Methyl- and (Trifluoromethyl)alkene Peptide Isosteres:  Synthesis and Evaluation of Their Potential as β-Turn Promoters and Peptide Mimetics

Abstract

Despite the promise of amide bond isosteres for improving the resistance toward degradation by exoproteases by several orders of magnitude, the use of nonhydrolyzable substitutes for the amide group has often led to disappointing decreases in biological activity. 1 The frequent lack of success with ground-state amide bond mimetics stands in contrast to the very promising use of hydroxyethylene protease inhibitors as mimics of the tetrahedral intermediate in amide bond hydrolysis. 2 Nonetheless, the development of effective amide bond isosteres holds considerable promise as a stepping stone toward the rational design of small molecule analogues of bioactive oligo-and polypeptides. Analogues such as thiomethylene and aminomethylene isosteres, however, exchange the conformationally restricted amide function with highly flexible single bonds. Disubstituted (E)-alkene isosteres 1 provide a better fit for the C i -(R)-C i+1 (R) distance (3.8 Å) but are inadequate mimetics of the electrostatic potential surface as well as the backbone φ,ψ-dihedral angles. Gellman and co-workers designed the tetrasubstituted (E)-alkene Gly-Gly dipeptide mimetic 2 to induce conformational rigidification and promote -hairpin formation. 3 More recently, Hoffman and co-workers reported the use of gauche pentane interactions for the design of -hairpin analogue 3. 4 We were interested in exploring the use of trisubstituted (E)-alkene isosteres such as 4 as -turn mimetics. A combination of A 1,3 -and A 1,2 -strain leads to considerable restrictions in φ,ψ-dihedral angles in these substrates, and the Ramachandran plot of the methylalkene isostere of alanine is closely related to the parent amino acid. 5 In contrast, the disubstituted (E)-alkene analogue is conformationally much more flexible. Even greater steric restrictions are observed for a trifluoromethylated derivative 5 where only ca. 15% of the Ramachandran plot area remains within 15 kJ/mol of the energy minimum. Methylalkene moieties are abundant in terpenes and polypropionate natural products and have indeed been shown to serve as surrogates of backbone amide functions in enzymeinhibitor complexes. 6The mimicry of the electronic properties of the amide bond represents perhaps the most challenging parameter for effective isostere design. Electrostatically, the (trifluoromethyl)alkene represents a better match of the amide bond than any other common alkene isostere ( Figure 1).Efficient synthetic approaches toward diastereomerically and enantiomerically pure alkene peptide isosteres are under intense investigation. 8 A particularly promising convergent pathway utilizes the S N 2′-addition of cuprate reagents to alkenyl aziridines and allylic mesylates. 9 The former approach has also been applied to solid-phase synthesis. 10 We have now extended these methods toward a general synthesis of methyl-and (trifluoromethyl)alkene isosteres and, for the first time, systematically compared the solid state conformations of these peptide mimetics.Swern oxidation of the epoxy alcohol 6, obtained in...

Evaluating β-turn mimics as β-sheet folding nucleators

“…1). ␤-Turn mimics 1, 4, and 6 were designed to replace the i ϩ 1 and i ϩ 2 residues of a type IIЈ ␤-turn and were anticipated to match the right-handed twist of Pin WW (21,25). Compound 1 has reduced conformational freedom relative to 4 and 6.…”

“…The and dihedral angle equivalents in 4 are restricted by allylic strain (A 1,2 and A 1,3 ) relative to 6 (39). Compound 5, designed to replace the i ϩ 1 and i ϩ 2 residues of a type II ␤-turn (25), was expected to introduce a Pin WW twist preference mismatch. Although 1 has been incorporated into folded proteins (40,41), its influence on folding kinetics is unknown.…”

“…1) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). For the purpose of this paper, ␤-turn mimics are defined as molecules that replace the i ϩ 1 and i ϩ 2 amino acid residues of a ␤-turn.…”

Protein/peptide secondary structural mimics: design, characterization, and modulation of protein–protein interactions

“…Based on previous developments, Wipf and coworkers compared different trisubstituted (E)-alkene isosteres 90 ( Fig. 4c).…”

Synthesis of a bicyclic δ-amino acid as a constrained Gly-Asn dipeptide isostere

“…The most interesting feature displayed by d-amino acids is their structural analogy with dipeptides, and many d-amino acids as peptidomimetics have been constructed to mimic dipeptide sequences with added structural constraints . Relevant examples of d-amino acids include linear (Wipf et al, 1998;Gardner et al, 1999;Shankaramma et al, 1999;Casimir et al, 2000), cyclic (Poitout et al, 1995;Graf von Roedern et al, 1996;Suhara et al, 1996;Wattersom et al, 2003;Durrat et al, 2004), bicyclic (Hanessian et al, 1997;Van Well et al, 2003), and spiro (Genin and Johnson, 1992;Khalil et al, 1999;Alonso et al, 2001) compounds, and different templates have been applied for the generation of such amino acids. Moreover, since the b-turn is a common structural feature of proteins associated with the dipeptide unit, much research about d-amino acids has been concentrated on the creation of reverse turn mimetics, where the central amide bond is replaced by a rigid moiety (Kim and Germanas, 1997a, b;Belvisi et al, 1999;Estiarte et al, 2000;Trabocchi et al, 2002).…”