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PubMedDate not supplied

Isosteric replacement of amide by ester function. Synthesis and benzodiazepine receptor affinity of indol-3-ylglyoxylyl ester derivatives.

A number of benzyl and phenylethyl esters of indol-3-ylglyoxylic acid were synthesized and tested for their ability to displace [3H]Ro 15-1788 binding from bovine brain membranes. In these new compounds the oxygen atom of the ester function replaced the amide NH group of a class of previously described indolylglyoxylylamides, since it is reported in literature that in the beta-carboline series an ester function is more favourable to the activity than an amide group. However, none of the compounds showed an affinity at the Benzodiazepine receptor higher than that of the corresponding amides, demonstrating that the presence of the amide NH group is favourable to the interaction of ligands with the receptor site.

Amides↗
PubMed1998

Bioactive amides of fatty acids.

Amides of fatty acids are lipid bioregulators formed from long chain saturated and unsaturated fatty acids via amidation by the corresponding amines. Ethanolamides of fatty acids are the most well-studied species of this group; an alternative pathway for their biosynthesis includes hydrolysis of N-acylated phosphatidylethanolamines by phospholipase D. Ethanolamides of fatty acids bind to the cannabinoid receptors of the central nervous system (CB1) or peripheral tissues (CB2) and can be considered as endogenous ligands of these receptors. Their pharmacological properties are similar to that of cannabimimetics. Simple amides of fatty acids are also endogenous bioregulators acting like sleep-inducing (oleamide) or angiogenic factors (erucamide). A new group of bioregulators comprise the amides of fatty acids and biologically active amines (vanillinamine, dopamine, and serotonin).

Amides↗
PubMed1998

Inhibition of R-[3H]-baclofen binding to rat brain synaptic membranes by a homologous series of phenyl alcohol amides anticonvulsants and their evaluation as GABAB receptor blockers.

The inhibition of the specific R-[3H]-baclofen binding to GABAB (gamma-aminobutyric acid) sites by a homologous series of phenyl alcohol amides was tested in rat brain synaptic membranes. Some of these phenyl alcohol amides were designed as anticonvulsants as well as antagonists of the GABAB receptor. These anticonvulsants showed a high affinity to the GABAB receptor. DL-2-hydroxy-2-(4'-chlorophenyl)butyramide and DL-3-hydroxy-3-(4'-chlorophenyl)pentanamide (DL-Cl-HEPP) were as effective as GABA and R-baclofen and were the most potent examined. DL-2-hydroxy-2-phenylbutyramide (DL-HEPA), (+)-HEPA, (-)-HEPA, DL-3-hydroxy-3-phenylpentanamide (DL-HEPP) and DL-4-hydroxy-4-phenylhexanamide (DL-HEPB) were as potent as DL-baclofen. The phenyl alcohol amides with fluorine in the para position of the phenyl ring were less active than DL-2-hydroxysaclofen. DL-4-hydroxy-4-(4'-chlorophenyl)hexanamide was the least active of the series. In addition, R-baclofen antagonized very effectively the anticonvulsant activity of both DL-HEPP and DL-Cl-HEPP in a dose-dependent fashion. These results support the assumption that some of these phenyl alcohol amides anticonvulsants are GABAB receptor blockers.

Amides↗
PubMed1998

Neuropeptidergic control of the optic gland of Octopus vulgaris: FMRF-amide and GnRH immunoreactivity.

In cephalopods, the endocrine optic glands on the optic tract control the maturation of the gonads. The glands are innervated by the optic gland nerve, which originates in the central nervous system. To explore the involvement of neuropeptides in the nervous control of the optic gland of Octopus vulgaris, the presence and distribution of Phe-Met-Arg-Phe-NH2 (FMRF-amide)-like and gonadotropin releasing homone (GnRH)-like peptides were examined in the central nervous system and optic gland by immunohistochemistry. For GnRH immunodetection, antibodies against four different forms of GnRH were used: cGnRH-I, cGnRH-II, sGnRH, and mGnRH. The optic gland nerve provides direct and indirect signals coming from the centres of integration of chemical, visual, and olfactive stimuli to modulate the glandular activity. In these centres, the subpedunculate area, the olfactory and optic lobes, and FMRF-amide-like and GnRH-like immunoreactivities were detected. The subpedunculate area seems to be the source of the FMRF-amide-like peptide, whereas the posterior olfactory lobule is the source of the GnRH-like peptide. The immunoreactive fibres for both neuropeptides leave their sources and directly enter the optic gland nerve. FMRF-amide- and GnRH-immunoreactive nerve endings are seen on the glandular cells. The evidence of a possible neuropeptidergic control of optic gland activity reinforces the analogies and the functional parallels in the octopus, insect, crustacean, and vertebrate hormonal systems.

Animals↗
PubMed1997

A two-dimensional NMR study of exchange behavior of amide hydrogens in a lysozyme derivative with an extra cross-link between Glu35 and Trp108--quenching of cooperative fluctuations and effects on the protein stability.

Two-dimensional nmr spectra [correlated spectroscopy (COSY), homonuclear Hartmann-Hahn (HOHAHA), nuclear Overhauser effect spectroscopy (NOESY)] have been observed for cross-linked lysozyme, a chemically modified lysozyme derivative with an extra ester cross-link between residues E35 and W108. Eight shifted cross-peaks were found in the fingerprint region of COSY spectra. By searching COSY, HOHAHA and NOESY spectra, they have been assigned to A32, E35, S36, 158, A107, W108, V109, and A110. The NOE connectivities (dNN and d alpha N) found for the cross-linked lysozyme are quite similar to those for the intact lysozyme. Exchange behavior of amide hydrogens has been studied for both intact and cross-linked lysozymes by observing the fingerprint region of COSY spectra. Hydrogen exchange reactions were carried out at pH 7.0 and at several temperatures. There exist 41 amide hydrogens whose exchange reactions are detectable under this experimental condition. Not only exchange rates but also their activation enthalpies were determined for individual amide hydrogens. They are classified into two groups, which are called categories III and IV. Category III hydrogens are distributed in relatively flexible peripheral parts of protein, and category IV hydrogens are deeply buried in the core region of protein. Category III hydrogens are exchanged through localized unfolding around their sites with a low activation enthalpy ranging from 10 to 25 kcal/mol. The formation of an extra cross-link affects neither the exchange rate nor the activation enthalpy of category III hydrogens. However, amide hydrogens of residues 34-39 in the vicinity of the hinge are exceptions. They are easily exchanged in the intact lysozyme but their exchange rates are drastically retarded by cross-linking. In the intact lysozyme, structural fluctuations mediating the exchange of category IV hydrogens are highly cooperative with a large activation enthalpy. These large-scale structural fluctuations are the global unfolding of the overall structure and also concerted motions within a domain. Especially near 38 degrees C, it was found that the dominant fluctuation occurring in the alpha-domain is different from that in the beta-domain. However, these concerted motions are strongly quenched by the formation of the cross-link because of the cooperativity of such a large-scale fluctuation. The stabilization of a localized area of protein by cross-linking results in the great suppression of large-scale and concerted motions. The exchange rates of category IV hydrogens are extremely retarded in the cross-linked lysozyme, so that they are exchanged through the so-called penetration mechanism characterized by a low activation enthalpy. These experimental results are discussed with regard to the contribution of cross-linking to the stabilization of the folded structure of protein.

Cross-Linking Reagents↗
PubMed1998

Synthesis and antibacterial activities of new carbapenems having a proline reverse amide moiety at the C-2 position.

The synthesis of new 1 beta-methylcarbapenems (1a-l) having a proline reverse amide moiety at the C-2 position and their in vitro antibacterial activities are described. The compounds were evaluated by the Mueller-Hinton agar dilution method and compared with meropenem as control. Aliphatic amides (1a-h) are found to show greater antibacterial activity than aromatic amides (1i-l). Moreover, C-2 free amino compound (1m) reveals greater activity than any other amide compounds (1a-l).

Anti-Infective Agents↗
PubMed2001

Contribution of tertiary amides to the conformational stability of collagen triple helices.

The collagen triple helix is composed of three polypeptide strands, each with a sequence of repeating (Xaa-Yaa-Gly) triplets. In these triplets, Xaa and Yaa are often tertiary amides: L-proline (Pro) and 4(R)-hydroxy-L-proline (Hyp). To determine the contribution of tertiary amides to triple-helical stability, Pro and Hyp were replaced in synthetic collagen mimics with a non-natural acyclic tertiary amide: N-methyl-L-alanine (meAla). Replacing a Pro or Hyp residue with meAla decreases triple-helical stability. Ramachandran analysis indicates that meAla residues prefer to adopt straight phi and psi angles that are dissimilar from those of the Pro and Hyp residues in the collagen triple helix. Replacement with meAla decreases triple-helical stability more than does replacement with Ala. All of the peptide bonds in triple-helical collagen are in the trans conformation. Although an Ala residue greatly prefers the trans conformation, a meAla residue exists as a nearly equimolar mixture of trans and cis conformers. These findings indicate that the favorable contribution of Pro and Hyp to the conformational stability of collagen triple helices arises from factors other than their being tertiary amides.

Amino Acid Substitution↗
PubMed2000

Amphiphilic poly(ether ester amide) multiblock copolymers as biodegradable matrices for the controlled release of proteins.

Amphiphilic poly(ether ester amide) (PEEA) multiblock copolymers were synthesized by polycondensation in the melt from hydrophilic poly(ethylene glycol) (PEG), 1,4-dihydroxybutane and short bisester-bisamide blocks. These amide blocks were prepared by reaction of 1,4-diaminobutane with dimethyl adipate in the melt. A range of multiblock copolymers were prepared, with PEG contents varying from 23-66 wt %. The intrinsic viscosity of the PEEA polymers varied from 0.58-0.78. Differential scanning calorimetry showed melting transitions for the PEG blocks and for the amide-ester blocks, suggesting a phase separated structure. Both the melting temperature and the crystallinity of the hard amide-ester segments decreased with increasing PEG content of the polymers. The equilibrium swelling ratio in phosphate buffered saline (PBS) increased with increasing amount of PEG in the polymers and varied from 1.7 to 3.7, whereas the polymer that contained 66 wt % PEG was soluble in PBS. During incubation of PEEA films in PBS, weight loss and a continuous decrease in the resulting inherent polymer viscosity was observed. The rate of degradation increased with increasing PEG content. The composition of the remaining matrices did not change during degradation. A preliminary investigation of the protein release characteristics of these PEEA copolymers showed that release of the model protein lysozyme was proportional to the square root of time. The release rate was found to increase with increasing degree of swelling of the polymers.

Biocompatible Materials↗
PubMed2001

Homo- and heterocomplexes of sodium and lithium amides--structures in solution.

Addition of the chiral amine (S)-methyl(1-phenyl-2-pyrrolidinoethyl)[15N]amine (1) to a large excess of nBuNa resulted in the formation of a mixed sodium amide/nBuNa complex. This is the first observation of such a complex. Addition of nBuLi to the chiral sodium amide dimer 3 gave a new mixed lithium/sodium amide 5. The use of 15N,6Li coupling constants showed that the lithium in 5 occupied the tetracoordinated site. The use of chiral sodium amide 3 in the desymmetrization of cyclohexene oxide gave a modest enantiomeric excess (ee) of 37%. The corresponding lithium amide gave an ee of 70% of the same enantiomer. This is the first example of the comparison of asymmetric induction by sodium as cation with that of lithium.

Journal Article↗
PubMed1996

Inositolphosphoglycans and diacyglycerol are possible mediators in the glycogenic effect of GLP-1(7-36)amide in BC3H-1 myocytes.

A potent glycogenic effect of GLP-1(7-36)amide has been found in rat hepatocytes and skeletal muscle, and specific receptors for this peptide, which do not seem to be associated with the adenylate cyclase-cAMP system, have been detected in these tissue membranes. On the other hand, inositolphosphoglycan molecules (IPGs) have been implicated as second messengers of the action of insulin. In this work, we have found, in differentiated BC3H-1 myocytes, specific binding of [125I]GLP-1(7-36)amide, and a stimulatory effect of the peptide on glycogen synthesis, confirming the findings in rat skeletal muscle. Also, GLP-1(7-36)amide modulates the cell content of radiolabelled glycosylphosphatidylinositols (GPIs) and increases the production of diacylglycerol (DAG), in the same manner as insulin acts, indicating hydrolysis of GPIs and an immediate and short-lived generation of IPGs. Thus, IPGs and DAG could be mediators in the glycogenic action of GLP-1(7-36)amide in skeletal muscle.

Animals↗
PubMed2007

An easy-to-use, regioselective, and robust bis(amidate) titanium hydroamination precatalyst: mechanistic and synthetic investigations toward the preparation of tetrahydroisoquinolines and benzoquinolizine alkaloids.

Amidate-supported titanium amido complexes are efficient and regioselective precatalysts for intermolecular hydroamination of terminal alkynes with primary amines. The synthesis and characterization of the first bis(amidate)-supported titanium-imido complex is reported. Its role as the active catalytic species is suggested in the course of product distribution studies using deuterated substrates. The bis(amidate)-supported precatalysts exhibit good functional-group tolerance, even performing hydroaminations in the presence of ester and amide groups. This functional-group tolerance was exploited in the synthesis of a variety of 1-substituted tetrahydroisoquinoline alkaloids and a one-pot hydroaminative procedure for the high yielding preparation of the benzo[a]quinolizine skeleton.

Alkaloids↗
PubMed2007

Direct analysis of 15N-label in amino and amide groups of glutamine and asparagine.

A novel method for on-line determination of the amount and position of 15N-labeling in complex mixtures of amino acids is presented. Underivatized amino acids were analyzed by ion-pair chromatography in combination with mass spectrometry. This enables the direct determination of the 15N label distribution. The fragmentation pathways of the nitrogen moieties of glutamine (Gln) and asparagine (Asn) were studied in detail using all mono 15N isotopomers, which led to a method for differentiating between 15N-amide and 15N-amino labeling. The fragmentation involving the amino and amide groups of Gln led to distinct ion structures. The equivalent fragmentation pattern was not observed for Asn. Instead, the amide group of Asn was eliminated as HNCO in a secondary process. The developed analytical method was evaluated by analysis of a range of standard mixtures taking into account different levels of 15N abundance and distribution between the amino and amide groups. The detection limit (3 SD) for the presence of a 15N label was 0.7 and 1.0% for Gln and Asn, respectively. The determination of the positional labeling follows a nonlinear function. A representative example at 30% 15N was used as a benchmark resulting in average relative standard deviations of 2.7 and 15% for Gln and Asn, respectively. The corresponding expectation windows for the positional labeling were found to be 2 and 12%, respectively.

Asparagine↗
PubMed1993

Facilitated transport of two model steroids by esters and amides of clofibric acid.

A series of novel dermal penetration enhancers, esters and amides of clofibric acid, was synthesized. The permeation parameters and skin retention of two steroids (hydrocortisone-21-acetate and betamethasone-17-valerate) in propylene glycol were studied with athymic nude mouse skin by in vitro diffusion cell techniques in the presence of the novel enhancer compounds. Isopropyl myristate, dimethyl lauramide, and 1-dodecylazacycloheptan-2-one (laurocapram, Azone) were used as control enhancers. The most satisfactory enhancement of both the ester and amide series was observed with clofibric acid octyl amide; coadministration increased skin retention of hydrocortisone acetate after 24 h by 3.5-fold and that of betamethasone valerate by 2.9-fold. Diffusion cell receptor concentrations increased 51.6- and 10.3-fold, respectively, during the same time period. However, the enhancer compound in this case was applied to the skin 1 h prior to each of the steroids. The amide analogues were more effective than the equivalent ester compounds of the same carbon chain length. The best enhancer compounds (2c, 3d, 3e, and 3f) were nonirritating to athymic mouse skin in vivo.

Animals↗
PubMed2005

Sequence determination in aliphatic poly(ester amide)s by matrix-assisted laser desorption/ionization time-of-flight and time-of-flight/time-of-flight tandem mass spectrometry.

Poly(ester amide)s from dimethyl sebacate or sebacic acid and 2-aminoethanol or 4-amino-1-butanol were characterized by post-source decay matrix-assisted laser desorption/ionization time-of-flight (PSD-MALDI-TOF) and time-of-flight/time-of-flight tandem mass spectrometry (MALDI-TOF/TOF-MS/MS). Sodiated oligomers were selected as precursor ions for dissociation studies. PSD analysis was performed on dimethyl sebacate, dicarboxylic, carboxylic and amino alcohol, and diamino alcohol terminated oligomers. PSD-MALDI-TOF mass spectra yielded information on the fragmentation mechanisms of the poly(ester amide) chains, showing that the main cleavages proceed through a beta-hydrogen transfer rearrangement. MALDI-TOF/TOF-MS/MS provided structural information concerning ester/amide sequences in the polymer chains. As expected, together with the ions appearing in the PSD-MALDI mass spectrum, several new abundant fragment ions in the low-mass range are present in MALDI-TOF/TOF-MS/MS spectra. These new product ions proved to be diagnostic and made it possible to establish the presence of random sequences of ester and amide bonds in the poly(ester amide)s samples.

Journal Article↗
PubMed1995

The inactivation of bifunctional peptidylglycine alpha-amidating enzyme by benzylhydrazine: evidence that the two enzyme-bound copper atoms are nonequivalent.

Peptidylglycine alpha-amidating enzyme catalyzes the two-step conversion of C-terminal glycine-extended peptides to C-terminal alpha-amidated peptides and glyoxylate in a reaction that requires O2, ascorbate and 2 mol of copper per mole of enzyme [Kulathila et al. (1994) Arch. Biochem. Biophys. 311, 191-195]. Peptides with a C-terminal alpha-hydroxyglycine residue are intermediates in the amidation reaction. Benzylhydrazine inactivates the enzymatic conversion of dansyl-Tyr-Val-Gly to dansyl-Tyr-Val-NH2 in a time- and concentration-dependent manner. In contrast, the enzymatic conversion of dansyl-Tyr-Val-alpha-hydroxyglycine to dansyl-Tyr-Val-NH2 is unaffected by benzylhydrazine. The plot of 1/(inactivation rate) vs 1/[benzylhydrazine] is parabolic, indicating that the inactivation results from the interaction of 2 mol of benzylhydrazine per mole of enzyme. EPR spectra obtained from benzylhydrazine inactivation reactions carried out in the presence of a radical trap, alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone, show the formation of a carbon-centered benzyl radical. The benzyl radical most likely results from redox chemistry between benzylhydrazine and the enzyme-bound Cu(II) ions because EPR studies show that enzyme-bound Cu(II) is reduced to Cu(I) in the presence of benzylhydrazine. The kinetic constants for benzylhydrazine as a reductant in the amidation reaction were determined at benzylhydrazine concentrations too low to cause significant enzyme inactivation. Mimosine exhibits mixed inhibition vs benzylhydrazine; however, previous results have shown that benzylhydrazine is competitive vs ascorbate [Miller et al. (1992) Arch. Biochem. Biophys. 298, 380-388]. This change in kinetic mechanism coupled with the nonlinear inactivation kinetics have lead to a proposal that the two enzyme-bound Cu(II) atoms are nonequivalent with respect to their reduction by benzylhydrazine.

Animals↗
PubMed1999

Consecutive halogen transfer between various functional groups induced by reaction of hypohalous acids: NADH oxidation by halogenated amide groups.

Cyclic dipeptides (c-Gly(2), c-Ser(2), c-Gly-Phe, etc.) were used as simple protein models to investigate the HOCl-induced generation and reactivity of chlorinated amide groups. The pH dependence of the kinetics of amide chlorination reveals that ClO(-) (not HOCl) is the reactive agent. N-Chlorinated cyclopeptides are stable up to 30 min, they exhibit narrow absorption bands around 215 nm, and they are capable of oxidizing certain biological substrates, the reactivity decreasing in the order GSH > ascorbate > methionine > NADH >> GSSG. The chloroamide is less reactive, but much more selective in its reactions, than HOCl or ClO(-); thus, with formation of the chloroamide prolonged oxidative effects, directed toward specific target molecules, can be expected. Chlorination of NADH, yielding a catalytically inactive species (NAD/Cl), was investigated in most detail because it is likely to be an important and highly lethal process. The chloroamide group is far more reactive toward NADH than chloroamines derived from primary amines. Chloronucleotides formed by reaction of ClO(-) with inosine, GMP, TMP, or UMP are capable of quantitative chlorine transfer to cyclopeptides; however, no chlorine transfer between the amide nitrogen and primary amines is detectable, in either direction. The results presented enable prediction of chlorine transfer cascades induced by HOCl/ClO(-), involving nucleotides, peptide amide groups, and final target molecules. Chlorinated NAD(P)H, as a stable terminal product of consecutive chlorine transfer reactions, might be a useful biological marker for assessing the role of HOCl in inflammatory events. Bromination by BrO(-) of cyclopeptides is more than two orders of magnitude faster than chlorination by ClO(-), and the reactivity of bromoamide with NADH exceeds that of chloroamide by more than four orders of magnitude.

Chlorine↗
PubMed1994

Isolation and functional expression of human pancreatic peptidylglycine alpha-amidating monooxygenase.

Pancreastatin (PST) is processed from chromogranin A and the C-terminal amide of the peptide is an absolute requirement for biological activities. Human pancreatic carcinoma cells QGP-1 which produce both chromogranin A and PST were used to isolate cDNAs encoding two forms of peptidylglycine alpha-amidating monooxygenase (PAM). The two forms are a full length bifunctional enzyme and a variant lacking the transmembrane domain-coding region. When the cDNAs of these two forms were expressed in COS-7 cells, cells transfected with the predicted soluble form released into the culture medium a very much higher amidating activity which converts human chromogranin A-(273-302) to PST-29. The optimal pH for amidating activity was 5.4 and Cu2+, ascorbate and catalase were required as cofactors for the both forms of PAM. Km values for the membrane-bound and the soluble forms of PAM were 15.7 +/- 3.1 microM and 12.4 +/- 1.6 microM, respectively. These results demonstrate that both forms of PAM can function in the posttranslational processing of chromogranin A to PST in the environment of a secretory vesicle.

Amino Acid Sequence↗
PubMed1996

An expression system for the single-step production of recombinant human amidated calcitonin.

Amidating mouse pituitary cells (AtT-20) have been engineered to secrete human calcitonin (hCT) in the fully active amidated form, without the need of additional enzymatic or chemical modifications. The 141-residue human calcitonin precursor has first been cloned in the eucaryotic expression vector pRc/RSV, and the resulting plasmid pRc/RSV/hCT introduced in AtT-20 cells. After transfection, 122 independent clones resistant to G-418 were selected and screened for calcitonin production using a competitive ELISA specifically designed to detect the amidated form of calcitonin. One of these clones was amplified and showed expression of 17 ng/ml of hCT, with a 70% increase in productivity after cAMP treatment. Calcitonin was partially purified from culture medium by two sequential steps of reverse-phase chromatography and characterized in terms of immunoreactivity and molecular weight by TOF-MALDI mass spectroscopy, which confirmed the intended chemical nature and the presence of the C-terminal amidated residue.

Amino Acid Sequence↗