Contrasting solution conformations of peptides containing α,α‐dialkylated residues with linear and cyclic side chains

Abstract

The conformational properties of alpha,alpha-dialkylated amino acid residues possessing acyclic (diethylglycine, Deg; di-n-propylglycine, Dpg; di-n-butylglycine, Dbg) and cyclic (1-aminocycloalkane-1-carboxylic acid, Acnc) side chains have been compared in solution. The five peptides studied by nmr and CD spectroscopy are Boc-Ala-Xxx-Ala-OMe, where Xxx = Deg (I), Dpg (II), Dbg (III), Ac6c (IV), and Ac7c (V). Delineation of solvent-shielded NH groups have been achieved by solvent and temperature dependence of NH chemical shifts in CDCl3 and (CD3)2SO and by paramagnetic radical induced line broadening in peptide III. In the Dxg peptides the order of solvent exposure of NH groups is Ala(1) > Ala(3) > Dxg(2), whereas in the Acnc peptides the order of solvent exposure of NH groups is Ala(1) > Acnc(2) > Ala(3). The nmr results suggest that Acnc peptides adopt folded beta-turn conformations with Ala(1) and Acnc(2) occupying i + 1 and i + 2 positions. In contrast, the Dxg peptides favor extended C5 conformations. The conformational differences in the two series are clearly borne out in CD studies. The solution conformations of peptides I-III are distinctly different from the beta-turn structure observed in crystals. Low temperature nmr spectra recorded immediately after dissolution of crystals of peptide II provide evidence for a structural transition. Introduction of an additional hydrogen-bonding function in Boc-Ala-Dpg-Ala-NHMe (VI) results in a stabilization of a consecutive beta-turn or incipient 3(10)-helix in solution.

Human Growth Hormone-Releasing Hormone hGHRH(1−29)-NH2: Systematic Structure−Activity Relationship Studies

“…However, a significant body of work shows that nonhelical structure, particularly the -turn, can dominate the conformational manifold of short biologically active Aib-containing peptides. 54 Karle et al 55 have shown the importance of solvent on secondary structure using model Aibcontaining peptides with a central Gly-Gly feature, and corroboration has been found in model studies of R,Rdialkylated peptides 56 and the peptaibol antibiotics. 57 Thus, while the present hypothesis correlating enhanced helicity with biological potency may have served as a practical rationale for the synthesis of Aib analogues 31-39, confirming the hypothesis awaits detailed structural (NMR) analysis.…”

Conformational investigations on glycosylated threonine-oligopeptides of increasing chain length

“…The resonances reported in Table 1 for the internal NH protons are arbitrarily listed in a decreasing order. Obviously, with increasing peptide mainchain length, the number of NH proton doublets increases and their occurrence in a narrow range of chemical shifts may be considered as a first indication of a closely related structural environment for all internal NH groups, particularly in the higher member of the series, and represents a preliminary indication of the involvement of these protons in a Hbonding scheme [11,14]. In the weakly interacting medium CDCl 3 , both main-chain elongation and temperature variation induce remarkably small effects in the NH chemical shifts of the II 1±5 oligomers ( Table 1).…”

“…The 1 H-NMR parameters for the NH resonances in the oligomers of the three series are summarized in Table 1. Chemical shifts, NH±CH a coupling constants and temperature coefficients [13,14] were determined in DMSO-d 6 for the I 1±4 and III 1±5 series and in DMSO-d 6 and CDCl 3 for the II 2±5 series. In both solvents, CDCl 3 and DMSO-d 6 , the NH resonance of the N-terminal residue (Thr 1 ) of all the homopeptides, owing to the presence of the urethane protecting group, is considerably shifted upfield from the remaining NH signals which arise from an NH involved in a peptide bond [15,16].…”

HOBt·DCHA-Mediated Synthesis of Sterically Hindered Peptides employing Fmoc-Amino Acid Chlorides in Both Solution-Phase and Solid Phase Methods

“…The efficacy of HOBtÁDCHA-mediated coupling is further demonstrated by the synthesis of dipeptides containing C aa -dialkylglycines [22,23] (H 2 N-CR 1 R 2 -COOH) with linear substitutents [a-aminoisobutric acid (Aib), diethylglycine (Deg), dipropylglycine (Dpg), and dibutylglycine (Dbg)] and cyclic substitutents [1-aminocyclopentane-1-carboxylic acid (Ac 5 c), and 1-aminocyclo hexane-1-carboxylic acid (Ac 6 c), and 1-aminocycloheptane-1-carboxylic acid (Ac 7 c)]. The duration of such couplings required about 2 h, and the resulting peptides were obtained in 65-72% yield (Table 1).…”