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PubMed1995

Structural effects of the selective reduction of amide carbonyl groups in motilin 1-12 as determined by nuclear magnetic resonance.

Motilin is a 22-residue peptide stimulating stomach and intestinal motility. The motilin 1-12 fragment displays biological effects similar to the native peptide. Selective reduction of the amide carbonyl groups to form CH2NH analogs leads to a significant reduction in activity for the first two N-terminal positions and to a complete loss of activity for all other positions. The structures of motilin 1-12 and ten reduced analogs were investigated using the temperature dependence of the amide NH chemical shifts. In all the analogs, the structure of the N-terminal region (residues 1-5) was different from the structure of motilin 1-12, which is characterized by hydrogen bonding between Phe1 and Ile4. The structure of the C-terminal region of analogs was similar to the structure of motilin 1-12 for the first two reduction positions only (1-2 and 2-3), indicating that the C-terminal portion of motilin 1-12 is more critical for biological activity. Complete structural characterizations of motilin 1-12, [CH2NH]1-2, and [CH2NH]4-5-motilin 1-12 were performed by two-dimensional NMR spectroscopy and molecular modeling. The structural features observed confirm the differences based on the temperature dependence of the amide NH chemical shifts. These results demonstrate that conservation of the amide bond rigidity is essential for the activity of non-hydrolyzable analogs.

Amides↗

PubMed1984

Nature and location of amide-bound (R)-3-acyloxyacyl groups in lipid A of lipopolysaccharides from various gram-negative bacteria.

It has previously been demonstrated [Eur. J. Biochem. 124, 191-198 (1982) and 137, 15-22 (1983)] that the lipid A component of Salmonella and Proteus lipopolysaccharides contains amide-linked (R)-3-acyloxyacyl residues. In the present study lipid A of other gram-negative bacteria was analysed for the presence of amide-bound 3-acyloxyacyl residues. It was found that such residues are constituents of all lipid A tested (Agrobacterium tumefaciens, Chromobacterium violaceum, Pseudomonas aeruginosa, Xanthomonas sinensis, Bacteroides fragilis, Vibrio cholerae, Fusobacterium nucleatum, Rhodospirillum tenue, Acinetobacter calcoaceticus, and Escherichia coli). Amide-linked (R)-3-acyloxyacyl groups, therefore, represent common and ubiquitous structural elements of bacterial lipid A. The composition of 3-acyloxyacyl groups differed considerably among different bacteria. As amide-bound (R)-3-hydroxy fatty acids straight chain and isobranched acyl groups with 10-17 carbon atoms were identified. The most frequently encountered fatty acids, substituting the 3-hydroxyl group of 3-hydroxy fatty acids, were nonhydroxylated straight chain and isobranched acyl residues with 10-17 carbon atoms as well as (S)-2-hydroxy fatty acids with 12 carbon atoms. In some cases, using laser desorption mass spectrometry, the distribution of 3-acyloxyacyl residues over the two available glucosamine amino groups of the lipid A backbone was investigated.

Acinetobacter↗

PubMed1995

Recombinant and chemical derivatives of apamin. Implication of post-transcriptional C-terminal amidation of apamin in biological activity.

The use of the colicin A lysis protein to direct the extracellular release of a fusion protein from Escherichia coli was investigated as an approach for the preparation of recombinant animal toxins. Apamin, a bee venom neurotoxin, was used as the model toxin. It is reticulated by two disulfide bridges and interacts with small conductance Ca(2+)-activated K+ channels. Substantial amounts of free recombinant apamin were obtained by CNBr cleavage of the fusion protein [col-(1-171)-apa] and HPLC purification. It was recognized by conformation-dependent monoclonal antibodies with a K0.5 value close to that for natural apamin, indicating that folding was correct. In toxicity and binding experiments, the recombinant apamin displayed low activity. The recombinant and natural molecules differed by the amidation of the C-terminal histidine residue. Previous structure/activity relationship studies do not implicate this C-terminal residue in activity but the role of its amidation was not investigated. An apamin analog with a non-amidated C-terminal residue was then chemically synthesized. The biological properties of both recombinant and chemical molecules were determined. Amidation of the C-terminal alpha-carboxyl of apamin appears to be essential for full expression of its biological activity.

Amides↗

PubMed1989

Ability of cofactors to support peptide amidation is cell-type specific.

The ability of various cofactors to substitute for ascorbate in the biosynthesis of alpha-aidated peptides from pro-ACTH/endorphin (PAE) was compared in corticotrope tumor cells (AtT-20) and in primary anterior and intermediate pituitary cultures. In all three systems, ascorbate was the most potent cofactor tested. In AtT-20 cells, dopamine, norepinephrine, epinephrine, dehydroascorbate and dihydro- and tetrahydrobiopterin supported significant alpha-amidation of joining peptide [PAE(77-94)NH2]. In contrast, amidation of joining peptide by primary corticotropes was stimulated only slightly by catecholamines and not by tetrahydrobiopterin. Neither catecholamines nor tetrahydrobiopterin stimulated peptide amidation by melanotropes. The ability of cofactors to support the synthesis of alpha-amidated peptides is cell-type specific.

Adrenocorticotropic Hormone↗

PubMed1994

Growth of human cells on plasma polymers: putative role of amine and amide groups.

The attachment and growth of human endothelial cells and fibroblasts was studied on polymer surfaces fabricated by the polymerization of volatile amine and amide compounds in a low pressure gas plasma, and by the treatment of various surfaces in ammonia plasmas, which served to increase the nitrogen content of the surface layers. Infrared spectra showed the presence of amide groups, including those cases where the volatile compound ('monomer') did not contain oxygen. The performance of the surfaces in cell attachment correlated with the surface hydrophilicity and the nitrogen content, although for the latter a fair degree of scatter indicated that a more complex relationship applies. All these surfaces supported the attachment and growth of human cells. Generally, amide plasma polymers were best but the individual monomer and the plasma parameters also played a role. From comparisons of the various surfaces, it is suggested that the amide group is the main promoter of cell attachment in nitrogen-containing plasma surfaces.

Amides↗

PubMed2003

Design and synthesis of phosphonoacetic acid (PPA) ester and amide bioisosters of ribofuranosylnucleoside diphosphates as potential ribonucleotide reductase inhibitors and evaluation of their enzyme inhibitory, cytostatic and antiviral activity.

Continuing our investigations on inhibitors of ribonucleotide reductase (RNR), the crucial enzyme that catalyses the reduction of ribonucleotides to deoxyribonucleotides, we have now prepared and evaluated 5'-phosphonoacetic acid, amide and ester analogues of adenosine, uridine and cytidine with the aim to verify both substrate specificity and contribution to biological activity of diphosphate mimic moieties. A molecular modelling study has been conducted on the RNR R1 subunit, in order to verify the possible interaction of the proposed bioisosteric moieties. The study compounds were finally tested on the recombinant murine RNR showing a degree of inhibition that ranged from 350 microM for the UDP analogue 5'-deoxy-5'-N-(phosphon-acetyl)uridine sodium salt (amide) to 600 microM for the CDP analogue 5'-O-[(diethyl-phosphon)acetyl]cytidine (ester). None of the tested compounds displayed noteworthy cytostatic activity at 100-500 microM concentrations, whereas ADP analogue 5'-N-[(diethyl-phosphon) acetyl]adenosine (amide) and 5'-deoxy-5'-N-(phosphon-acetyl)adenosine sodium salt (amide) showed a moderate inhibitory activity (EC50: 48 microM) against HSV-2 and a modest inhibitory activity (EC50: 110 microM) against HIV-1, respectively.

Amides↗

PubMed1984

Peptide alpha-amidation activity in mouse anterior pituitary AtT-20 cell granules: properties and secretion.

Mouse anterior pituitary corticotropic tumor cells (AtT-20/D-16v) were homogenized and subjected to subcellular fractionation. A secretory granule associated enzyme activity was detected which could convert D-Tyr-Val-Gly into D-Tyr-Val-NH2. The enzyme activity was dependent on the presence of molecular oxygen, copper ions, and reduced ascorbate. Potent endogenous inhibitors of the enzyme obscured the activity unless appropriate levels of copper ions were added. The production of radiolabeled D-Tyr-Val-NH2 from labeled D-Tyr-Val-Gly was inhibited by a wide variety of peptides possessing COOH-terminal glycine residues but not by a number of other peptides, suggesting that many peptides with COOH-terminal glycine residues can function as substrates in the alpha-amidation reaction. Kinetic studies with varied concentrations of D-Tyr-Val-Gly demonstrated Michaelis-Menten kinetics; both the Km for D-Tyr-Val-Gly and maximum velocity (Vmax) increased upon addition of ascorbate to the reaction. Under optimized assay conditions, the secretory granule pool contains enough alpha-amidation activity to alpha-amidate all the relevant peptides in granules in a small fraction of the total time required for complete biosynthetic processing. Secretion of alpha-amidation activity was stimulated along with secretion of pro-ACTH/endorphin-derived peptides upon addition of synthetic corticotropin releasing factor or 8-bromo-cAMP.

Amides↗

PubMed2000

Stereoselective reactions. XXXII. Enantioselective deprotonation of 4-tert-butylcyclohexanone by fluorine-containing chiral lithium amides derived from 1-phenylethylamine and 1-(1-naphthyl)ethylamine.

Enantioselective deprotonation of 4-tert-butylcyclohexanone was examined using 1-phenylethylamine- and 1-(1-naphthyl)ethylamine-derived chiral lithium amides having an alkyl or a fluoroalkyl substituent at the amide nitrogen. The lithium amides having a 2,2,2-trifluoroethyl group on the amide nitrogen are easily accessible in both enantiomeric forms, and were found to induce good enantioselectivity in the present reaction.

Amides↗

PubMed2000

Adrenomedullin amidation enzyme activities in hypertensive patients.

Adrenomedullin (AM) is a potent vasodilating peptide secreted from the vasculature of various organs. It is biologically active when its C-terminus is amidated. Recently, an RIA method was developed for measurement of the active form of AM, or mature AM. We here employed this method to investigate the significance of amidation of AM in controlling cardiovascular function. Thirty-six patients under hemodialysis were recruited and divided into hypertensive (n = 25; 157/86 mmHg) and normotensive (n= 11; 116/66 mmHg) groups. Mature AM, immature AM and blood pressure were monitored during hemodialysis in all patients. There was a significant reduction in blood pressure during hemodialysis in both groups, although after hemodialysis blood pressure was still higher in hypertensives than in normotensives (139 +/-14.8/76 +/- 2.5 mmHg vs. 110 +/- 5.1/66.7 +/- 3.1 mmHg). Mature AM before hemodialysis were lower in hypertensives than normotensives and it decreased in both groups. Although mature AM decreased more in normotensives than in hypertensives (-27 +/- 8% vs. -17 +/- 5%), at the end point, its level was still higher in normotensives. The ratio of mature AM/immature AM decreased only in normotensives (-11.4 8.7%), whereas it remained stable in hypertensives (0.2 +/- 5.6%). Both groups showed similar changes in ANP, endothelin, catecholamines, cGMP, and NOx. The low level in mature AM level in hypertensives may have contributed to the higher blood pressure in this group. The attenuation of AM amidation in normotensives indicates that an unspecified amidative enzyme of AM was regulated in order to normalize blood pressure.

Adrenomedullin↗

PubMedDate not supplied

Insecticidal activity of synthetic amides on Spodoptera frugiperda.

The phytochemistry of the genus Piper (Piperaceae) has been widely studied due to the biological properties of amides from these plants. In this work, we have synthesized and evaluated the toxic effect of 11 amides against the fall armyworm Spodoptera frugiperda larvae. The naturally occurring piperine was also evaluated. The most active amide was N-[3-(3',4'-methylenedioxyphenyl)-2-(E)-propenoyl]piperidine with a LD50 of 1.07 microg mg(-1) larvae. This amide was also evaluated by ingestion.

Amides↗

PubMed2003

Synthesis and antimelanoma activity of tertiary amide analogues of N-acetyl-4-S-cysteaminylphenol.

The biosynthetic pathway to melanin is a realistic target for therapeutic intervention in the development of new drugs to combat malignant melanoma. N-Acetyl-4-S-cysteaminylphenol (1) is an analogue of a biosynthetic intermediate in the pathway to melanin. It probably acts as a prodrug and is oxidized selectively in melanocytes to an o-quinone, which can alkylate cellular nucleophiles resulting in interference with cell growth and proliferation. We previously synthesized a range of more lipophilic analogues of 1 by varying the acyl portion and introducing substitution alpha to the nitrogen. Most of the new compounds displayed greater cytotoxicity than the original lead compound 1. We have now prepared 12 new compounds with varying acyl portions and three different substituents on the nitrogen of the amide in order to increase lipophilicity and to reduce the possibility of hydrolysis of the amides. Most of the tertiary amides showed greater cytotoxicity towards five representative melanoma cell lines than the parent secondary amide. The highest cytotoxicity, comparable to cisplatin, was observed for the benzyl substituted compounds 4, 8, 12, and 16 and the cyclohexylacetamide derivatives 13-15 against these five cell lines. The moderate activity of 13-16 against SK-Mel-24 (non-tyrosinase containing) and an ovarian cell line suggests that interference with the melanin pathway may not be the only mode of action of these new compounds.

Amides↗

PubMedDate not supplied

Effect of the amide fragment on 5-HT1A receptor activity of some analogs of MP 3022.

A new set (3-11) of analogs of MP 3022 (1) containing the amide bond inserted into the intermediate chain linking the terminal heteroaromatic and 1-(2-methoxyphenyl)piperazine moieties were prepared and their 5-HT1A and 5-HT2A receptor affinities were determined. Only compounds with trimethylene chain between amide and arylpiperazine fragments (5a, 5b, 7a, 7b and 11) showed satisfactory affinity for 5-HT1A receptor (Ki = 42-87 nM) and high 5-HT2A/5-HT1A selectivity. The new 5-HT1A receptor ligands were investigated in vivo to determine their 5-HT1A agonistic or antagonistic properties. Compounds 7a and 7b with terminal indazole fragment as well as 11 with phenyl substituent behaved like weak 5-HT1A receptor antagonists. The structure-affinity relationship studies in this series of compounds revealed that the amide group along with the terminal aromatic fragments contributed to interaction with 5-HT1A receptor sites, whereas in vivo results indicated that introduction of the amide group into presented arylpiperazine structures was not a profitable modification for their 5-HT1A functional activity.

Amides↗

PubMedDate not supplied

The tripeptide glycyl-prolyl-glycine amide does not affect the early steps of the human immunodeficiency virus type 1 replication.

OBJECTIVE: To determine whether the peptide glycyl-prolyl-glycine amide (GPG-NH2) corresponding to a conserved motif in the tip of the third hypervariable region of gp120 affected the early events in the human immunodeficiency virus type 1 (HIV-1) replication. DESIGN/METHODS: Glycyl-prolyl-glycine amide was tested for its effect on HIV-1 adsorption, co-receptor usage, proviral DNA synthesis, messenger RNA (mRNA) synthesis and splicing, translation, tat/TAR transactivation, and virus protease activity. RESULTS: Glycyl-prolyl-glycine amide did not appear to affect the early events of the virus replication. HIV-1 having glycine-leucine-glycine instead of GPG in the V3 loop and the mutants deleted of the GPG motif were still inhibited by the peptide. Glycyl-prolyl-glycine-NH2 had no discernible effect on any of the other steps in the virus replication cycle tested. The only effect observed was an increased sodium dodecyl sulfate polyacrylamide amide gel electrophoresis mobility of gp160/120 at high concentrations of GPG-NH2. CONCLUSIONS: The tripeptide GPG-NH2 is a nontoxic compound that inhibits the replication of HIV-1 by an apparently new mode of action.

Amides↗

PubMed1975

[Synthesis of virostatically acting N[adamantyl-(1)]-carbonic acid amides].

By introduction of carboxylic acid amide groupings into 1-amino-adamantant (I), remarkable virustatic effects have been obtained, particularly which N-(1-adamantyl) cinnamic acid amide (VIIa) and N-(1-adamantyl)-3-(4'-methoxyphenyl)-acrylic acid amide (VIIc). The synthesis of the N-(1-adamantyl)-carboxylic acid amides (IV, VII, X) could be reallzed by interaction of I with carboxylic acids (II, V, VIII) via the carboxylic acid chlorides (III, VI, IX), the latter not being isolated for the simplification of the process.

Adamantane↗

PubMed1991

Carboxypeptidase mediated C-terminal amidation of polypeptide acids.

The possibilities of obtaining polypeptide amides in good yields from polypeptide acids by carboxypeptidase catalyzed transpeptidation have been investigated in different C-terminal amidations catalysed by CPD-Y, placing particular emphasis on the structure of the leaving group. In models for GRF(1-29) acid, larger hydrophilic leaving groups like threonine were particularly useful in reactions with arginine amide acting as nucleophile. In models for calcitonin acids, good results were obtained using also large hydrophobics like methionine and tryptophane in amidations with ammonia acting as nucleophile. Influences on both rate and synthetic efficiency of similar trend, but different magnitude, were observed in both salmon and human calcitonin models and high yields were attainable also in longer peptides or if recombinant secreted enzyme was employed.

Amides↗

PubMed1985

Nonenzymatic peptide alpha-amidation. Implications for a novel enzyme mechanism.

An abiotic system is described which chemically catalyzes the formation of less than Glu-His-Pro-NH2 (thyrotropin-releasing hormone) from less than Glu-His-Pro-amino acid in the presence of copper, ascorbate, and molecular oxygen. Evidence is presented to support the participation of hydroxyl and carbon radicals as reaction intermediates in the production of a peptide amide and an aldehyde or ketone. The characteristics of this model system closely mimic the characteristics of enzymatic peptide amidation, and an oxidative, free-radical mechanism for enzymatic peptide amidation is proposed as an alternative to the mechanism for enzymatic amidation offered by Bradbury et al. (Bradbury, A. F., Finnie, M. D. A., and Smyth, D. G. (1982) Nature 298, 686-688).

Amides↗

PubMed1979

Analyses of infrared amide bands of chitin.

Infrared spectra of chitin isolated from various biological species were measured by Fourier transform technique. The recorded spectra were decomposed into component bands within 1500--1750 cm-1 and 3000--3500 cm-1 spectral regions; it allowed us to establish the precise position of amide I and amids II bands. It was shown that the positions of amide I and amide II bands are independent of the source from which chitin was isolated.

Amides↗

PubMed1983

[Mechanism of oxygen exchange in the amide group of substrates during their hydrolysis catalyzed by leucine aminopeptidase and pepsin].

Oxygen exchange in the amide group of leucine amide catalyzed by leucine aminopeptidase, and in leucyltyrosine amide catalyzed by porcine pepsin, was found to proceed mainly by the transfer of the leucyl residue onto the ammonia or tyrosine amide which are formed during the hydrolysis. Thus oxygen exchange in the non-hydrolyzed substrate can not be a proof of the tetrahedral intermediate formation in the course of the catalysis by proteolytic enzymes.

Amides↗