Crystallography, X-Ray; Cyclization; Diketopiperazines - chemical synthesis; Diketopiperazines - chemistry; Exact sciences and technology; Hydrogen Bonding; Magnetic Resonance Spectroscopy - methods; Magnetic Resonance Spectroscopy - standards; Models, Chemical; Models, Molecular; Molecular Conformation; Organic chemistry; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Physical Sciences; Preparations and properties; Reference Standards; Science & Technology; Stereoisomerism; TURNS; DESIGN; SOLID-PHASE SYNTHESIS; HYDROGEN-BOND; AMINO-ACIDS; SECONDARY STRUCTURES; TEMPLATE; RECEPTORS; BINDING; PEPTIDE; Chemical solution; Hairpin loop; Cyclic peptides; Peptidomimetic compound; Conformational analysis; Bifunctional compound; NMR spectrometry; Peptide chain; Diketone; Modeling; Hydrogen 1; Infrared spectrometry; α-Aminoacid; Amine; Cyclization; Carboxylic acid; Aminoacid; Circular dichroism spectrometry; Dipeptides; Aspartic acid; Peptide synthesis; Chemical synthesis; Hydrogen bond
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo702072z

A practical synthesis of a new bifunctional diketopiperazine (DKP) scaffold 1, formally derived from the cyclization of l-aspartic acid and (S)-2,3-diaminopropionic acid, is reported. DKP-1 bears a carboxylic acid and an amino functionalities in a cis relationship, which have been used to grow peptide sequences. Tetra-, penta-, and hexapeptidomimetic sequences were prepared by solution-phase peptide synthesis (Boc strategy). Conformational analysis of these derivatives was carried out by a combination of 1H NMR spectroscopy, IR spectroscopy, CD spectroscopy, and computer modeling, and reveals the formation of β-hairpin mimics involving 10-membered and 18-membered H-bonded rings and a reverse turn of the growing peptide chain.