Conformationally homogeneous cyclic tetrapeptides: Useful new three-dimensional scaffolds

The most commonly recognized motifs in protein-protein interactions are γ and β turns, which are defined by three to four contiguous amino acids in a peptide sequence. Cyclic tetrapeptides thus represent minimalist turn mimetics, but their usefulness is compromised by strain in their 12-membered rings, making them difficult to cyclize, unstable to hydrolysis/metabolism, and conformationally heterogeneous in polar solvents. Appropriate placement of a β amino acid in a tetrapeptide creates a 13-membered ring that is shown to be easier to cyclize, hydrolytically more stable, and conformationally homogeneous in polar solvents such as DMSO and water. Three-dimensional structures reveal that these cyclic tetrapeptides are novel rigid scaffolds, their unique side-chain projections matching a structurally diverse range of useful nonpeptidic templates, including sugars and spirocyclic compounds, found as components of natural products. The results provide a potentially useful link between protein architecture and organic natural products. On the basis of protein turn sequences (not protein structures) alone simple cyclic tetrapeptide libraries with a β amino acid can be rationally designed as conformationally restricted, easily synthesized, and stereochemically controlled screening tools for rapidly identifying pharmacophore space that can then be computer-matched to more complex known natural product templates for drug development

Synthesis of Difficult Cyclic Peptides by Inclusion of a Novel Photolabile Auxiliary in a Ring Contraction Strategy

Cyclic peptides comprise a large and important class of biologically active molecules. They are generally synthesized through amide bond-forming reactions of the C- and N- termini under high dilution conditions. Yields of such processes are highly dependent on the size of the ring being formed and on the particular amino acids of the linear precursor, giving rise to the well-known sequence-dependent effect of cyclization. To overcome this problem, we have developed a peptide cyclization strategy that proceeds through a ring closure/ring contraction process. The linear peptide Ala-Phe-Leu-Pro-Ala, which does not generate monocyclic product under conventional cyclization conditions, was used as a model to probe a range of auxiliaries. This has led to the development of a new photolabile peptide cyclization auxiliary. The 6-nitro-2-hydroxybenzyl group is readily and quantitatively introduced at the N-terminus via a reductive alkylation. Cyclization of the auxiliary-peptide initially proceeds through a cyclic nitrophenyl ester that preorganizes the peptide for lactamization. As the C- and N- termini are in close proximity, lactamization is achieved via an intramolecular O-N acyl transfer step to produce the N-substituted target cycle. The auxiliary is then removed by mild photolysis to produce the target cyclic peptide, cyclo-[Ala-Phe-Leu-Pro-Ala], in good yield. This strategy should find further useful applications in the assembly of libraries of small cyclic peptides

Synthesis of All- L cyclic tetrapeptides using pseudoprolines as removable turn inducers

(Figure Presented) Cyclic tetrapeptides have generated great interest because of their broad-ranging biological properties. In order to synthesize these highly strained 12-membered cyclic compounds, a cyclization strategy using pseudoprolines as removable turn inducers has been developed. The pseudoproline derivatives induce a cisoid amide bond in the linear peptide backbone which facilitates cyclization. After cyclization, the turn inducers can be readily removed to afford cyclic tetrapeptides containing serine or threonine residues