Peptides & Foldamers

Cycloalkane and azacycloalkane β- and g-amino acids

The development of new methodologies for the asymmetric synthesis of β-amino acids is of immense current synthetic interest, primarily as β-amino acids occur as fragments within peptidic natural products with potent biological activity and mainly because β-amino acids have been used for the generation of pseudo peptide sequences with highly ordered secondary and tertiary structures. Moreover, these systems are more resistant than a-peptides to microorganisms and to protease and peptidase degradation and their conformational stability facilitates their interaction with receptors and enzymes.

Among the plethora of β-amino acids, 2-aminocyclopentanecarbxylic acids (ACPC) and 2-aminocyclohexanecarboxylic acids (ACHC) are particularly attractive because their b-peptides exhibit specific folding properties and their homooligomers show a high tendency to fold in very rigid secondary structures in short peptide sequences (ACPC fold as 12-helix and ACHC fold as 14-helix) and structural properties that often gives them enhanced biostability and activity.

We are now strongly embarqued on studies in the following aspect of this field.

• Hybrid cycloalkane-based b-peptides.

In the search of possibilities offered by β-peptides based on ACPC and ACHC we have recently established that the folding properties of β-peptides are influenced not only by their intrinsic structural properties but also by the medium. In fact, it was found that the hybrid β-peptide I (n=3) shows a random coil structure in solution but it can be forced to fold as a 14-helix in a micellar medium, as displayed in the following figure:

Our finding that the solvent can have a cooperative effect on the folding of β-peptides opens opportunities for increasing the structural diversity in cycloalkane-based β-peptides, a fact of evident interest for new applications in biology and in molecular materials. It encouraged us to start a robust study of this kind of hybrid peptides. We are now involved in the solid phase synthesis of β-peptides II and studies similar to those carried out with peptides I. ´Specifically we hope to establish the structural factor that govern the folding of this kind of hybrid peptides.

A second class of hybrid cycloalkane-based b-peptides we are interested in are peptides incorporating polyhydroxylated cycloalkane b-amino acids. Our interest in this unexplored field is related to preliminary molecular modeling studies carried out in our research groups. Specifically, it was found that peptide III, an octamer of polysubstituted cyclopentane b-aminoacid, folds in a very stable 12-helix where the substituents are disposed at the external face, exposed to interactions with solvents. This suggested that polyhydroxylated cycloalkane b-amino acids could provide access to lipo- and hydrosoluble b-peptides, depending on the protection or deprotection of the hydroxy substituents.

According to this theoric prediction, we started a program on polyhydroxylated cycloalkane b-peptides that first required the development of synthetic methodology for the preparation of these structurally complex b-amino acids. Thus, we have developed several approaches for the synthesis of polyhydroxylated cyclopentane b-amino acids from sugars, as a preliminary step for access to their b-peptides.  But our present efforts are directed to the study of peptides of (-)-shikimic acid-based b-amino acids, because they are more accessible, due to the convenient structural properties of (-)-shikimic acid that combines a preformed cyclohexane ring with three hydroxy substituents with a precise spatial orientation and a b-unsaturated carboxylic acid moiety able for the generation of the amino acid moiety of our b-amino acid targets by Michael addition of properly amines.