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Probing the Proteolytic Stability of β‐Peptides Containing α‐Fluoro‐ and α‐Hydroxy‐β‐Amino Acids
Author(s) -
Hook David F.,
Gessier François,
Noti Christian,
Kast Peter,
Seebach Dieter
Publication year - 2004
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200300827
Subject(s) - amino acid , steric effects , chemistry , proteolysis , residue (chemistry) , stereochemistry , enantiopure drug , peptide , peptide bond , proteolytic enzymes , amide , side chain , peptidomimetic , enzyme , combinatorial chemistry , biochemistry , organic chemistry , polymer , enantioselective synthesis , catalysis
Abstract One of the benefits of β‐peptides as potential candidates for biological applications is their stability against common peptidases. Attempts have been made to rationalize this stability by altering the electron availability of a given amide carbonyl bond through the introduction of polar substituents at the α‐position of a single β ‐amino acid. Such β‐amino acids (β‐homoglycine, β‐homoalanine), containing one or two fluorine atoms or a hydroxy group in the α‐position, were prepared in enantiopure form. A versatile method for preparing these α‐fluoro‐β‐amino acids by the homologation of appropriate α‐amino acids and C‐OH → C‐F or CO → CF 2 substitution with DAST, is described. Consequently, a series of β‐peptides possessing an electronically modified residue at the N terminus or embedded within the chain was synthesized, and their proteolytic stability was investigated against a selection of enzymes. All ten β‐peptides tested were resilient to proteolysis. Introducing a polar, sterically undemanding group, into the α‐position of β‐amino acids in a β‐peptide chain does not appear to facilitate localized or general enzymatic degradation.