A Multicomponent Conjugation Strategy to Unique N-Steroidal Peptides: First Evidence of the Steroidal Nucleus as a β-Turn Inducer in Acyclic Peptides

• Published in: Chemistry : a European journal 2014-10, Vol.20 (41), p.13150-13161
• Main Authors: Rivera, Daniel G., Vasco, Aldrin V., Echemendía, Radell, Concepción, Odette, Pérez, Carlos. S., Gavín, José A., Wessjohann, Ludger A.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino acids; Conjugation; Cyclization; Derivatives; Inducers; Isomerism; macrocycles; Magnetic Resonance Spectroscopy; Molecular Conformation; multicomponent reactions; Peptides; Peptides - chemistry; Protein Structure, Secondary; Steroids; Steroids - chemistry; Strategy; Three dimensional
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201403773

Constraining small peptides into specific secondary structures has been a major challenge in peptide ligand design. So far, the major solution for decreasing the conformational flexibility in small peptides has been cyclization. An alternative is the use of topological templates, which are able to induce and/or stabilize peptide secondary structures by means of covalent attachment to the peptide. Herein a multicomponent strategy and structural analysis of a new type of peptidosteroid architecture having the steroid as N‐substituent of an internal amide bond is reported. The approach comprises the one‐pot conjugation of two peptide chains (or amino acid derivatives) to aminosteroids by means of the Ugi reaction to give a unique family of N‐steroidal peptides. The conjugation efficiency of a variety of peptide sequences and steroidal amines, as well as their consecutive head‐to‐tail cyclization to produce chimeric cyclopeptide–steroid conjugates, that is, macrocyclic lipopeptides, was assessed. Determination of the three‐dimensional structure of an acyclic N‐steroidal peptide in solution proved that the bulky, rigid steroidal template is capable of both increasing significantly the conformational rigidity, even in a peptide sequence as short as five amino acid residues, and inducing a β‐turn secondary structure even in the all‐s‐trans isomer. This report provides the first evidence of the steroid skeleton as β‐turn inducer in linear peptide sequences. Size matters: When located as an internal N‐substituent of a short peptide, the bulky steroid skeleton is capable of folding back a peptide chain to form a β‐turn (see figure), even in the all‐s‐trans structure. Such unique N‐steroidal peptides can be synthesized by a one‐pot procedure based on the Ugi four‐component reaction (Ugi‐4CR) and subsequently cyclized to give cyclopeptide–steroid chimeras.