Cyclo-hexapeptides

In the group of Jung [90], a new approach has been developed for the use of selector libraries for chiral separations. Complex peptide libraries consisting of 183 different cyclo-hexapeptides in each sublibrary have been used as chiral additive in capillary electrophoresis. Three libraries separated enantiomers of a-amino acid derivatives as well as, e.g., Troger s base (Fig. 10.7). Meanwhile, our approach has also been applied successfully by Chiari et al. [91], who described the deconvolution of cyclopeptide libraries down to single selectors. 

Equations (7.8a) and (7.8b) show that the cis or trans arrangement of the amide bond has little influence on the dihedral angle dependency. Eq. (7.10) is derived from values measured in a rigid model of known geometry, alumichrome, which is analogous to the ferric cyclo-hexapeptide ferrichrome A (D 8). This equation is convenient for esti-... 

Fig. 3-3. Comparison of the values of enantiomeric resolution of different DNP-D,L-amino acids at different deconvolution stages of a cyclic hexapeptide sublibrary. Resolution values in a cyclo(Arg-Lys-X-X-X-P-Ala) sublibrary, in the first line, are compared to those obtained in sublibraries with a progressively increasing number of defined positions. All the sublibraries were 30 mM in the running buffer while the completely defined cyclo(Arg-Lys-Tyr-P-Tyr-P-Ala) peptide is used at 10 mM concentration. Conditions cyclopeptide sublibrary in 20 mM sodium phosphate buffer, pH 7.0 capillary, 50 pm i.d., 65 cm total length, 57 cm to the window V = -20 kV, I = 40 electrokinetic injection, -10 kV, 3 s detection at 340 nm. (Reprinted with permission from ref. [75]. Copyright 1998, American Chemical Society.)...

Synthesis. The synthesis of cyclo retro enantlcxner 6 Is outlined in Scheme 1. Compounds 4, 5, 7> and 9 were prepared by an analogous route. Initially, a protected linear hexapeptide was prepared by solid phase synthesis on 2% crossllnked polystyrene resin beginning with a protected lysine resin. The peptide was then removed from the polymer by hydrazlnolysis. Cycllzatlon was... 

With synthetic cyclic hexapeptides Cycio-(X-D-Phe-fto)2 (87) and Cyclo-(X-Pro-D-Phe)2 (88), where X = Ala, Om, and His, the extent of solvent exposure of NH proton was also assessed on the basis of the line broadenittg due to the added stable free radical. 

Cyclic peptides containing glutamic acid or aspartic acid are useful for investigating the effect of the side chains, which can be modified by esterification, on the main-chain conformation. However, few cyclic peptides containing acidic amino acid residues have been synthesized. The present author has synthesized a series of cyclic hexapeptides Cyclo-(Gly-X-Gly)2 where X = Glu(OBzl), Glu(OMe), Glu, Asp (OBzl), and Asp, and investigated their solution conformations using NMR spectroscopy 113). 

The confonnations of Cyclo-(Gly-Glu(OMeH y)2 and Cyclo-(Gly-Observed/values values) suggested for these ( clic hexapeptides the same Cj-symmetric conformation as in DMSO. However, the temperature coefficients implied that in water the internally hydrogen-bonded Qy-NH protons are more solvent-exposed than in DMSO, the latter solvent being less accepting for hydrogen bonding. 

Finally, the conformation of Cyclo-(Pro-Gly-Gly)2, where two sarcosine residues of Cyclo- Sar-Gly-Gly)2 were replaced by proline residues, was analyzed. This cyclic hexapeptide has been investigated by Schwyzer etaL (25,117.120) and Pease et al. (116) and was shown to take a C2-tymmetric conformation with two Gly-NH protons intramolecularly hydrogen-bonded. Schwyzer et aL (117,120) and Pease etal. (116) investigated and NMR spectra of Cydo-(Pro-(3y-(3y)2 and... 

Kopple etal. 88) synthesized cyclic hexapeptides Cyclo-(D-Phe-X-Pro)2, where X = Ala, Orn, and His, and investigated the solution confonnation using NMR and... 

It was noted that the intramolecular acyl transfer proceeded faster with Cyclo-(Tyr-His) than with Cyclo-(Gly-His-<3y-Tyr-Gly-Gly). This difference could be interpreted in either of the following ways (i) that in the cyclic hexapeptide the ade... 

The conformational diaracteristics of cyclic hexapeptides containing sarcosine and/or proline are summarhEed in Table 9, which have been explained in the discussions described above. Peptide bonds involvii imino acid residues can take either cis or trans form. As a consequence, cis and trans peptide bonds distribute randomly along the peptide backbone, vii such complex NMR spectra as observed for Cyclo-(Sar ), Cyclo-(Sar-Sar-cyclic hexapeptides increased (Table 9). The introduction of ycine residue reduced the conformational multiplicity of the cyclic hexapeptides. 

The peptide NH protons which became more solvent-exposed as a result of conformational change are subjected to the polar effect of solvent. The downfield shift due to the polar effect is proportional to the square of the electric field 134). The Gly-NH proton of Cyclo-(Sar-Gly) is exposed to solvent and the downfield shift 0.15 ppm (see Fig. 28) could be considered as the polar effect which the present cydic hexapeptides suffer. As a consequence, the sum of the magnetic anisotropic effect and the polar effect amounts to 0.37 ppm. 

No change of NMR spectra was detected at all with Cyclo-(Pio-Sar-Gly)2 and Cyclo Sar-Gly-Gly)2 when alkali-metal thiocyanates were added to DMSO-d solutions. The complexation may not have occurred in these cyclic hexapeptide-salt sterns. 

Three papers in the same line of work have been published from Kopple s school. Kopple and Nitecki (161) found that in the hydrolyses of PNPA and 2,4-dinitrophenyl acetate by Cyclo-(Gly-His-Gly-Tyr-Gly-Gly), the acylation by the sub-arate occurs fira at the histidyl imidazole group, and then the acyl group migrates intramoleculaily to the phenolic oxygen of the tryosyl teadue. This reaction route is different from that of a-chymotrypsin, but it is quite interesting to show that the functional groups of the cyclic hexapeptide interact mwe or less. 

A new phenomenon is introduced with the cyclic hexapeptides in that the same compound can assume a number of different conformations. For example, each unit cell in the crystal of cyclic hexaglycine contains four different conformers of the molecule (Karle and Karle, 1963). Each conformer has all-trans planar peptide groups, but only one conformer contains intramolecular hydrogen bonds, a pair of parallel 4 1 bonds (Fig. 9). Two of the conformers contain a center of symmetry coincident with centers in the crystal the conformer with the transannular hydrogen bonds also contains a center, although it is not required by the symmetry elements of the crystal and the fourth conformer is asymmetric. The centers of symmetry in the cyclo Gly)e molecules are possible since glycine residues do not contain asymmetric C atoms. 

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