Impact of β-perfluoroalkyl substitution of proline on the proteolytic stability of its peptide derivatives.

A series of all stereoisomers of β-CF 3 or β-C 2 F 5 substituted prolines and their dipeptide derivatives were synthesized. Mouse plasma stability assay was carried out to study the impact of fluoroalkyl substituents on the proteolytic stability of proline-derived peptides. The effect of the ( R )-/( S )-configuration at the C-2 atom in combination with electronic and steric effects imposed by fluoroalkyl groups was addressed to rationalize the difference in the half-life stability of diastereomeric β-CF 3 -Pro-Gly and β-C 2 F 5 -Pro-Gly derivatives and compared to those of parent ( S )-Pro-Gly and ( R )-Pro-Gly dipeptides. The steric effect was predominant when the β-CF 3 or β-C 2 F 5 group was placed properly to create a spatial interference within the pockets of proteases, thereby protecting the substances from degradation ( e.g. , for cis -isomeric derivatives). Otherwise, a smaller electronic effect accelerating proteolysis was in charge ( i.e. , for the (2 S ,3 S ) isomers).