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PubMed2001

Novel C-terminus modifications of the Dmt-Tic motif: a new class of dipeptide analogues showing altered pharmacological profiles toward the opioid receptors.

The design, synthesis and pharmacological evaluation of a novel class of Dmt-Tic dipeptide analogues are described. These resulting analogues bearing different C-terminal functionalities were found to bind to the human delta receptor with high affinity. One specific class of dipeptides bearing urea/thiourea functionalities showed partial to full activation of the delta receptor. Several dipeptides also showed good binding affinities with full activation of the human kappa receptor, a novel property for those ligands.

Dipeptides↗
PubMed1998

Potent dipeptide inhibitors of the pp60c-src SH2 domain.

The design, synthesis, and evaluation of dipeptide analogues as ligands for the pp60c-src SH2 domain are described. The critical binding interactions between Ac-Tyr-Glu-N(n-C5H11)2 (2) and the protein are established and form the basis for our structure-based drug design efforts. The effects of changes in both the C-terminal (11-27) and N-terminal (51-69) portions of the dipeptide are explored. Analogues with reduced overall charge (92-95) are also investigated. We demonstrate the feasibility of pairing structurally diverse subunits in a modest dipeptide framework with the goal of increasing the druglike attributes without sacrificing binding affinity.

Crystallography, X-Ray↗
PubMed1999

Ligands for the tyrosine kinase p56lck SH2 domain: discovery of potent dipeptide derivatives with monocharged, nonhydrolyzable phosphate replacements.

p56lck is a member of the src family of tyrosine kinases. Through modular binding units called SH2 domains, p56lck promotes phosphotyrosine-dependent protein-protein interactions and plays a critical role in signal transduction events that lead to T-cell activation. Starting from the phosphorylated dipeptide (2), a high-affinity ligand for the p56lck SH2 domain, we have designed novel dipeptides that contain monocharged, nonhydrolyzable phosphate group replacements and bind to the protein with KD's in the low micromolar range. Replacement of the phosphate group in phosphotyrosine-containing sequences by a (R/S)-hydroxyacetic (compound 8) or an oxamic acid (compound 10) moiety leads to hydrolytically stable, monocharged ligands, with 83- and 233-fold decreases in potency, respectively. This loss in binding affinity can be partially compensated for by incorporating large lipophilic groups at the inhibitor N-terminus. These groups provide up to 13-fold increases in potency depending on the nature of the phosphate replacement. The discovery of potent (2-3 microM), hydrolytically stable dipeptide derivatives, bearing only two charges at physiological pH, represents a significant step toward the discovery of compounds with cellular activity and the development of novel therapeutics for conditions associated with undesired T-cell proliferation.

Crystallography, X-Ray↗
PubMed2001

Effect of progressive benzyl substitution on the conformations of aminocaproic acid-cyclized dipeptides.

The constraint of dipeptides into a beta-turn conformation can be accomplished by linking the two ends of a standard dipeptide with a linker derived from aminocaproic acid (Aca). To elucidate the possibility of using substituted Aca linkers in peptidomimetic design, a series of five macrocycles composed of a monobenzylated Aca linker (containing the benzyl group on each of the five methylene groups of the parent linker) and Gly-Gly were synthesized. The requisite linkers were made by regiochemically controlled ring expansion techniques (for substitution on Aca positions C-3, C-4, or C-5), an Evans alkylation route (for C-2), or by chain extension of L-phenylalanal (for C-6). The solution-phase conformations of the macrocycles were examined by NMR and CD techniques; in addition, crystal structures of the C-4- and C-6-benzyl-substituted linkers were obtained. Four out of the five macrocycles were found to exist with the dipeptide portion taking up either a type II or II' beta-turn conformation, but the Gly-Gly unit in the compound derived from 4-benzyl-Aca did not correspond to one of the standard beta-turn types.

Aminocaproic Acid↗
PubMed2002

Diastereoselective synthesis of new psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type alkene dipeptide isosteres by organocopper reagents and application to conformationally restricted cyclic RGD peptidomimetics.

Diastereoselective synthesis of new psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type alkene dipeptide isosteres corresponding to dipeptides having one N-methylamino acid, and application to bioactive peptides, are described. In a key reaction introducing the chiral alpha-alkyl group of the isosteres, organocopper-mediated alkylation of syn-beta-methylated gamma-mesyloxy-alpha,beta-enoate 26a afforded E- and Z-isomers of anti-S(N)2' products in a solvent-dependent manner. The resulting two isosteres, D-Phe-psi[(E)-CH=CMe]-L-Val 27a and D-Phe-psi[(Z)-CH=CMe]-L-Val 28b, which corresponded to trans- and cis-conformers of D-Phe-L-MeVal, respectively, were utilized in a structure-activity relationship study on cyclic RGD peptides 1 and 2, in company with a psi[(E)-CH=CH]-type alkene dipeptide isostere, D-Phe-psi[(E)-CH=CH]-L-Val. The cyclic isostere-containing pseudopeptides 3, 4, and 40 were synthesized and biological activity against integrin alpha(V)beta(3) and alpha(IIb)beta(3) receptors were also evaluated.

Alkenes↗
PubMed2006

Stereoselective synthesis of (Z)-alkene-containing proline dipeptide mimetics.

In peptides and proteins, the peptide bond between an amino acid and proline exists as an equilibrium mixture of the cis-imide and trans-imide due to the low energy barrier in their interconversion. This feature greatly influences the structure and function of the proline-containing peptides and proteins. Therefore, restricting the amide bond with an (E)- or (Z)-alkene should provide a promising method for elucidating the structure-activity relationships of the peptide and the proteins. In this report, the regio- and stereoselective synthesis of cis-alanylproline (Ala-Pro) type (Z)-alkene dipeptide mimetic is described. The key steps of this synthesis are to introduce a C3 unit onto a gamma-phosphoryloxy-alpha,beta-unsaturated-delta-lactam with an organocopper-mediated anti-S(N)2' reaction and subsequently construct a five-membered proline-like cyclic structure with an intramolecular Suzuki coupling reaction. Hydrolysis of the amide bond in the resulting bicyclic lactam yields the desired cis-Ala-Pro type (Z)-alkene dipeptide isostere. The presented synthetic methodology should be applicable to the general syntheses of other cis-aminoacylproline type (Z)-alkene dipeptide mimetics.

Alkenes↗
PubMed2005

Side chain dependence of intensity and wavenumber position of amide I' in IR and visible Raman spectra of XA and AX dipeptides.

A series of AX and XA dipeptides in D2O have been investigated by FTIR, isotropic, and anisotropic Raman spectroscopy at acidic, neutral, and alkaline pD, to probe the influence of amino acid side chains on the amide I' band. We obtained a set of spectral parameters for each peptide, including intensities, wavenumbers, half-widths, and dipole moments, and found that these amide I' parameters are indeed dependent on the side chain. Side chains with similar characteristic properties were found to have similar effects on the amide I'. For example, dipeptides with aliphatic side chains were found to exhibit a downshift of the amide I' wavenumber, while those containing polar side chains experienced an increase in wavenumber. The N-terminal charge causes a substantial upshift of amide I', whereas the C-terminal charge causes a moderate decrease of the transition dipole moment. Density functional theory (DFT) calculations on the investigated dipeptides in vacuo yielded different correlations between theoretically and experimentally obtained wavenumbers for aliphatic/aromatic and polar/charged side chains, respectively. This might be indicative of a role of the hydration shell in transferring side chain-backbone interactions. For Raman bands, we found a correlation between amide I' depolarization ratio and wavenumber which reflects that some side chains (valine, histidine) have a significant influence on the Raman tensor. Altogether, the obtained data are of utmost importance for utilizing amide I as a tool for secondary structure analysis of polypeptides and proteins and providing an experimental basis for theoretical modeling of this important backbone mode. This is demonstrated by a rather accurate modeling for the amide I' band profiles of the IR, isotropic Raman, and anisotropic Raman spectra of the beta-amyloid fragment Abeta(1-82).

Amides↗
PubMed2006

Conformational analysis of XA and AX dipeptides in water by electronic circular dichroism and 1H NMR spectroscopy.

We measured the temperature-dependent electronic circular dichroism (ECD) spectra of AX, XA, and XG dipeptides in D2O. The spectra of all XA and AX peptides indicate a substantial population of the polyproline II (PPII) conformation, while the ECD spectra of LG, KG, PG, and AG were found to be quantitatively different from the alanine-based dipeptides. Additional UV absorption data indicate that the ECD spectra of the XG peptides stem from electronic coupling between the peptide and the C-terminal group, and that spectral differences reflect different orientations of the latter. We also measured the 1H NMR spectra of the investigated dipeptides to determine the 3JHalphaNH coupling constants for the C-terminal residue. The observed temperature dependence of the ECD spectra and the respective room-temperature 3JHalphaNH coupling constants were analyzed by a two-state model encompassing PPII and a beta-like conformation. The PPII propensity of alanine in the XA series is only slightly modulated by the N-terminal side chain, and is larger than 50%. As compared to AA, XA peptides containing L, P, S, K V, E, T, and I all cause a relative stabilization of the extended beta-strand conformation. The PPII fractions of XA peptides varied between 0.64 for AA and 0.58 for DA, whereas the PPII fractions of AX peptides were much lower. From the investigated AX peptides, only AL and AQ showed the expected PPII propensity. We found that AT, AI, and AV clearly prefer an extended beta-strand conformation. A quantitative comparison of AA, AAA, and AAAA revealed a hierarchy AAAA > AAA approximately AA for the PPII population, in agreement with predictions from MD calculations and results from Raman optical activity studies (McColl et al. J. Am. Chem. Soc. 2004, 126, 5076).

Alanine↗
PubMed1997

Solid state stability studies of model dipeptides: aspartame and aspartylphenylalanine.

Some solid-state pharmaceutical properties and the solid-state thermal stability of the model dipeptides aspartame (APM) and aspartylphenylalanine (AP), have been investigated. Studies by differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), high-performance liquid chromatography, powder X-ray diffraction, and optical microscopy have shown that the dipeptides undergo solid state intramolecular aminolysis of the type, solid --> solid + gas. This reaction was observed for APM at 167-180 degrees C with the liberation of methanol and for AP at 186-202 degrees C with the liberation of water. The exclusive solid product of the degradation reaction of both dipeptides is the cyclic compound 3-(carboxymethyl)-6-benzyl-2,5-dioxopiperazine. The rates of the degradation reactions were monitored by isothermal TGA and by temperature-ramp DSC and were found to follow kinetics based on nucleation control with activation energies of about 266 kJ mol(-1) for APM and 234 kJ mol(-1) for AP.

Aspartame↗
PubMedDate not supplied

hPEPT1 affinity and translocation of selected Gln-Sar and Glu-Sar dipeptide derivatives.

The intestinal di- and tripeptide transporter hPEPT1 is considered responsible for the absorption of di- and tripeptides arising from digestion, along with several drugs and prodrugs. In order to gather information on the binding site of the protein, several structure-affinity relationships have been suggested. However, these are not necessarily predictive of compounds that are actually translocated by hPEPT1. More information on affinity to and translocation via hPEPT1 of side-chain-modified dipeptides may be gained by conducting a study of selected dipeptide derivatives with variety in size, hydrophobicity, and bond type. The aim of the present study was to synthesize new esters and amides based on L-Glu-Sar and investigate the effects that bond type and size of modification of the N-terminal side chain of sarcosine-containing dipeptides have on the affinity to and translocation via hPEPT1. The esters L-Glu(O-i-Bu)-Sar and L-Glu(OCH(2)Ada)-Sar and the amides L-Gln(N,N-dimethyl)-Sar and L-Gln(N-piperidinyl)-Sar were synthesized, and affinity to and translocation via hPEPT1 were investigated in mature Caco-2 cell monolayers, grown on permeable supports. Affinity was estimated in a competition assay using (14)C-labeled Gly-Sar. Translocation was measured as fluorescence ratios induced by the substrates using the fluorescent probe BCECF and an epifluorescence microscope setup. All compounds showed high affinity to hPEPT1, but only the amides L-Gln(N,N-dimethyl)-Sar and L-Gln(N-piperidinyl)-Sar were translocated by hPEPT1. hPEPT1 is very susceptible to modifications of the N-terminal amino acid side chain of dipeptidomimetic substrates, in terms of achieving compounds with high affinity for the transporter. However, as affinity is not predictive of translocation, derivatization in this position must be performed with great caution since some of the compounds investigated turn out not to be translocated by the transporter.

Amides↗
PubMed2004

Synthesis of a Gln-Phe hydroxy-ethylene dipeptide isostere.

[structure: see text] The protected Gln-Phe hydroxyethylene dipeptide isostere 1 was synthesized as a precursor for preparation of potential inhibitors of Botulinum neurotoxin B metalloprotease. The method allows for the synthesis of additional hydroxyethylene dipeptide isosteres such as 2 with functionalized P1 side chains. The isosteres prepared were coupled with a dipeptide to produce protected pseudotetrapeptide derivatives.

Dipeptides↗
PubMed2002

Dipeptides and diketopiperazines in the Yamato-791198 and Murchison carbonaceous chondrites.

The Yamato-791198 and Murchison carbonaceous chondrites were analyzed for dipeptides and diketopiperazines as well as amino acids and hydantoins by gas chromatography combined with mass spectrometry. Glycylglycine (gly-gly) and cyclo(gly-gly) were detected at the concentrations of 11 and 18 pmol g-1, respectively, in Yamato-791198, and 4 and 23 pmol g-1, respectively, in Murchison. No other dipeptide and diketopiperazine were detected. Five hydantoins were detected at 8 to 65 pmol g-1 in Yamato-791198 and seven in Murchison at 6 to 104 pmol g-1. Total concentration of the glycine (gly) dimers is approximately four orders of magnitude less than the concentration of free gly in Yamato-791198, and three orders of magnitude less than that in Murchison. The absence of L- and LL-stereoisomers of dipeptides consisting of protein amino acids indicates that gly-gly and cyclo(gly-gly) detected are native to the chondries and not from terrestrial contaminants. A possibility was discussed that the gly dimers might have been formed by condensation of gly monomers but not formed through N-carboxyanhydrides of gly.

Amino Acids↗
PubMed1999

Dipeptide derivative synthesis catalyzed by Pseudomonas aeruginosa elastase.

Pseudomonas aeruginosa elastase was used to synthesize various N-protected dipeptide amides. The identity of the products was confirmed by FAB(+)-MS. After recrystallization, the yield of their synthesis was calculated, their purity was checked by RP-HPLC and their melting point was measured. With regard to the hydrolysis, it is well-established that the enzyme prefers hydrophobic amino acids in P'1 position and it has a wide specificity for the P1 position. This specificity was demonstrated to be quite unchanged when comparing the initial rates of peptide bond formation between different carboxyl donors (Z-aa) and nucleophiles (aa-NH2). The elastase, but not the thermolysin, was notably able to incorporate tyrosine and tryptophan in P'1 position. Furthermore, synthesis initial rates were at least 100 times faster with the elastase. To overcome the problematic condensation of some amino acids during chemical peptide synthesis, it has been previously suggested that enzymatic steps can combine with a chemical strategy. We demonstrated that the elastase readily synthesizes dipeptide derivatives containing various usual N-protecting groups. It was especially able to condense phenylalaninamide to Fmoc- and Boc-alanine. Increasing interest in peptides containing unnatural amino acids led us to try the elastase-catalyzed synthesis of Z-dipeptide amides including those amino acids in the P1 position. A synthesis was demonstrated with alphaAbu, Nle, Nva and Phg.

Catalysis↗
PubMed1999

Synthesis of N-carboxyalkyl and N-aminoalkyl functionalized dipeptide building units for the assembly of backbone cyclic peptides.

To improve the assembly of backbone cyclic peptides, N-functionalized dipeptide building units were synthesized. The corresponding N-aminoalkyl or N-carboxyalkyl amino acids were formed by alkylation or reductive alkylation of amino acid benzyl or tert-butyl esters. In the case of N-aminoalkyl amino acid derivatives the aldehydes for reductive alkylation were obtained from N,O-dimethyl hydroxamates of N-protected amino acids by reduction with LiAlH4. N-carboxymethyl amino acids were synthesized by alkylation using bromoacetic acid ester and the N-carboxyethyl amino acids via reductive alkylation using aldehydes derived from formyl Meldrums acid. Removal of the carboxy protecting group leads to free N-alkyl amino acids of very low solubility in organic solvents, allowing efficient purification by extraction of the crude product. These N-alkyl amino acids were converted to their tetramethylsilane-esters by silylation with N,O-bis-(trimethylsilyl)acetamide and could thus be used for the coupling with Fmoc-protected amino acid chlorides or fluorides. To avoid racemization the tert-butyl esters of N-alkyl amino acids were coupled with the Fmoc-amino acid halides in the presence of the weak base collidine. Both the N-aminoalkyl and N-carboxyalkyl functionalized dipeptide building units could be obtained in good yield and purity. For peptide assembly on the solid support, the allyl type protection of the branching moiety turned out to be most suitable. The Fmoc-protected N-functionalized dipeptide units can be used like any amino acid derivative under the standard conditions for Fmoc-solid phase synthesis.

Amino Acids↗
PubMed1999

Amino acid specificity of glycation and protein-AGE crosslinking reactivities determined with a dipeptide SPOT library.

Advanced glycation end products (AGEs) contribute to changes in protein conformation, loss of function, and irreversible crosslinking. Using a library of dipeptides on cellulose membranes (SPOT library), we have developed an approach to systematically assay the relative reactivities of amino acid side chains and the N-terminal amino group to sugars and protein-AGEs. The sugars react preferentially with cysteine or tryptophan when both the alpha-amino group and the side chains are free. In peptides with blocked N-terminus and free side chains, cysteine, lysine, and histidine were preferred. Crosslinking of protein-AGEs to dipeptides with free side chains and blocked N termini occurred preferentially to arginine and tryptophan. Dipeptide SPOT libraries are excellent tools for comparing individual reactivities of amino acids for nonenzymatic modifications, and could be extended to other chemically reactive molecules.

Amino Acid Sequence↗
PubMed2001

Selective inhibition of human inducible nitric oxide synthase by S-alkyl-L-isothiocitrulline-containing dipeptides.

The aim of this study was to investigate the structure-activity relationship of S-alkyl-L-isothiocitrulline-containing dipeptides towards three partially purified recombinant human nitric oxide synthase (NOS) isozymes, as well as the effects of these compounds on cytokine-induced NO production by human DLD-1 cells. In an in vitro assay, S-methyl-L-isothiocitrulline (L-MIT) was slightly selective for human neuronal NOS (nNOS) over the inducible (iNOS) or endothelial (eNOS) isozyme, but the combination of a hydrophobic L-amino acid (L-Phe, L-Leu or L-Trp) with L-MIT dramatically altered the inhibition pattern to give selective iNOS inhibitors. Introduction of a hydroxy, nitro, amino or methoxy group at the para position of the aromatic ring of L-MIT-L-Phe (MILF) decreased the selectivity and inhibitory potency. A longer or larger S-alkyl group also decreased the selectivity and potency. Dixon analysis showed that all of the dipeptides were competitive inhibitors of the three isoforms of human NOS. The enzymatic time course curves indicated that MILF was a slow binding inhibitor of human iNOS. These results suggest that the human NOS isozymes have different-sized cavities in the binding site near the position to which the C-terminal of L-arginine binds, and the cavity of iNOS is hydrophobic. Interestingly, L-MIT-D-Phe (MIDF) showed little inhibitory activity or selectivity, suggesting that the cavity of human iNOS is located in a well-defined direction from the alpha carbon atom. NO production in cytokine-stimulated human DLD-1 cells was measured with a fluorescent indicator, DAF-FM. MILF, L-MIT-L-Trp(-CHO) (MILW) and L-MIT-L-Tyr (MILY) showed more potent activity than L-MIT in this whole-cell assay. Thus, S-alkyl-L-isothiocitrulline-containing dipeptides are selective inhibitors of human iNOS, and work efficiently in cell-based assay.

Citrulline↗
PubMed2005

The low energy tautomers and conformers of the dipeptides HisGly and GlyHis and of their sodium ion complexes in the gas phase.

The low-lying conformers of the dipeptides HisGly and GlyHis, and of their sodium cation complexes, have been studied with a combination of Monte Carlo search with the Amber force field and local geometry optimization at the ab initio HF/6-31G(d) level, completed with MP2(full)/6-311+G(2d,2p) energetics at the HF/6-31G(d) geometries. For each dipeptide, both the N(delta)-H and N(epsilon)-H tautomers of the imidazole side chain of His were considered. For each of the four isomeric dipeptides, 20-30 conformers were fully characterized at the ab initio level. All low energy structures are found to involve H-bonding at the N(delta) position of imidazole, either as a N-H donor or a N acceptor, depending upon the tautomer. In three out of the four species, the most stable conformer involves a C-terminus carboxylic acid in its less favorable trans conformation, in order to maximize intramolecular H bonding. It turns out that the lowest energy tautomer of HisGly is N(epsilon)-H, while that of GlyHis is N(delta)-H. This result argues in favor of the diversity of His tautomeric states in peptides and proteins. The sodium cation complexes of both GlyHis and HisGly have been studied as well, again considering both tautomers in each case. In three out of the four species, the most stable structure involves chelation of sodium by the two carbonyl oxygens and the imidazole ring. On the contrary, the sodium complex of the N(delta)-H tautomer of HisGly favors chelation to the peptidic carbonyl oxygen, the imidazole ring and the amino terminus. In the N(epsilon)-H tautomers of both peptides, the most favorable binding site of imidazole is the N(delta) nitrogen, while in the N(delta)-H tautomers, it is the pi cloud which provides side chain interaction. As a result, both GlyHisNa+ and HisGlyNa+ favor the N(epsilon)-H tautomer of His, in contrast to what was found for the free peptides.

Computer Simulation↗
PubMed2006

Synthesis of a precursor dipeptide of RGDS (Arg-Gly-Asp-Ser) catalysed by the industrial protease alcalase.

Synthesis of Bz-Arg-Gly-NH(2) (N-benzoylargininylglycinamide) [a precursor dipeptide of RGDS (Arg-Gly-Asp-Ser)] catalysed by protease in water/organic co-solvent systems was studied. Starting substrates were N-benzoyl-L-arginine ethyl ester hydrochloride (acyl donor) and glycinamide (nucleophile). Acetonitrile was selected as the organic solvent. Alcalase, an industrial alkaline protease, was applied to the synthesis of the target dipeptide. The conditions of the synthesis reaction were optimized by examining the effects of several factors, including water content, temperature, pH, molar ratio of the substrates and reaction time, on the yield of Bz-Arg-Gly-NH(2). The optimum conditions were established to be pH 10.0, 45 degrees C, in acetonitrile/0.1 M Na(2)CO(3)/NaHCO(3) buffer system (90:10, v/v) for 1 h with a dipeptide yield of 82.9%.

Catalysis↗