Fine‐Tuning the Proteolytic Stability of Peptides with Fluorinated Amino Acids

Abstract

The decoration of organic compounds with fluorine substituents is a strategy well‐known to medicinal chemists. Around 25 % of drugs on the market contain at least one fluorine atom, as fluorine's unique properties very often produce effects that cannot be achieved by any other known functional group. The changes in molecular properties due to the incorporation of fluorine most relevant to medicinal chemistry are conformation, pKa values of neighboring functional groups, and interaction with proteins and membranes. The introduction of fluorine dramatically impacts these and in turn the pharmacokinetics and biological half‐lives of not only small molecules but peptides, which show high binding affinity and selectivity for their target and are, therefore, also desirable lead compounds in drug development. Unfortunately, several factors can limit the efficacy of peptides and biologicals including low bioavailability and protease digestion. Although the literature has numerous examples showing that fluorine can improve the latter aspect, there are also cases to the contrary. This review aims to provide an overview of the influence of fluorinated amino acids on the proteolytic stability of peptides.

Anodic Fluorination and Cathodic Michael Addition of Schiff Bases Bearing Trifluoromethyl and Ester Groups

“…Cathodic Michael addition to acrylonitrile took place to give the corresponding adduct 4b in moderate yield (45 %) ( Table 5, run 9) while the use of acrylamide resulted in no formation of the expected adduct (run 10). In this case, the coresponding propanamide derived from 1a was detected in the crude product by 19 F NMR and MS spectra.…”

“…16 (Insert Schemes 1 and 2 here) Fluorinated α-amino acids are biologically interesting and highly useful since they have various bio-organic medicinal applications. [17][18][19][20] Although synthesis of side chain-fluorinated amino acids and fluorinated β-amino acids has been well established, synthetic methods of α-fluoro-α-amino acids have been underdeveloped so far.…”

“…by19 F NMR. b) By-product 5 (3 %) was detected by19 F NMR. c) Isolated yield is shown in parentheses.d) CF 3 CH 2 NHCHPh 2 was detected by19 F NMR (5.85 ppm (t, J = 9 Hz)) and MS spectra (m/e = 265 [M + ]) Anodic methoxylation and acetoxylation of trifluoroethyl sulfides, selenides and anilines Anodic acetoxylation of CF 3 -containing imine and imidate Synthesis and defluorination of an N-unprotected α-fluoro-α-amino acid Scheme Anodic fluorination of N-protected thiazoline and 1,3-oxazoline Scheme An attempt of anodic fluorination of N-protected glycine ethyl ester Synthesis of α-fluoro-α-amino acid derivatives via photoredox-catalyzed carbofluorination α-Fluoroglycine Schiff base as α-fluoroglycine ester equivalent Synthesis of a stable difluoroglycine derivative Scheme Generation of an anion α to a CF 3 group by using an electrogenerated base and α-alkylation…”

Synthesis of α-CF3-proline derivatives by means of a formal (3 + 2)-cyclisation between trifluoropyruvate imines and Michael acceptors

“…The synthesis of fluorine-containing α-amino acids became a heavily investigated topic over the last years. 1–3 The large interest in the hereby accessed fluorinated amino acids is based on the fact that the incorporation of fluorine-containing α- or β-amino acids into peptides and proteins heavily effects their (bio)-chemical and (bio)-physical properties. 3 One particularly appealing approach to alter the nature of biologically active molecules is the introduction of a trifluoromethyl group.…”

“…1–3 The large interest in the hereby accessed fluorinated amino acids is based on the fact that the incorporation of fluorine-containing α- or β-amino acids into peptides and proteins heavily effects their (bio)-chemical and (bio)-physical properties. 3 One particularly appealing approach to alter the nature of biologically active molecules is the introduction of a trifluoromethyl group. 4,5 A broad variety of different synthesis strategies to install either a single fluorine atom, or a polyfluorinated group have been developed in the past.…”