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PubMed2002

Iodine(V) reagents in organic synthesis. Part 1. Synthesis of polycyclic heterocycles via Dess-Martin periodinane-mediated cascade cyclization: generality, scope, and mechanism of the reaction.

The scope, generality, and mechanism of the Dess-Martin periodinane-mediated cyclization reaction of unsaturated anilides discovered during the total synthesis of the CP-molecules (phomoidrides A and B) are delineated. A plethora of heterocyclic compounds are accessible by employing gamma,delta-unsaturated amides (derived from anilines and carboxylic acids), urethanes, or ureas (derived from isocyanates and allylic alcohols and amines) as substrates. Optimization of the reaction led to room-temperature conditions, while isotope labeling studies allowed a mechanistic rationale for this cascade reaction.

Anilides↗
PubMed2002

Iodine(V) reagents in organic synthesis. Part 2. Access to complex molecular architectures via Dess-Martin periodinane-generated o-imidoquinones.

o-Imidoquinones, a rather rare class of compounds, are prepared from anilides by the action of Dess-Martin periodinane (DMP) and water. Their chemistry has been extensively investigated and found to lead to p-quinones and polycyclic systems of diverse molecular architectures. Applications of this methodology to the total synthesis of the naturally occurring compounds, epoxyquinomycin B and BE-10988, are described. Finally, another rare chemical entity, the ketohydroxyamide moiety, has been accessed through this DMP-based synthetic technology, and its reactivity has been studied. Among its most useful reactions is a set of cascade heterocyclic annulations leading to a variety of polycyclic systems of possible biological relevance.

Alkenes↗
PubMed1993

Inhibitors of acyl-CoA:cholesterol acyltransferase. 5. Identification and structure-activity relationships of novel beta-ketoamides as hypocholesterolemic agents.

A study of structure-activity relationships of substituted beta-ketoamide ACAT inhibitors I and II was performed. The results of this study suggest that whereas the beta-keto group was tolerated with no loss in activity, beta-hydroxy and oxime moieties led to significantly reduced activity in vitro and in vivo. The most potent inhibitor from the acyclic series (I) (11, IC50 = 0.006 microM) contained a C-13 alkyl chain. This compound reduced plasma total cholesterol by 38% and 66% at 3 and 30 mg/kg, respectively, in cholesterol-fed rats. Dimethylation alpha to the anilide core (5) and subsequent N-methylation of the amide NH (6) decreased in vitro potency significantly. It was also found that high potency was retained with inhibitors which incorporated the carbonyl into a lactam ring (II).

Anilides↗
PubMed1979

Structural analogues of L-glutamic Acid gamma-(4-hydroxyanilide) and gamma-(3,4-dihydroxyanilde) as potential agents against melanoma.

Nine heretofore unknown mono- and dihydroxyanilide analogues of the cytotoxic mushroom metabolites L-glutamic acid gamma-(4-hydroxyanilide) (1) and L-glutamic acid gamma-(3,4-dihydroxyanilide) (3, agaridoxin) were synthesized and tested as inhibitors of the growth of B16 mouse melanoma cells in culture. The naturally occurring anilides 1 and 3 had ID50 values of 0.10 and 0.27 mM, respectively. The analogue of 1 in which the gamma-L-glutamyl moiety was replaced by beta-L-aspartyl showed only a threefold decrease in activity, whereas attachment of the phenolic OH group to the meta instead of the para position resulted in a tenfold decrease. Other structural modifications, such as O-methylation or deletion of the carboxyl or amino group in the side chain, led to compounds of still lower activity (ID50 greater than 1.0 mM). The only analogue in the series with more activity than either 1 or 3 against B16 cells was L-glutamic acid gamma-(2,5-dihydroxyanilide) (14), which had an ID50 value of 0.051 mM. These data suggest that the gamma-L-glutamyl side chain in 1 or 3 plays a significant role in the biological action of these compounds, though some flexibility appears to exist insofar as the positioning of OH groups on the aromatic ring is concerned.

Anilides↗
PubMed1999

Virtual combinatorial syntheses and computational screening of new potential anti-herpes compounds.

The activity of new anti-HSV-1 chemical structures, designed by virtual combinatorial chemical synthesis and selected by a computational screening, is determined by an in vitro assay. A virtual library of phenol esters and anilides was formed from two databases of building blocks: one with carbonyl fragments and the other containing both substituted phenoxy and phenylamino fragments. The library of virtually assembled compounds was computationally screened, and those compounds which were selected by our mathematical model as active ones were finally synthesized and tested. Our antiviral activity model is a "tandem" of four linear functions of topological graph-theoretical descriptors. A given chemical structure was selected as active if it satisfies every discriminant equation in that model. The final result was that five new structures were selected, synthesized, and tested: all of them demonstrated activity, and three showed appreciable anti-HSV-1 activity, with IC(50) values of 0.9 microM. The same model, applied to a database of known compounds, has identified the anti-herpes activity of the following compounds: 3,5-dimethyl-4-nitroisoxazole, nitrofurantoin, 1-(pyrrolidinocarbonylmethyl)piperazine, nebularine, cordycepin, adipic acid, thymidine, alpha-thymidine, inosine, 2, 4-diamino-6-(hydroxymethyl)pteridine, 7-(carboxymethoxy)-4-methylcoumarin, 5-methylcytidine, and others that showed less activity.

Anilides↗
PubMed1994

The role of intramolecular nucleophilic catalysis and the effects of self-association on the deamidation of human insulin at low pH.

The influence of intramolecular catalysis and self-association on the kinetics of deamidation at the A-21 Asn residue of human insulin was explored at low pH and 35 degrees C. Observed rate constants of overall insulin degradation were determined as a function of pH over a pH range of 2.0-5.0 and as a function of total insulin concentration between pH 2.0-4.0. The pH-rate behavior of both monomeric and associated insulin degradation from pH 2.0 to 5.0 indicated intramolecular catalysis by the unionized carboxyl terminus of the A chain. Anhydride trapping with aniline at pH 3.0 provided evidence supporting the formation of a cyclic anhydride intermediate in the rate limiting step indicative of intramolecular nucleophilic catalysis. Insulin in the presence of aniline at low pH formed two anilide products, A-21 N delta 2-phenyl asparagine and N delta 2-phenyl aspartic acid human insulin, at the expense of desamido A-21 formation, consistent with the partitioning of a common intermediate. Self-associated insulin degraded at a rate approximately 2.5 times greater than that of the monomer at pH 2.0 and pH 3. However, self-association had a negligible or slight stabilizing effect on insulin decomposition at pH 4.0. An apparent downward shift in the pKa of the carboxyl terminus of approximately 0.75 units upon self-association and a catalytic rate constant which increases with -COOH acidity are proposed to account for these observations.

Amides↗
PubMed1983

Lipogenesis in liver, lung and adipose tissue of rats fed with oleoylanilide.

Oleoylanilide was administered orally to groups of rats according to different patterns. Subcellular fractionation of liver, lung and adipose tissue was then carried out in order to study the main enzyme activities involved in the lipogenesis. The observed findings indicate that adipose tissue and lung are the main target organs for the anilide, adipose tissue being involved in a general decrease of the enzyme activities, whereas transacylation reaction exhibits the most marked depletion of all the enzyme activities in the lung. The enzyme activities in liver were not markedly affected by this oral administration, although some data support the existence of a latent liver toxicity. These data suggest that oleoylanilide has the capacity to alter lipid metabolism of lung and adipose tissue to a considerable extent, whereas no major effect was produced in the liver. This different organ response could be related to the lymphatic gland via absorption of the substance.

Adipose Tissue↗
PubMed2006

Nitric oxide and liver microcirculation during autoregulation and haemorrhagic shock in rabbit model.

BACKGROUND: Direct evidence of nitric oxide (NO) involvement in the regulation of hepatic microcirculation is not yet available under physiological conditions nor in haemorrhagic shock. METHODS: A laser Doppler flowmetry was used to measure liver perfusion index and a specific NO-sensitive electrode was inserted into liver parenchyma of anaesthetized rabbits. Hepatic autoregulation during moderate hypovolaemia {mean arterial pressure at 50 mm Hg without liver perfusion alteration; blood withdrawal 17.7 (4.2) ml [mean (SD)]} or haemorrhagic shock [mean arterial pressure at 20 mm Hg associated with liver perfusion impairment and lactic acidosis; blood withdrawal 56.0 (6.8) ml] were investigated over 60 min and were followed by a rapid infusion of the shed blood. Involvement of NO synthases was evaluated using a non-specific inhibitor, NAPNA (Nomega-nitro-L-arginine P-nitro-anilide). RESULTS: In the autoregulation group, a decrease [30.0 (4.0) mm Hg] of mean arterial pressure did not alter liver perfusion index, whereas the liver NO concentration increased and reached a plateau [125 (10)%; compared with baseline; P<0.05]. This NO concentration was reduced to zero by the administration of NO synthase inhibitor. Haemorrhagic shock led to a rapid decrease in liver perfusion index [60 (7)%; compared with baseline; P<0.05] before an immediate and continuous increase in NO concentration [250 (50)%; compared with baseline; P<0.05]. Infusion of NO inhibitor before haemorrhagic shock reduced the NO concentration to zero and hepatic perfusion by 60 (8)% (P<0.05) of the baseline. Mean arterial pressure increased simultaneously. In these animals, during haemorrhage, a continuous increase in NO concentration still occurred and liver perfusion slightly increased. In all groups but NAPNA+haemorrhagic shock, blood replacement induced recovery of baseline values. CONCLUSIONS: NO plays a physiological role in the liver microcirculation during autoregulation. Its production is enzyme-dependent. Conversely, haemorrhagic shock induces a rapid increase in hepatic NO that is at least partially enzyme-independent.

Anilides↗
PubMed1997

Monitoring nitric oxide (NO) in rat locus coeruleus: differential effects of NO synthase inhibitors.

A porphyrinic microsensor combined with in vivo voltammetry was used to monitor extracellular nitric oxide (NO) in the locus coeruleus (LC) of anaesthetized rats. Administration of N omega-nitro-L-arginine p-nitro-anilide (100 mg/kg, i.p) or 7-nitro indazole (30 mg/kg, i.p.), which both inhibit preferentially neuronal NO synthase (NOS), induced a marked decrease in the NO oxidation peak height. On the other hand, N omega-nitro-L-arginine methyl ester (L-NAME) (200 mg/kg, i.p.), a less selective NOS inhibitor, failed to decrease the NO signal. Moreover, intra LC administration of NMDA, known to activate LC noradrenergic neurones, increased the NO signal. This study demonstrates the usefulness of in vivo voltammetry to monitor basal levels of NO and their changes in the LC. Differential effects of NOS inhibitors show that their central activity need to be assessed through in situ measurement of NO before using these inhibitors as neuropharmacological tools.

Anilides↗
PubMed1994

Peptidic p-nitroanilide substrates of interleukin-1 beta-converting enzyme.

Peptidic p-nitroanilides are useful colorimetric substrates for enzymes. With the aim of developing a convenient, quantitative assay for inhibitors of interleukin-1 beta-converting enzyme (ICE), we have explored three approaches to the synthesis of peptidic p-nitroanilides relevant to this enzyme. The first approach involved a late stage oxidation of a p-aminoanilide such as CbzValAlaAsp(beta- tert-butyl)-p-(t-Boc-amino)anilide. The second and third approaches used the preformed amino acid p-nitroanilides HAsp-p-nitroanilide hydrochloride and HAsp(beta-tert-butyl)-p-nitroanilide which were coupled iteratively with preactivated amino acid derivatives or with an appropriate peptide, respectively. While each approach had it merits and limitations, all three produced p-nitroanilides that were substrates for ICE.

Amino Acid Sequence↗
PubMedDate not supplied

Evaluation of the toxicity of substituted benzthioanilides by using in vitro tests.

The cytotoxicity of 12 benzthioanilides substituted in the N-aromatic ring, and of two commercial preparations (imaverol and thiuram) for comparison, was studied with clone 81 cat cells, by determining the highest tolerated dose, and by using the neutral red uptake assay and the kenacid blue assay for total protein. The concentrations that induced 20%, 50% and 80% (IC20, IC50 and IC80) inhibition relative to controls were calculated from dose-response curves. For some compounds, rat LD50 values were also determined. All the benzthioanilide preparations showed in vitro toxicities lower than those of the fungicides imaverol and thiuram. It was confirmed that the cytotoxicities of the compounds depend on the type of substituent. The least toxic compound contained a CONHCH(2)CO(2)H substituent in the para position of the N-aromatic ring, and the most toxic compounds contained chloro and fluoro, or three chloro substituents in the anilide moiety. All the benzthioanilides tested showed fungistatic activity for dermatophytes; two of the compounds (compound 5 and compound 12) also inhibited the development of yeasts at concentrations lower than those which caused toxicity in vitro. The LD50 values and the cytotoxic concentrations in vitro were linearly related.

Anilides↗
PubMed1987

ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen.

Pure antiandrogens, like flutamide, antagonize androgen action both peripherally and centrally at the hypothalamic-pituitary axis, which leads to an increase in LH and testosterone secretion. A new non-steroidal antiandrogen ICI 176,334 [2RS)-4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'- trifluoromethyl)propion-anilide) has now been discovered which causes regression of the accessory sex organs but does not increase serum concentrations of LH and androgens. ICI 176,334 binds to rat prostate androgen receptors with an affinity around fourfold that of hydroxyflutamide. When administered s.c. concurrently with testosterone propionate (200 micrograms/kg) for 7 days to immature castrated rats, ICI 176,334 (10 mg/kg) significantly (P less than 0.001) inhibited growth of the seminal vesicles and ventral prostate gland. Oral administration of ICI 176,334 at doses of 1, 5 and 25 mg/kg for 14 days to adult rats caused a dose-related reduction in accessory sex organ weights but had no effect on the testes. None of these doses caused a significant increase in serum LH and testosterone. Flutamide was around fourfold less potent and significantly increased serum LH and testosterone at the higher doses. ICI 176,334 was well tolerated. ICI 176,334 should, therefore, prove useful for the treatment of androgen-responsive benign and malignant diseases.

Androgen Antagonists↗
PubMed1994

N-phenyllinoleamide metabolism by human polymorphonuclear leukocytes.

1. N-phenyllinoleamide (NPLA), the anilide of linoleic acid, has been associated with the epidemiology of Toxic Oil Syndrome, but so far data available on its metabolism are scarce. On account of the similarities in chemical structure between linoleic acid and NPLA, the objective here has been to investigate the oxidative metabolism of this xenobiotic by human polymorphonuclear leukocytes. 2. Human polymorphonuclear leukocytes were incubated with 0.1 mM NPLA spiked with NPLA labelled either on the aniline or the fatty acid moieties. The metabolites were separated by high-performance liquid chromatography and individually collected prior to gas chromatography-mass spectrometry analysis. 3. Identification of the metabolites as N-phenyl-9-hydroxy- and N-phenyl-13-hydroxy-10,12-octadecenamide (9-HNPLA and 13-HNPLA) and their corresponding non-amidated metabolites, the 9-hydroxy- and 13-hydroxyoctadecenoic acids (9-HODE and 13-HODE), suggests that NPLA can be metabolized via the same hydroperoxidative processes acting upon linoleic acid. 4. Identification of free aniline as a NPLA metabolite suggests an amidase-like activity with liberation of aniline and the free fatty acid moieties.

Anilides↗
PubMed1976

Synthesis of N-acetylcysteine compounds.

The preparation of some anilides, esters and amides of N-acetyl and N,S-diacetyl-cysteine is described. Of the compounds synthesized, particular interest was aroused by the p-hydroxyanilide derivatives of N-acetyl and N,S-diacetyl-L-cysteine owing to their analgesic, antiinflammatory and antipyretic activity.

Acetylcysteine↗
PubMed1976

[Retrospective analysis of drug projection using correlative technics].

The problem of choosing substituents to allow correct correlative analysis according to the "Hausch Approach" is discussed. The problem of colinearity among parameters is considered in a case study on 296 anilides which inhibit the Hill reaction. The difficulty in of determining whether, pi or MR is the important variable in changes in activity is shown. "Cluster analysis" is discussed and proposed as a rational method for the selection of substituents to be introduced into biologically active structure in order to explore the scope of each defined physico-chemical parameter. An example of the use of this method conerning auxin activity of 1- and 2-benzotriazole derivatives is given.

Anilides↗
PubMed2002

[Ononis arvensis in vitro--abiotic elicitation].

The effect of two abiotic elicitors--two newly synthesized compounds (substituted anilides of pyrazine-2-carboxylic acids)--on the formation of flavonoids in the callus culture of Ononis arvensis L. was tested. The compounds markedly influenced the production of flavonoids in an in vitro culture. Particularly after elicitation with a solution of compound No. 1 (4-hydroxyanilide 6-chloro-5-terc.butylpyrazine-2-carboxylic acid) in a concentration of 3.32.10(-7) mol.l-1 and within 48 hours of elicitation an increase in flavonoid formation by 976% versus the control took place.

Anilides↗
PubMed1975

Kinetic studies of carboxypeptidase Y. I. Kinetic parameters for the hydrolysis of synthetic substrates.

Kinetic parameters for carboxypeptidase Y [EC 3.4.12.1], characterized as a nonspecific enzyme, are given for the hydrolysis of a series of acylated peptides, acylated amino acid esters, and amides. We confirmed that the enzyme released COOH-terminal proline and beta-alanine at an appreciable rate, as well as neutral amino acids with aromatic and aliphatic side chains at a very high speed. The rates of hydrolysis of ester and amide substrates were compatible with those produced by chymotrypsin [EC 3.4.21.1]. Stereospecificity was also demonstrated by the failure to hydrolyze peptide, ester, amide, and anilide substrates containing a D-amino acid. The effects of pH, solvents, and salt concentrations on the kinetic parameters of hydrolysis of peptide and ester substrates are also described.

Anilides↗
PubMed1985

[New 2,4-dibromo-6-(N-cyclohexyl-N-methyl)-aminomethylanilides of derivatives of cysteine and cystine with expectorant activity].

New 2,4-dibromo-6-(N-cyclohexyl-N-methyl)aminomethylanilides of N-acetylcysteine and N-acetyl-S-carboxymethylcisteine derivatives, N-benzyloxycarbonylcysteine and N,N'-bisbenzyloxycarbonylcystine were synthesized. The compounds were tested for the expectorant activity in rabbit and mouse. N,N'-Bisbenzyloxycarbonylcystin-bis [2,4-dibromo-6-(N-cyclohexyl-N-methyl)aminomethyl]anilide (XIX) was selected for further investigations.

Anilides↗