Diketopiperazine Ring Research Articles

Influence of D and L amino‐acid residues on the conformation of peptides in solution: A carbon‐13 nuclear magnetic resonance study of cyclo(prolyl‐leucyl)

AbstractThe 13C chemical shifts and spin‐lattice relaxation times are reported for cyclo(L‐Pro‐L‐Leu) and cyclo(L‐Pro‐D‐Leu). The chemical shifts of the D and L leucyl residues in the cyclic peptides differ from each other by 1.8 and 3.6 parts per million for the α and β carbons, respectively. The α‐carbons of the prolyl residues differ by 1.0 ppm as a consequence of proximity to a D or an L leucyl residue. The 13C spin‐lattic relaxation time(T1) of the prolyl residues, but not the leucyl residues, in both compounds are indicative of difference in conformational equilibria within the pyrrolidine ring in the L‐L isomer as compared to the L‐D isomer. Anisotropic overall molecular reorientation is not responsible for the differences observed in the T1 values. The differences in T1 values and chemical shifts between cyclo(L‐Pro‐L‐Leu) and cyclo(L‐Pro‐D‐Leu) appear to result from a difference in conformations of the two diketopiperazine rings.

Crystal structure and conformation of the cyclic dipeptide cyclo-L-prolyl-D-phenylalanyl

The structure of cyclo-L-prolyl-D-phenylalanyl has been rifined to a final R of 0.030 for 1439 observed reflexions. The space group is P2 t , with a=8.107, b=6.638, c=12.083 A, β=96.43°, Z=2. The molecular packing coefficient is about 0.72, with pairs of molecules held together by an N-H…O hydrogen bond between the peptide N and O (2.855 A). The molecule is in the folded conformation (γ½=75.0°) with tha aromatic side chain facing the diketopiperazine ring. The latter assumes a boat conformation with the α-carbon atoms deviating about 0.2 A from the plane through the two peptide bonds. The pyrrolidine ring assumes a half-chair conformation with approximate C 2 symmetry.

Conformations of peptides in solution by nuclear magnetic resonance spectroscopy. Part III. Cyclic dipeptide ring conformations

The determination of the degree of folding (β) of the diketopiperazine ring (DKP) of cyclic dipeptides from 3J(HNCH) and 5J(HH), the homoallylic coupling across peptide bonds, is discussed. From measurements of the 100 MHz 1H n.m.r. spectra of cyclic dipeptides containing glycine or sarcosine[i.e. cyclo-Gly(Sar)-X where X = amino acid] it is concluded that β increases with the bulkiness of amino-acid X for both D2O and DMSO solutions. The results are in agreement with those determined from the c.d. spectra of the same cyclic dipeptides in aqueous solution. A correlation is observed between the magnetic non-equivalence of the Gly (or Sar) methylene group and the degree fo folding of cyclic dipeptides containing amino-acids not substituted by aromatic rings at the β-carbon atom.

Hormone‐Receptor Interactions. Synthesis and Conformational Study of cyclo‐L‐Cystathionine

AbstractThe purpose of this work was to see whether the replacement of a sulfur atom in a cystine disulfide bridge by a methylene group is an only superficial ‘isosteric’ substitution, i.e. with regard to size, hydrophobia, bond angles, etc., or whether it would also encompass such parameters as preferred conformations in solution (M‐ or P‐helicity of the bridge). The methods involved the synthesis of a model compound, cyclo‐L‐cystathionine (cyclo‐L‐carbacystine), and its investigation by 1H‐ and 13C‐NMR. It is concluded that the conformations of the CH2(β)CH2(γ)SCH2(β') bridge, and of the diketopiperazine ring are closely similar to the analogous elements in cyclo‐L‐cystine (DMSO as solvent). This knowledge might help to explain the fact that carba analogs of heterodetic‐cyclic polypeptide hormones are often biologically very active.

Conformational studies of cyclo-gly-pro(S) by X-ray diffraction and proton magnetic resonance

The X-ray crystal structure and the PMR spectrum in 2H 2O and DMSO-d 6 of cyclo-glycyl-4-thiaprolyl has been determined. In the crystal, the diketopiperazine ring of the molecule adopts a boat conformation and the thiazolidine ring an envelope conformation, very similar to the analogous compound cyclo-glycyl-prolyl. Comparison of proton-proton dihedral angles derived from the crystal structure and from vicinal coupling constants in solution indicates that the conformation of cyclo-glycyl-4-thiaprolyl is nearly the same in crystal and in solution in the limits of applied mehods.

Conformations of peptides in solution by nuclear magnetic resonance spectroscopy. Part II. Homoallylic coupling in cyclic dipeptides

Using the crystal structure data of numerous cyclic dipeptides the scope of analysing 5,J(HH) of peptides in terms of homoallylic coupling is discussed. From the observed correlation between 3J(HNCH) and 5J(HCαNC′CαH) of cyclic dipeptides in DMSO and CDCl3 solutions it is shown that five bond coupling can be rationalised in terms of homoallylic coupling. Assuming the same angular dependence for 5J(HH) for peptides in all solvents, the conformational properties of the substituted diketopiperazine rings are determined for cyclic dipeptides in different solvents; in particular, detailed conformational properties are discussed for cyclic dipeptides in D2O solutions where 3J(HNCH) cannot be observed. The analysis is extended to explain changes with conformation in observed 5J(α-CH,NR) of N-substituted cyclic dipeptides (R = CH3 or δ-CH2 of proline).

Pulse fluorometry of cyclo-(glycyl-l-tryptophyl)

The fluorescence of cyclo-(glycyl-L-tryptophyl) in trimethyl phosphate has been studied in a temperature range varying from room temperature to −85°C. At room temperature, the fluorescence decay is the sum of two exponentials, the relative amplitude of which depends on the emission wavelength. This can be explained by the presence of the two following emitting molecular states: on one hand the unfolded state, the fluorescence decay time and the emission spectrum of which are close to these of skatole; on the other hand the folded state which has a shorter decay time and a blue-shifted spectrum. By lowering the temperature, the fluorescence spectrum shifts to the blue, while the skatole spectrum shifts to the red, This behavior corresponds to an increase of the folded conformation concentration in agreement with the NMR results, Furthermore the rate Of exchange between the folded and the unfolded conformations decreases. Accordingly the Wavelength dependence of the fluorescence decay lessens. There are two possible values of the conformational angle X 2 differing by 180°, which correspond to the folded state; due to the indole asymmetry, the interactions between the indole and diketopiperazine rings differ in these conformers. Consequently the fluorescence decay remains biexponential even at − 85° C.

Conformation of histidine model peptides. I. Conformational energy calculations for L-alanyl-L-histidine diketopiperazine.

AbstractSemiempirical conformational energy calculations were carried out for the cyclic dipeptide L‐alanyl‐L‐histidine diketopiperazine. The results indicate that electrostatic effects are probably significant in determining the conformation assumed by this molecule. When the imidazole group is in its uncharged state the most stable conformations of the molecule are those with the imidazole ring folded over the diketopiperazine ring (χ1 = 60°). Upon protonation of the imidazole group the folded conformation may be destabilized relative to conformations characterized by χ1 positions near 180°.

ChemInform Abstract: THE CRYSTAL AND MOLECULAR STRUCTURE OF BICYCLOMYCIN, A NEW ANTIBIOTIC

Chemischer InformationsdienstVolume 5, Issue 37 Physical Organic Chemistry ChemInform Abstract: THE CRYSTAL AND MOLECULAR STRUCTURE OF BICYCLOMYCIN, A NEW ANTIBIOTIC YOJI TOKUMA, YOJI TOKUMASearch for more papers by this authorSHIGETAKA KODA, SHIGETAKA KODASearch for more papers by this authorTOSHIO MIYOSHI, TOSHIO MIYOSHISearch for more papers by this authorYUKIYOSHI MORIMOTO, YUKIYOSHI MORIMOTOSearch for more papers by this author YOJI TOKUMA, YOJI TOKUMASearch for more papers by this authorSHIGETAKA KODA, SHIGETAKA KODASearch for more papers by this authorTOSHIO MIYOSHI, TOSHIO MIYOSHISearch for more papers by this authorYUKIYOSHI MORIMOTO, YUKIYOSHI MORIMOTOSearch for more papers by this author First published: September 17, 1974 https://doi.org/10.1002/chin.197437087AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume5, Issue37September 17, 1974 RelatedInformation

1H NMR study of cyclo‐L‐Thr‐L‐Thr and cyclo‐L‐Thr‐L‐His conformations

AbstractCyclodipeptides containing L‐Thr and L‐His residues have been studied by 1H NMR in D2O and DMSO‐d6. In the neutral form in D2O as in DMSO‐d6, the folded form of the L‐His residue is not unique. The diketopiperazine ring seems to be not strictly planar.

The optical properties of alanine and proline diketopiperazines.

AbstractThe optical properties of the diketopiperazine chromophore of the cyclic dipeptides have been investigated as a function of molecular conformation. The rotatory strengths of L‐alanyl–L‐alanine diketopiperazine and L‐prolyl–L‐proline diketopiperazine have been calculated as a function of the angle of fold of the diketopiperazine ring. The results of these theoretical calculations have been compared with experimental circular dichroism and optical rotatory dispersion data. It is shown that the observed optical properties of these molecules can be explained only if their diketopiperazine rings are folded in opposite directions. The direction of fold is established for each molecule. In solution, the diketopiperazine ring of L‐alanyl‐L‐alanine diketopiperazine is folded in the direction opposite to that found by X‐ray diffraction analysis of crystals. It has been observed that the degree of conservatism of the π → π* couplet of L‐propyl–L‐proline diketopiperazine depends markedly upon the nature of the solvent that is used. In addition, a shoulder has been discovered in the CD spectrum of L‐alanyl–L‐alanine diketopiperazine, which may not be directly attributable to the n → π* and π → π* transitions of the peptide chromophores.

The Crystal and Molecular Structure of Bicyclomycin, a New Antibiotic

Abstract The molecular structure of a new antibiotic, Bicyclomycin (C12H18O7N2), has been elucidated by X-ray diffraction analysis. Bicyclomycin crystallizes from aqueous solution in two forms, an orthorhombic and a monoclinic systems. The crystal data for the former are a=11.72, b=12.72, c=8.80 Å and the space group P212121, while those for the latter are a=10.27, b=10.91, c=6.67 Å, β=101.4°, and the space group P21 The crystal structure of the former was solved by the direct method and refined by least-squares method to a final R factor of 0.07 for 1623 reflections. The established structure is (Remark: Graphics omitted.) The diketopiperazine ring is folded into a boat form. The conformations of the side chain are all gauche or nearly so. All the oxygen and nitrogen atoms participate in two intramolecular and four intermolecular hydrogen bonds.

Low Temperature Circular Dichroism of Tyrosyl and Tryptophanyl Diketopiperazines

Abstract Diketopiperazines have been used as a model system to evaluate the factors determining the shapes and intensities of the near ultraviolet circular dichroism (CD) bands of the tyrosyl and tryptophanyl moieties in proteins. Cooling to 140°K or below brings out fine structure CD bands in all of the diketopiperazines examined. Studies with c-Gly-l-Tyr, c-l-Val-l-Tyr, and c-l-Phe-l-Tyr confirm that the tyrosyl 1lb CD spectrum normally has about the same shape as the absorption spectrum. The CD spectra of c-l-Tyr-l-Tyr, however, are somewhat distorted, because of a small exciton CD contribution superimposed on the normal tyrosyl CD spectrum. The shapes of the tryptophanyl CD bands cannot be determined as precisely due to overlap of the 1la and 1lb electronic bands. Nevertheless, the relative heights of the two major 1lb bands are similar in the CD spectra of c-Gly-l-Trp, c-l-Phe-l-Trp, c-l-Val-l-Trp, and c-d-Val-l-Trp. In the c-l-Trp-l-Trp CD spectra, however, a different ratio of 1lb intensities is observed, suggesting that c-l-Trp-l-Trp may also have a small exciton CD contribution. The tyrosyl and tryptophanyl 1lb fine structure CD bands evident at low temperature can be identified in the same diketopiperazine when these bands are much more intense than the 1la tryptophanyl bands, as is the case for c-l-Trp-l-Tyr. The identification is not as feasible when the 1lb intensities are low, as occurs in c-d-Trp-l-Tyr. The CD intensities are enhanced greatly in those diketopiperazines having two aromatic residues with the l configuration. This enhancement seems to result from coupling of the 1lb electronic transition in either a tyrosyl or tryptophanyl moiety with the far ultraviolet transitions in the second aromatic side chain. Conformational equilibria were examined by cooling the diketopiperazines. The increase in CD intensity upon cooling is much less for the diketopiperazines than for the noncyclic, monomeric tyrosine and tryptophan derivatives. This finding confirms that the diketopiperazines have fewer conformers than do the noncyclic derivatives. For diketopiperazines containing only a single aromatic residue, the conformer with the aromatic side chain folded over the diketopiperazine ring is dominant even at room temperature. In diketopiperazines having 2 aromatic residues with the l configuration, the most stable conformer has both aromatic side chains sharing the space over the diketopiperazine ring.

Neurosine, a New Oligopeptide Isolated from the Brain of Fish and Other Cold-blooded Vertebrates.: I. Identification and Partial Characterization

Analysis of fish brain for the dipeptide homocarnosine has led to the discovery of a new oligopeptide which is named neurosine. This substance contains γ-aminobutyric acid (GABA) and histidine residues. Most of the histidine present in a water soluble fraction from fish brain appears to be in the form of a tetrapeptide consisting of glycine, glutamic acid, GABA and histidine. Neurosine is ninhydrin negative, heat stable, and has a high Rf value when chromatographed in a butanol–acetic acid–water solvent system. The evidence at present suggests that this compound may be a cyclopeptide or contains a pyrrolidone or diketopiperazine ring structure.Neurosine is present in high concentration in the brain of the killifish, Fundulus heteroclitus, approximately 0.1–1.0 μg of peptide per milligram of tissue. It also has been found in other bony fish, amphibians and reptiles but is absent in cyclostomes, elasmobranchs, birds and mammals. Neurosine is not present in any tissue but brain.

Synthesis of cyclodepsipeptides by the insertion of?-hydroxy acid groups in the diketopiperazine ring

Synthesis of cyclodepsipeptides by the insertion of?-hydroxy acid groups in the diketopiperazine ring