Impact of β-perfluoroalkyl substitution of proline on the proteolytic stability of its peptide derivatives. Issue 47 (15th September 2022)

• Record Type: Journal Article
• Authors: Chernykh, Anton V.; Aloshyn, Danylo; Kuchkovska, Yuliya O.; Daniliuc, Constantin G.; Tolmachova, Nataliya A.; Kondratov, Ivan S.; Zozulya, Sergey; Grygorenko, Oleksandr O.; Haufe, Günter
• Is Part Of: Organic & biomolecular chemistry. Volume 20:Issue 47(2022)
• Page Start: 9337
• Page End: 9350
• Publication Date: 2022-09-15
• Subjects: Chemistry, Organic -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1039/d2ob01430k
• Languages: English
• ISSNs: 1477-0520

Abstract

Abstract : The synthesis of all enantiopure N -Boc-protected β-CF3 - and β-C2 F5 -prolines and the stability of their model dipeptide derivatives towards proteolytic degradation are reported. Abstract : A series of all stereoisomers of β-CF3 or β-C2 F5 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-CF3 –Pro–Gly and β-C2 F5 –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-CF3 or β-C2 F5 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).