β²-Amino Acids in the Design of Conformationally Homogeneouscyclo-Peptide Scaffolds

Abstract

Herein, we report studies on the influence of chiral beta(2)-amino acids in the design of conformationally homogeneous cyclic tetrapeptide scaffolds. The cyclic alpha-tetrapeptide cyclo(-Phe-D-Pro-Lys-Phe-) (1) and its four mixed analogues, having one of the alpha-Phe replaced by either an (S)- or an (R)-beta(2)hPhe residue (i.e., cyclo(-(R)-beta(2)hPhe-D-Pro-Lys-Phe) (2a), cyclo(-(S)-beta(2)hPhe-D-Pro-Lys-Phe-) (2b), cyclo(-Phe-D-Pro-Lys-(R)-beta(2)hPhe-) (3a), and cyclo(-Phe-D-Pro-Lys-(R)-beta(2)hPhe-) (3b)), were all synthesized through solid-phase procedures followed by solution-phase cyclization. Initially, all five cyclo-peptides were analyzed by (1)H NMR spectroscopic studies in different solvents and at variable temperatures. Subsequently, a detailed 2D NMR spectroscopic analysis of three of the mixed peptides in water was performed, and the information thus extracted was used as restraints in a computational study on the peptides' conformational preference. An X-ray crystallographic study on the side chain-protected (Boc) 2a revealed the solid-state structure of this peptide. The results presented herein, together with previous literature data on beta(3)-amino acid residues, conclusively demonstrate the potential of beta-amino acids in the design of conformationally homogeneous cyclic peptides that are homologous to peptides with known applications in biomedicinal chemistry and as molecular receptors.

Ring size in cyclic endomorphin-2 analogs modulates receptor binding affinity and selectivity

“…Indeed, 4 contains two β-amino acid residues, Asp and Dap, and it has been demonstrated that the presence of β-residues in cyclotetrapeptides and cyclopentapeptides tends to favor the formation of the well-defined γ-or β-turn structures in opposite regions of the cyclic structure. [32][33][34] As for cyclopeptide 5, which has the same sequence as 1 deprived of one Phe residue, the analysis of the trajectories of MD showed a strong tendency to give a β-turn centered on Phe-Asp, with an H-bond between the CvO of D-Lys and D-LysNHε (Fig. 2).…”

Cyclization-activated Prodrugs

“…Intramolecular cyclization has been demonstrated to improve biological properties of bioactive peptides [28][29][30][31][32][33][34][35][36][37][38], in many cases allowing one to improve selectivity for a given receptor and/or metabolic stability [39][40][41]. Cyclic peptides can be divided into homodetic and heterodetic, the first being obtained by formation of an intramolecular peptide (amide) bond, whereas heterodetic refers to all cyclic peptides where the intramolecular bond newly formed is other than an amide (e.g., lactone, ether, thioether and, most commonly, disulphide bridges).…”

Discovery of Potent and Selective Histone Deacetylase Inhibitors via Focused Combinatorial Libraries of Cyclic α3β-Tetrapeptides

“…Numerous analogs of these natural compounds have been investigated as well 52–63. For the medicinal chemist, cyclic tetrapeptides built from all α-amino acids often present significant challenges as drug targets due to poor macrolactamization yields for closing the 12-membered ring and multiple three-dimensional conformations on the NMR time scale 64–66. We were recently able to minimize these shortcomings by developing synthetic HDAC inhibitor scaffolds ( 3 , Figure 1) that have an α→ β -amino acid substitution in the backbone to give a 13-membered ring 67.…”