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PubMed2003

Fast enantioseparation of arylglycine amides by capillary electrophoresis with highly sulfated-beta-cyclodextrin as a chiral selector.

Nine racemic arylglycine amides were synthesized and successfully enantioseparated by capillary electrophoresis (CE) using highly sulfated beta-cyclodextrin (HS-beta-CD) as a chiral selector. Baseline enantioseparation of the analytes was obtained around neutral pH but not in the acidic conditions that are commonly used. HS-beta-CD content, buffer pH, type and concentration, and organic modifier concentration were studied and optimized for fast and efficient separation. A chiral CE separation system composed of 1.5% (w/v) HS-beta-CD, 0 to 10% (v/v) methanol and 20 mM 3-(N-morpholino)propanesulfonic acid at pH 6.5 was shown suitable for baseline enantioseparation of the mentioned amides within 6 min, including simultaneous enantioseparation of three positional isomer series (methyl-, methoxyl or chloro-substituted). By using this system, D-enantiomers migrated ahead of the L-enantiomers and the enantiomeric resolution order of arylglycine amides was more or less parallel to the pK(a), order of the analytes.

Amides↗
PubMed1998

New ligands for HLA DRB1*0301 by random selection of favourable amino acids ranked by competition studies with undecapeptide amide sublibraries.

An efficient screening procedure for the identification of high affinity HLA class II ligands and their binding pattern has been established to characterize peptide specificities for the HLA allele DRB1*0301. The method is based on the screening of 209 synthetic undecapeptide amide sublibraries O/X10-NH2 representing collections of 19(10) individual peptides in a competition ELISA using HLA DRB1*0301 protein and the biotinylated natural ligand ApoB 2877-2894. Screening results represent the effect on competition induced by an individual amino acid residue in its sequence position of undecapeptide amides. Amino acids clustered as active in their position were randomly selected for the same position of a restricted set of 96 individual undecapeptide amides. This novel approach for the design of ligands was introduced to compensate for the inaccuracy induced by the translational invariance of amino acids in peptide libraries characterized by one defined amino acid. Translational invariance is facilitated by shifted docking of O/X10-NH2 libraries in the binding cleft and protrusion from the ends of the cleft. A second more directed deduced set of 24 peptides was obtained by combination of the most favourable residues in each position. All individual peptides were investigated in the competition assay. The most active HLA DRB1*0301 ligands were obtained by random selection of favourable amino acids and six of them showed improved affinity in comparison to the model ligand alpha AChR 310-325.

Alleles↗
PubMed2000

Antifungal amides from Piper hispidum and Piper tuberculatum.

Piper hispidum and Piper tuberculatum accumulate amides bearing isobutyl, pyrrolidine, dihydropyridone and piperidine moieties. The isolation and characterization of several representatives including two hitherto unreported amides were performed by chromatographic techniques and by analysis of spectroscopic data. The antifungal activity of each amide was determined by direct bioautography against Cladosporium sphaerospermum.

Amides↗
PubMed1998

vir-Gene-inducing activities of hydroxycinnamic acid amides in Agrobacterium tumefaciens.

Expression of Agrobacterium tumefaciens virulence genes and transformation of dicots by this organism are dependent upon host plant phenolic compounds. Several alkylsyringamides have recently been shown to be powerful inducers of these vir-genes. These synthetic amides, and especially ethylsyringamide, are much stronger inducers than syringic acid. In this work, four alkylamides derived from ferulic or sinapic acids were synthesized by a dicyclohexylcarbodiimide method and tested for their potential to induce vir-gene expression on A. tumefaciens strains harbouring virB::lacZ or virE::lacZ fusion plasmids. Their effectiveness was compared to that of ethylsyringamide and tyraminylferulamide, a naturally occurring amide in plants. Whatever the amine moiety of the amide (ethylamine, propylamine, tyramine or beta-alanine ethyl ester) conjugation of the acid functional group clearly diminished the toxicity to the bacteria of the respective acid at high concentration and thereby increased the vir-inducing potential. However, none of the inducers tested exhibited higher activity than acetosyringone, the reference compound for vir-gene induction, with the exception of ethylsyringamide at concentrations above 1mM. When tested on Agrobacterium tumefaciens strain A348(pSM243cd), ethylferulamide and ethylsinapamide were more efficient than the corresponding phenolic acids but only above 100 microM.

Acetophenones↗
PubMed1998

N alpha- and N epsilon-D-galacturonoyl-L-lysine amides: properties and possible occurrence in plant cell walls.

Three representatives of a novel class of amide (isopeptide) glycoconjugates have been synthesised: N alpha-D-galacturonoyl-L-lysine and N epsilon-D-galacturonoyl-L-lysine and N epsilon-D-polygalacturonoyl-L-lysine. Galacturonoyl-lysine amide bonds were labile in 2 M trifluoroacetic acid at 120 degrees and in alkali, but relatively stable in cold acid. The amide bonds were resistant to digestion by Driselase, Pronase and trypsin. The polysaccharide backbone of N epsilon-D-polygalacturonoyl-L-lysine was hydrolysed by Driselase to yield two major ninhydrin-positive compounds which were shown by 1H and 13C NMR spectroscopy to be tri- and tetra-alpha-(1-->4)-D-galacturonoyl-L-lysines. To investigate the possible natural occurrence of N-galacturonoyl isopeptide bonds, we fed cell-suspension cultures of spinach and tomato with D-[6-14C]glucuronic acid, which radio-labels pectic polysaccharides. The radioactive cell walls were digested with, sequentially, Driselase, mild acid, and proteinases. On electrophoresis at pH 2.0, several of the radioactive digestion-products were cathodic. Some of the cathodic products yielded [14C]galacturonic acid upon complete acid hydrolysis. The existence of these products is compatible with the presence of novel N-galacturonoyl isopeptide bonds, which could serve as cross-links in plant cell walls.

Amides↗
PubMed1997

Structure-activity relationship studies of the amide functionality in (p-O-sulfamoyl)-N-alkanoyl tyramines as estrone sulfatase inhibitors.

Recently, we reported the synthesis and biomedical studies of a series of (p-O-sulfamoyl)-N-alkanoyl tyramines as nonsteroidal estrone sulfatase inhibitors. One of the most potent inhibitors in this series is (p-O-sulfamoyl)-N-tridecanoyl tyramine 1 with an 1C50 value of 61.3 nM. In this study, we synthesized four analogs of 1 (compounds 2-5) to investigate the structure-activity relationships of the amide functionality in (p-O-sulfamoyl)-N-tridecanoyl tyramine. Replacement of the amide functionality in 1 with an ethylene moiety to form the alkyl analog 5 resulted in complete loss of sulfatase inhibitory activity (IC50 of 61.3 nM vs. > 20 microM). The keto, hydroxy, and ester analogs (inhibitors 2-4) are 8-15 times less in affinity to the sulfatase than inhibitor 1. However, their inhibitory activities are significantly higher than the alkyl analog 5. The results suggest that the amide functionality is favorable for sulfatase inhibitory activity and that there may be a hydrogen bonding component to the enzyme interaction in this region.

Amides↗
PubMed2003

Glycine-extended adrenomedullin exerts vasodilator effect through amidation in the rat aorta.

Human adrenomedullin (hAM) is an endogenous peptide that has potent vasodilator activity. Mature AM is biosynthesized from its intermediate form, glycine-extended AM (AM-gly), by carboxy-terminal amidation. AM-gly is generally considered to be biologically inactive but is a major molecular form in human and rat plasma. The present study demonstrated that recombinant human AM-gly (hAM-gly) elicits potent vasodilator effect on isolated rat aorta. In aortic rings, hAM-gly produced dose-dependent (0.1-100 nM) relaxation in phenylephrine-precontracted strips (pD(2) 8.4+/-0.5). The vasorelaxant potency of hAM-gly was comparable to that of hAM (pD(2) 8.6+/-0.2) but hAM-gly took a significantly (P<0.01) longer time to reach the maximal relaxation compared with hAM (T(max) 23+/-4 vs. 5+/-2 min). Vasorelaxant responses to hAM-gly were abolished by endothelial removal. N(omega)-nitro-L-arginine (L-NNA) and AM(22-52) significantly (P<0.01) reduced the vasodilator effect of hAM-gly. Furthermore, 4-phenyl-3-butenoic acid (PBA), an alpha-amidation enzyme inhibitor, significantly (P<0.05) inhibited the vasorelaxant responses to hAM-gly without any effect on the hAM-induced relaxation, suggesting the possible process of amidation in the rat aorta. We further clarified that the aorta has the ability to convert exogenous hAM-gly to mature hAM and the conversion is inhibited by PBA. These results suggest that the circulating AM-gly may play a role in regulating vascular tone and increased plasma AM-gly may be involved in the pathophysiology of cardiovascular diseases.

Adrenomedullin↗
PubMed2000

The cardiovascular effects of PFRFamide and PFR(Tic)amide, a possible agonist and antagonist of neuropeptide FF (NPFF).

Neuropeptide FF (NPFF), an endogenous opioid-related neuromodulater, has been reported to show significant effects on the cardiovascular system, namely elevation of arterial blood pressure (BP) and heart rate (HR) in rats. In the present study, we synthesized two novel NPFF analogs, PFRFamide (putative NPFF agonist) and PFR(Tic)amide (putative NPFF antagonist), and examined their cardiovascular effect on BP and HR in anesthetized rats. The arterial mean BP and HR were measured by way of direct femoral artery catheterization. The data showed that PFRFamide increased BP in a dose-dependent manner, while PFR(Tic)amide decreased BP dose-dependently. These results revealed the possibility of PFRFamide and PFR(Tic)amide to be NPFF agonist and antagonist (or inverse agonist), respectively. These two NPFF analogs may possess potential in new drug design, and the NPFF system could be very important in mammalian cardiovascular function.

Amides↗
PubMed2002

Benzene fused monocyclic enediynyl amides: synthesis, reactivity and DNA-cleavage activity in comparison to the corresponding sulfonamides.

Monocyclic enediynyl amides 2a-2c have been synthesized via the corresponding free amine 5. Kinetic studies in chloroform revealed the reactivity of these amides towards Bergman cyclization to be less than that of the corresponding sulfonamides. However, differential scanning calorimetry (DSC) measurements in the solid state and DNA-cleavage studies in aqueous buffer showed higher reactivity for the amides than the sulphonamides.

Alkynes↗
PubMed1998

An endogenous sleep-inducing compound is a novel competitive inhibitor of fatty acid amide hydrolase.

2-Octyl gamma-bromoacetoacetate (O gamma Br), an endogenous compound originally isolated from human cerebrospinal fluid (CSF), has previously been demonstrated to increase REM sleep duration in cats. Based on the chemical structure of O gamma Br and its reported sleep-inducing effects, we synthesized O gamma Br along with chemically related analogs and tested these compounds as inhibitors of fatty acid amide hydrolase (FAAH), a brain enzyme that degrades neuromodulatory fatty acid amides. O gamma Br was found to competitively inhibit FAAH activity with IC50 and Ki values of 2.6 microM and 0.8 microM, respectively [for the (R)-enantiomer of O gamma Br (1)]. A set of synthetic analogs of O gamma Br was examined to define the structural features required for FAAH inhibition and inhibitor potencies were assessed at pH 9.0 (near the pH optimum of FAAH) and pH 7.0. Interestingly, at pH 7.0 the gamma-halo beta-keto ester inhibitors proved to be significantly more potent than the trifluoromethyl ketone of oleic acid, one of the most potent FAAH inhibitors described to date. This study supports the possibility that O gamma Br may be a physiological regulator of FAAH activity and fatty acid amide levels in vivo. Additionally, the characterization of gamma-halo beta-keto esters as powerful FAAH inhibitors near physiological pH may aid in future studies of the enzymology and biological properties of FAAH.

Acetoacetates↗
PubMed2002

Urea and amide-based inhibitors of the juvenile hormone epoxide hydrolase of the tobacco hornworm (Manduca sexta: Sphingidae).

A new class of inhibitors of juvenile hormone epoxide hydrolase (JHEH) of Manduca sexta and further in vitro characterization of the enzyme are reported. The compounds are based on urea and amide pharmacophores that were previously demonstrated as effective inhibitors of mammalian soluble and microsomal epoxide hydrolases. The best inhibitors against JHEH activity so far within this class are N-[(Z)-9-octadecenyl]-N'-propylurea and N-hexadecyl-N'-propylurea, which inhibited hydrolysis of a surrogate substrate (t-DPPO) with an IC(50) around 90 nM. The importance of substitution number and type was investigated and results indicated that N, N'-disubstitution with asymmetric alkyl groups was favored. Potencies of pharmacophores decreased as follows: amide>urea>carbamate>carbodiimide>thiourea and thiocarbamate for N, N'-disubstituted compounds with symmetric substituents, and urea>amide>carbamate for compounds with asymmetric N, N'-substituents. JHEH hydrolyzes t-DPPO with a K(m) of 65.6 microM and a V(max) of 59 nmol min(-1) mg(-1) and has a substantially lower K(m) of 3.6 microM and higher V(max) of 322 nmol min(-1) mg(-1) for JH III. Although none of these compounds were potent inhibitors of hydrolysis of JH III by JHEH, they are the first leads toward inhibitors of JHEH that are not potentially subject to metabolism through epoxide degradation.

Amides↗
PubMed2001

Amide and ester derivatives of N3-(4-methoxyfumaroyl)-(S)-2,3-diaminopropanoic acid: the selective inhibitor of glucosamine-6-phosphate synthase.

Several amide and ester derivatives of a glutamine analogue, N3-(4-methoxyfumaroyl)-(S)-2,3-diaminopropanoic acid (FMDP) (1-8), were synthesized and evaluated for the inhibitory activity in regard to glucosamine-6-phosphate synthase from Candida albicans. The syntheses were accomplished by the reaction of N2-tert-butoxycarbonyl-N3-(4-methoxyfumaroyl)-(S)-2,3-diaminopropanoic acid (BocFMDP) with the corresponding amines to give the FMDP amides (1-4) or with alkyl halides to give corresponding esters of FMDP (5-8). Among the synthesized compounds, the acetoxymethyl ester of FMDP was the most active inhibitor of the enzyme. Its IC50 value compared to that of FMDP (4 microM) was equal to 11.5 microM. The methyl and allyl esters and the N-hexyl-N-methyl-amide of FMDP exhibited a moderate enzyme inhibitory activity.

Amides↗
PubMed2001

A new scaffold for amide ligation.

Highly chemoselective amide forming ligation reactions have facilitated the synthetic access to proteins and other amide-linked bioconjugates. In order to generalize this approach, a N(alpha)-2-phenyl ethanethiol scaffold has been developed to promote S to N acyl transfer in a manner analogous to native chemical ligation with N-terminal cysteine residues. Analysis of scaffold-mediated ligation reactions in aqueous solution indicate that the ligation rate at Xaa-Gly junctions is sufficient for the synthesis of large polypeptides. In addition, it was found that the ligation rate is independent of the stereocenter in the scaffold and S- to N-acyl transfer is rate limiting. These studies indicate that the N(alpha)-2-phenyl ethanethiol scaffold is a good candidate for the development of a ligation chemistry for the formation of Xaa-Gly peptides and other unhindered amides.

Amides↗
PubMed1998

Actions of cyclic esters, S-esters, and amides of phenyl- and phenylthiophosphonic acids on mammalian and insect GABA-gated chloride channels.

Cyclic esters, S-esters, and amides of phenyl(thio)phosphonic acid were synthesized to probe the interaction between noncompetitive antagonists of ionotropic gamma-aminobutyric acid (GABA) receptors and their binding site. Some of these compounds competitively inhibited the specific binding of [3H]EBOB, a noncompetitive GABA antagonist, to rat-brain and housefly-head membranes. The trans isomer of the ester bearing a tert-butyl group at the 5-position and a bromine atom at the p-position (5t) was most potent in rat receptors with an IC50 value of 40 nM, while the trans isomer of the S-ester bearing the same substituents (10t) was most potent in housefly receptors with an IC50 value of 55 nM. In both cases, the corresponding amide analogue (12t) was less potent. The potencies of 5t and 12t tended to decrease in the presence of GABA, particularly in housefly receptors, while that of 10t remained unchanged. The rank order of activity in inhibiting [3H]EBOB binding to housefly-head membranes in the presence of GABA (10t > 5t > 12t) was in accord with that of insecticidal activity. S-Ester 10t depressed 10 microM and 300 microM GABA-induced 36Cl- influx into mouse cerebral synaptoneurosomes, whereas ester 5t depressed 10 microM GABA-induced 36Cl- influx but not 300 microM GABA-induced flux. Amide 12t was inactive at both GABA concentrations. These findings indicate that six-membered cyclic phenylthiophosphonic acid derivatives act as noncompetitive antagonists of GABA receptors and suggest that 10t is able to bind to the receptor in the open, desensitized, and closed states, whereas the affinity of 5t and 12t is lower in the open and desensitized states than in the closed state. The derivatives have similar structures except for the heteroatoms at the 1- and 3-positions, so that the heteroatoms may play a unique role when antagonists bring the open state of the GABA-gated channel to the desensitized or closed state.

Affinity Labels↗
PubMed1999

Solid-phase synthesis of irreversible human rhinovirus 3C protease inhibitors. Part 1: Optimization of tripeptides incorporating N-terminal amides.

The optimization of a series of irreversible human rhinovirus (HRV) 3C protease (3CP) inhibitors is described. These inhibitors are comprised of an L-Leu-L-Phe-L-Gln tripeptide containing an N-terminal amide moiety and a C-terminal ethyl propenoate Michael acceptor. Examination of approximately 500 compounds with varying N-terminal amides utilizing solid-phase synthesis and high-throughput assay techniques is described along with the solution phase preparation of several highly active molecules. A tripeptide Michael acceptor containing an N-terminal amide derived from 5-methylisoxazole-3-carboxylic acid is shown to exhibit potent, irreversible anti-3CP activity (k(obs)/[I] = 260,000 M(-1) s(-1); type-14 3CP) and broad-spectrum antirhinoviral properties (average EC50 = 0.47 microM against four different HRV serotypes).

3C Viral Proteases↗
PubMed1998

Measurement of amide hydrogen exchange by MALDI-TOF mass spectrometry.

Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) was used to determine amide proton/deuteron (H/D) exchange rates. The method has broad application to the study of protein conformation and folding and to the study of protein-ligand interactions and requires no modifications of the instrument. Amide protons were allowed to exchange with deuterons in buffered D2O at room temperature, pD 7.25. Exchanged deuterons were "frozen" in the exchanged state by quenching at pH 2.5, 0 degree C and analyzed by MALDI-TOF MS. The matrix mixture consisted of 5 mg/mL alpha-cyano-4-hydroxycinnamic acid, acetonitrile, ethanol, and 0.1% TFA. The matrix was adjusted to pH 2.5, and the chilled MALDI target was rapidly dried. Deuteration of amide protons on cyclic AMP-dependent protein kinase was measured after short times of incubation in deuterium by pepsin protein digestion and MALDI-TOF MS analysis. The unseparated peptic digest was analyzed in a single spectrum of the mixture. From five spectra, H/D exchange rates were determined for some 40 peptides covering 65% of the protein sequence.

Amides↗
PubMed2000

Synthetic catalysis of amide isomerization.

Rotation about the C-N bond in amides can be catalyzed by Bronsted and Lewis acids, as well as nucleophiles and bases. Catalysis of amide isomerization occurs in biological systems via "rotamase" enzymes; however, the mechanisms by which these proteins operate are not completely understood. We outline investigations that provide experimental support for mechanisms believed to be feasible for the catalysis of amide isomerization and present practical applications that have resulted from this work.

Amides↗
PubMedDate not supplied

Mechanism of amide formation by carbodiimide for bioconjugation in aqueous media.

To study the mechanism of amide formation between carboxylic acid and amine in aqueous media using 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (EDC), hydrogels with two different types of carboxyl group locations were employed as substrates containing the carboxylic acid, while ethylenediamine and benzylamine were used as amine. In parallel, a study was undertaken with cyclizable carboxylic acids (maleic acid and poly(acrylic acid) and noncyclizable carboxylic acids (fumaric acid and poly(ethylene glycol) with the terminal carboxyl groups) to assess the reaction products by 13C-NMR and IR. EDC rapidly lost its activity in aqueous media of low pH, producing the corresponding urea derivative, but was very stable at neutral and higher pH regions. EDC could react with carboxyl groups at a relatively narrow low pH range such as 3.5-4.5. If carboxyl groups were cyclizable, they would react quickly with EDC producing carboxylic anhydrides, which formed the corresponding amides when amine compounds were present. On the other hand, a trace of amide was formed in the case of noncyclizable carboxylic acids. In addition, an excess of EDC caused an undesired side reaction to form stable N-acylurea, regardless of the special location of carboxylic acids.

Amides↗