Cyclic Dipeptide Cyclo Research Articles

A MOLECULAR RECOGNITION MODEL FOR ENANTIOSELECTIVITY AND AUTOINDUCTION IN CYANOHYDRIN FORMATION CATALYZED BY CYCLO[(S)-HIS-(S)-PHE

A molecular recognition mechanism based on dimeric model for cyclic dipeptide Cyclo[(S)-His-(S)-Phe] (abridged CHP) catalyzed autoinduction is proposed according to the inference of previous experimental findings, which is supported by theoretical calculation with Oniom(B3LYP/3-21G*:AM1) method. The most unstable CHP dimer whose intermolecular hydrogen bonds are immensely lessened by two intramolecular hydrogen bonds is defined as the highest active component (IIa) existing in solid among the three possible dimers (Ia, IIa, and IIb). The carbonyl group of benzaldehyde coordinates to CHP dimer (IIa) by a hydrogen bond with Phe–NαH rather than His–NαH and HCN interacted with the imidazole moiety of His residue to form cyanide ion. In view of the theoretical calculation and experimental results, the structures of the nine-ring complexes derived from interaction between catalytic active dimer CHP(IIa) and cyanohydrins were postulated to explain the enantioselective autoinduction: The structure of no nitrile involved six-ring complex derived from interaction between catalytic active dimer CHP(IIa) and cyanohydrins were postulated to explain the elimination of enantioselective autoinduction.

Factor analysis of transient spectra. Free radicals in cyclic dipeptides containing methionine

Factor analysis is introduced and applied to resolving puzzling behavior in the free-radical chemistry of the cyclic dipeptide cyclo-(D-Met-L-Met). Previously, spectral analysis of the transient absorption spectra, following the hydroxyl radical-induced oxidation of cyclo-(D-Met-L-Met), failed to match expectations seen when transient conductivity was used to monitor the same reaction sequence. In the current work, factor analysis is used to show that a radical cation is formed via the stabilization of the oxidized sulfur through the formation of two-centered three-electron bonds with the lone pairs on oxygen. This previously undetected radical resolves the discrepancy between transient absorption and transient conductivity observations.

Improvement of the quality and shelf life of wheat bread by fermentation with the antifungal strain Lactobacillus plantarum FST 1.7

Lactobacillus plantarum FST 1.7 was screened for in vitro antimicrobial activity and was shown to be active against spoilage moulds and bacteria. Isolation of antimicrobial compounds from cell-free supernatant identified lactic acid, phenyllactic acid and the two cyclic dipeptides cyclo ( l-Leu- l-Pro) and cyclo ( l-Phe- l-Pro) as the major components responsible for this activity. L. plantarum FST 1.7 was tested for the ability to produce the antifungal compounds during sourdough fermentation and to produce bread of good quality and increased shelf-life. A rheofermentometer was used to examine the gaseous release and development characteristics of the dough. A range of parameters was determined including pH, TTA and specific loaf volume. The results were compared with those obtained using Lactobacillus sanfranciscensis, a chemically acidified and a non-acidified dough. The quality of sourdough and bread produced using L. plantarum FST 1.7 was comparable to that obtained using common sourdough starters, e.g. L. sanfranciscensis. Sourdoughs and breads were evaluated for the ability to retard growth of Fusarium culmorum and Fusarium graminearum two fungi found on breads. Sourdough and bread produced with strain FST 1.7 showed consistent ability to retard the growth of both Fusarium species, thus indicating that L. plantarum FST 1.7 has also the potential to improve the shelf-life of wheat bread.

Theoretical UV Circular Dichroism of Cyclo(l-Proline-l-Proline)

MP2, DFT, and molecular mechanics (AMBER, CVFF, and CFF91) geometry optimizations were performed on the cyclic dipeptide cyclo(L-Pro-L-Pro) starting from crystal structure data. Three stable conformations were identified as energy minima by all methods, but assignment of relative energy varied between the methods. The pi-pi transition feature of the UV circular dichroic (CD) spectrum was predicted for each minimized structure using the classical physics method of the dipole interaction model. The model was sensitive to the different conformations. The UV-CD predictions were compared individually and as a Boltzmann-weighted composite with published experimental CD spectra [Bowman, R. L.; Kellerman, M.; Johnson, W. C., Jr. Biopolymers 1983, 22, 1045]. For all structures, the original parameters of Applequist [Applequist, J. J. Chem. Phys. 1979, 71, 4324] with a bandwidth of 3000 cm(-1) most accurately replicated experiment, except for the CFF91 structures, which matched experiment best with a bandwidth of 4000 cm(-1). The inclusion of solvent by a continuum model did not significantly alter the minimized geometries obtained by molecular or quantum mechanics, but it did have an effect on the relative predicted energies of CFF91 and B3LYP conformations. The overall effect of solvent inclusion was negligible when Boltzmann-weighted spectra were considered. Gas-phase CFF91 structures were also reasonably good for prediction of CD spectra, and when water was included via a continuum model for energy calculations, the weighting scheme resembled that of the higher-level weightings. The CD calculated using the MP2/6-311G structures and energies for weighting were most descriptive of the 180 nm negative band in the experimental CD, but red-shifted the location of the 205 nm band. DFT structures were comparably, though not identically, as descriptive of the first pi-pi band, and did a better job with placement of the second (positive) pi-pi band. DFT calculations were less sensitive to basis set effect than the MP2 calculations, with 6-31G results in close agreement with 6-311G. The results suggest that it is possible to use geometries obtained from a variety of different methods (molecular mechanical or quantum mechanical) with the classical physics dipole interaction model to qualitatively reproduce the UV CD of model amides.

Induced Axial Chirality in the Biphenyl Core of the Proatropoisomeric, Cα‐Tetrasubstituted α‐Amino Acid Residue Bip in Peptides

An induced axial chirality in the biphenyl core of the 2',1':1,2;1'',2'':3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid (Bip) residue, a conformationally labile, atropoisomeric, C(alpha)-tetrasubstituted alpha-amino acid, was observed by CD and (1)H NMR spectroscopic techniques in the linear dipeptides Boc-Bip-Xaa*-OMe where Boc=tert-butoxycarbonyl, OMe=methoxy, and Xaa*=D- and/or L-Ala, -Val, -Leu, -Phe, -(alphaMe)Val and -(alphaMe)Leu. Chiral induction was significantly lower in the isomeric dipeptides Boc-Xaa*-Bip-OMe, with the Xaa* residue located at the N-terminus of Bip, as well as in the cyclic dipeptide cyclo-[Bip-L-Ala]. The results obtained in solution were confirmed by X-ray diffraction analysis of a crystalline sample of Boc-(R)-Bip-D-Ala-OMe.

Cholesterol modulates maculosin's orientation in model systems of biological membranes: Relevance towards putative molecular recognition

Fluorescence techniques were used to study (1) the extent of insertion of the bioactive cyclic dipeptide cyclo( l-tyrosyl- l-prolyl), maculosin, in model systems of membranes of 1, 2-palmitoyl-sn-glycero-3-phosphatidyl choline (DPPC) or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidyl choline (POPC), (2) its in-depth location in those lipidic membranes, and (3) the influence of cholesterol on the dipeptides's location and orientation. Partition into lipidic bilayers is extensive, mainly for liquid crystalline phase membranes ( K p = 1.3 × 10 4). Maculosin locates at the lipid head groups level regardless of the membrane system. Nevertheless, its orientation is lipid phase dependent. When maculosin was inserted in liquid crystalline phase bilayers, its phenolic ring was perpendicular to the membrane surface, whereas it changed orientation when inserted in gel phase membranes. Cholesterol was able to reverse the lipid phase influence on maculosin's orientation.

Vibrational and electronic couplings in ultraviolet resonance Raman spectra of cyclic peptides

Ultraviolet resonance Raman (UVRR) spectra are reported for a series of cyclic amides. 2-Azacyclotridecone, which has a 13-membered ring, shows a classic trans-amide UVRR spectral pattern, with comparable enhancement of the amide modes II, III and S. When the ring is diminished to eight (ε-caprolactam) or seven (2-azacyclooctanone) members, this pattern is replaced by a single strong band near 1497 cm −1, characteristic of the CN stretch of a cis-amide vibration (amide IIc). Further shrinkage of the ring decreases the amide IIc frequency. It is lowered over 100 cm −1 to 1389 cm −1 in the case of a 4-membered ring (2-azaidine), reflecting diminution of the CN bond order due to ring strain and pyramidalization of the C and N atoms. At the same time the amide Ic (CO stretching) frequency increases, reflecting the localization of the CO double bond. Also the sensitivity to hydrogen–deuterium exchange reverses for amide Ic and IIc modes as ring size decreases. The UV absorption maximum, which is red-shifted for cis-relative to trans-amides, shifts increasingly to the blue as the ring size decreases, again reflecting localization of the π bonding. In the case of amides with 5- and 6-membered rings (2-pyrrolidinone and δ-vareloctam) multiple UVRR bands are seen in the amide IIc region, whose relative intensities are temperature-dependent. These are assigned to conformers in which different members of the ring are out of the mean plane, resulting in variable perturbations of the amide bond. The cyclic dipeptides cyclo(Gly–Gly) and cyclo(Gly–Pro) have perturbed amide IIc frequencies, reflecting the kinematic mixing of the amide coordinates into in- and out-of-phase modes. Excitation profiles reveal electronic mixing as well, with the transition dipoles adding for the in-phase and canceling for the out-of-phase modes.

Lactobacillus plantarum MiLAB 393 produces the antifungal cyclic dipeptides cyclo(L-Phe-L-Pro) and cyclo(L-Phe-trans-4-OH-L-Pro) and 3-phenyllactic acid.

We have isolated a Lactobacillus plantarum strain (MiLAB 393) from grass silage that produces broad-spectrum antifungal compounds, active against food- and feed-borne filamentous fungi and yeasts in a dual-culture agar plate assay. Fusarium sporotrichioides and Aspergillus fumigatus were the most sensitive among the molds, and Kluyveromyces marxianus was the most sensitive yeast species. No inhibitory activity could be detected against the mold Penicillium roqueforti or the yeast Zygosaccharomyces bailii. An isolation procedure, employing a microtiter well spore germination bioassay, was devised to isolate active compounds from culture filtrate. Cell-free supernatant was fractionated on a C(18) SPE column, and the 95% aqueous acetonitrile fraction was further separated on a preparative HPLC C(18) column. Fractions active in the bioassay were then fractionated on a porous graphitic carbon column. The structures of the antifungal compounds cyclo(L-Phe-L-Pro), cyclo(L-Phe-trans-4-OH-L-Pro) and 3-phenyllactic acid (L/D isomer ratio, 9:1), were determined by nuclear magnetic resonance spectroscopy, mass spectrometry, and gas chromatography. MIC values against A. fumigatus and P. roqueforti were 20 mg ml(-1) for cyclo(L-Phe-L-Pro) and 7.5 mg ml(-1) for phenyllactic acid. Combinations of the antifungal compounds revealed weak synergistic effects. The production of the antifungal cyclic dipeptides cyclo(L-Phe-L-Pro) and cyclo(L-Phe-trans-4-OH-L-Pro) by lactic acid bacteria is reported here for the first time.

Synthesis and Biological Activity of Novel Neuroprotective Diketopiperazines

The cyclic dipeptide cyclo[His-Pro] (CHP) is synthesized endogenously de novo and as a breakdown product of thyrotropin-releasing hormone (TRH), a tripeptide with known neuroprotective activity. We synthesized two isomeric compounds based on the structure of CHP, in which the histidine residue was replaced by 3,5-di- tert-butyltyrosine (DBT), a phenolic amino acid that traps reactive oxygen species. These novel diketopiperazines prevented neuronal death in an in vitro model of traumatic injury. In addition, they dose-dependently prevented death caused by the direct induction of free radicals, and by calcium mobilization through an agent that evokes rapid, necrotic death. The drugs showed activity in the latter system at picomolar concentrations. The neuroprotective profile of these compounds suggests that they may be useful as treatments for neuronal degeneration in vivo, potentially through several different mechanisms.

Determination of the sign of long-range1H-13C scalar coupling constants to non-protonated carbons: application to assignment

The sign of the scalar coupling between a carbonyl carbon and α-proton J(C′,Hα), for the cyclic dipeptide cyclo(Leu–Gly) was determined relative to that between an amide proton and α-proton 3J(HN,Hα) by an E.COSY-type HSQC experiment. The pulse sequence used in this experiment gives a cross peak between the amide proton and carbonyl carbon which shows an E.COSY-type tilt caused by the α-proton. The sign information on J(C′,Hα) was used to distinguish between two-bond (intra-residue) and three-bond (inter-residue) J(C′,Hα)s, leading to the assignment of the carbonyl carbons of the cyclic dipeptide cyclo(Leu–Gly). Copyright © 1999 John Wiley & Sons, Ltd.

Determination of the sign of long‐range 1H–13C scalar coupling constants to non‐protonated carbons: application to assignment

The sign of the scalar coupling between a carbonyl carbon and α-proton J(C′,Hα), for the cyclic dipeptide cyclo(Leu–Gly) was determined relative to that between an amide proton and α-proton 3J(HN,Hα) by an E.COSY-type HSQC experiment. The pulse sequence used in this experiment gives a cross peak between the amide proton and carbonyl carbon which shows an E.COSY-type tilt caused by the α-proton. The sign information on J(C′,Hα) was used to distinguish between two-bond (intra-residue) and three-bond (inter-residue) J(C′,Hα)s, leading to the assignment of the carbonyl carbons of the cyclic dipeptide cyclo(Leu–Gly). Copyright © 1999 John Wiley & Sons, Ltd.

Examination and Enhancement of Enantioselective Autoinduction in Cyanohydrin Formation by Cyclo[(R)-His-(R)-Phe

The cyclic dipeptide cyclo[(R)-His-(R)-Phe] (1) has been known since 1981 to catalyze the enantioselective formation of cyanohydrins from aldehydes and HCN. Although 1 has proved to be very effective in the production of optically active cyanohydrins, the precise structure of its catalytically active form remains unresolved. The reaction of 3-phenoxybenzaldehyde and HCN in the presence of 1 has also been shown to exhibit enantioselective autocatalysis: the product (S)-3-phenoxymandelonitrile reacts with 1 to form a new, more enantioselective catalytic species. It is now demonstrated that this autocatalytic phenomenon is general and that, furthermore, it can be used to improve the enantioselectivity of cyanohydrin formation for several problematic substrates. Upon addition of a small (8 mol %) quantity of (S)-mandelonitrile or (S)-3-phenoxymandelonitrile to these reactions, the enantioselectivity of cyanohydrin formation was improved by as much as 20% ee. This effect has been ascribed to the formation of ...

The effects of N-methylation on the enantioselectivity of catalysis by cyclo[( R)-His-( R)-Phe

The cyclic dipeptide cyclo[( R)-His-( R)-Phe] 1 has been known since 1981 to catalyze the enantioselective formation of cyanohydrins from aldehydes and HCN. Although 1 has proved to be very effective in the production of optically active cyanohydrins, the precise structure of its catalytically active form remains unresolved. Two derivatives, in which the two amides in 1 were independently N-methylated, were synthesized as probes of the structural and functional requirements for catalysis by 1. Both derivatives were far more soluble in organic solvents and were found to catalyze the formation of racemic cyanohydrin, but differed greatly in their turnover rates. Mixtures of the two derivatives with each other and with 1 were also examined as hydrocyanation catalysts. Only the mixtures containing 1 demonstrated any enantioselectivity, but did not appear any more competent as catalysts than reduced quantities of 1. From these data, it is concluded that both amide bonds are essential for effective catalysis by 1, but that the amide containing the His N α appears to be involved in interactions with the substrate while the other amide plays a structural role, possibly for self-associative hydrogen bonding.

The oxidation of benzaldehyde to benzoic acid catalysed by cyclo-[(S)-His-(S)-Phe], and its implications for the catalytic asymmetric addition of HCN to aldehydes.

The cyclic dipeptide cyclo-[( S)-His-( S)-Phe] is found to catalyse the oxidation of benzaldehyde to benzoic acid. A mechanism is proposed both for this reaction, and for the asymmetric addition of HCN to aldehydes catalysed by this peptide based on a common intermediate for bothreactions.

A Conformational Study on Cyclo[(S)-Phenylalanyl-(S)-Histidyl] by Molecular Modelling and NMR Techniques

The conformation of the cyclic dipeptide cyclo[( S)-Phenylalanyl-( S)-Histidyl] is investigated by molecular modelling and NMR techniques. The results are of interest when considering the mechanism by which this compound acts as a catalyst for the asymmetric addition of HCN to aldehydes.

The cyclic dipeptide cyclo[(S)-phenylalanyl-(S)-histidyl] as a catalyst for asymmetric addition of hydrogen cyanide to aldehydes

The cyclic dipeptide cyclo[(S)-phenylalanyl-(S)-histidyl] as a catalyst for asymmetric addition of hydrogen cyanide to aldehydes

Comparison of the Antinociceptive Effect between the Cyclic Dipeptide Cyclo [Tyr(Et)-Homoarginine] and the Linear Dipeptide Boc-Tyr(Et)-Homoarginine-OMe in Rats*

The antinociceptive effect of the cyclic dipeptide cyclo[Tyr(Et)-homo-arginine] (C.TEHA) was examined utilizing the tail flick test and the digitus pinching test in rats in comparison with the linear dipeptide Boc-Tyr(Et)-homoarginine-OMe (B.TEHM). Though both dipeptides administered into the lateral, 3rd and 4th cerebroventricles produced antinociceptive effects equipotent to morphine, except for the 4th cerebroventricular administration of B.TEHM, the administration into the spinal subarachnoid space was without effect. The effect of B.TEHM was completely antagonized by the pretreatment of naloxone (i.p.) when administered into the 3rd cerebroventricle where its effect was demonstrated to be the most potent. However, naloxone had no significant effect on C.TEHA administered into the 3rd cerebroventricle in both tests. It was concluded that both dipeptides act on the upper brain stem, especially around the 3rd cerebroventricle. Moreover, it was also thought that the effect of B.TEHM may be involved in the brain opioid system, and that of C.TEHA can be produced via a naloxone-resistant opioid system or a non-opioid system.

Solvolysis of charged active esters of carboxylic acids with cyclo ( l- or d-Glu- l-His)

Cyclic dipeptide cyclo( l- or d-Glu- l-His) carrying an anionic site and a nucleophilic site has been synthesized and used as a catalyst for the solvolysis of cationic esters in aqueous alcohols. In the solvolysis of 3-acyloxy- N-trimethylanilinium iodide ( S + n , n = 2 and 10) and Cl −H 3N +(CH 2) 11COOPh(NO 2), no efficient nucleophilic catalysis was observed. On the other hand, in the solvolysis of Gly-OPh(NO 2)·HCl, Val-OPh(NO 2)·HCl and Leu-OPh(NO 2)·HCl a very efficient general base-type catalysis by cyclo( l-Glu- l-His) was observed. In particular, with the latter two substrates the catalysis by cyclo( l-Glu l-His) was more efficient than that by imidazole, although the catalysis was not enantiomer-selective. The diastereomeric cyclic dipeptide cyclo( d-Glu- l-His) was almost inactive under the same conditions. Confomation of cyclo( l- or d-Glu- l-His) in aqueous solution was investigated and the structure/catalysis relationship is discussed.

ChemInform Abstract: CRYSTAL STRUCTURE AND CONFORMATION OF THE CYCLIC DIPEPTIDE CYCLO‐(L‐HISTIDYL‐L‐ASPARTYL) TRIHYDRATE

Chemischer InformationsdienstVolume 9, Issue 20 Physical Organic Chemistry ChemInform Abstract: CRYSTAL STRUCTURE AND CONFORMATION OF THE CYCLIC DIPEPTIDE CYCLO-(L-HISTIDYL-L-ASPARTYL) TRIHYDRATE R. RAMANI, R. RAMANISearch for more papers by this authorK. VENKATESAN, K. VENKATESANSearch for more papers by this authorR. E. MARSH, R. E. MARSHSearch for more papers by this author R. RAMANI, R. RAMANISearch for more papers by this authorK. VENKATESAN, K. VENKATESANSearch for more papers by this authorR. E. MARSH, R. E. MARSHSearch for more papers by this author First published: May 16, 1978 https://doi.org/10.1002/chin.197820075AboutPDF 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 onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume9, Issue20May 16, 1978 RelatedInformation

The crystal structure and conformation of the cyclic dipeptide cyclo(-L-seryl-L-histidyl-) monohydrate

The crystal structure and conformation of the cyclic dipeptide <i>cyclo</i>(-<scp>L</scp>-seryl-<scp>L</scp>-histidyl-) monohydrate