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At least 19 recordsLinked to original sources
PubMed1990

N-[(arylmethoxy)phenyl] carboxylic acids, hydroxamic acids, tetrazoles, and sulfonyl carboxamides. Potent orally active leukotriene D4 antagonists of novel structure.

Four series of N-[(arylmethoxy)phenyl] compounds were prepared as leukotriene D4 (LTD4) antagonists. In the hydroxamic acid series, methyl 3-(2-quinolinylmethoxy)benzeneacetohydroxamate (Wy-48,422, 20) was the most potent inhibitor of LTD4-induced bronchoconstriction with an oral ED50 of 7.9 mg/kg. Compound 20 also orally inhibited ovalbumin-induced bronchoconstriction in the guinea pig with an ED50 of 3.6 mg/kg. In vitro, against LTD4-induced contraction of isolated guinea pig trachea pretreated with indomethacin and 1-cysteine, 20 produced a pKB value of 6.08. In the sulfonyl carboxamide series, N-[(4-methylphenyl)sulfonyl]-3-(2-quinolinylmethoxy)-benzamide (Wy-49,353, 30) was the most potent antagonist. Compound 30 orally inhibited both LTD4- and ovalbumin-induced bronchoconstriction with ED50s of 0.4 and 20.2 mg/kg, respectively. In vitro, against LTD4-induced contraction of isolated guinea pig trachea, 30 produced a pKB value of 7.78. In the carboxylic acid series, which served as intermediates for the above two series, 3-(2-quinolinylmethoxy)benzeneacetic acid (Wy-46,016, 5) was the most potent inhibitor of LTD4-induced bronchoconstriction (99% at 25 mg/kg, intraduodenally); however, the pKB for this compound was disappointing (5.79). In the tetrazole series, the most potent inhibitor was 2-[[3-(1H-tetrazol-5-ylmethyl)phenoxy]methyl]quinoline (Wy-49,451, 41). The respective inhibitory ED50s were 3.0 mg/kg versus LTD4 and 17.5 mg/kg versus ovalbumin. In the isolated guinea pig trachea, 41 produced a pKB value of 6.70.

Animals↗
PubMed1975

Inhibition of urease activity by hydroxamic acid derivatives of amino acids.

Hydroxamic acids have been reported to be potent and specific inhibitors of urease (EC 3.5.1.5) activity of plant and bacterial origin. The present investigation was performed on the inhibitory effect of hydroxamic acid derivatives of naturally occurring amino acids on the urease activity of the Jack Bean and the alimentary tracts of rats. Methionine-hydroxamic acid was the most powerful inhibitor (I50=3.9 X 10(-6) M) among nineteen alpha-aminoacyl hydroxamic acids. Phenylalanine-, serine-, alanine-, glycine-, histidine-, threonine-, leucine-, and arginine-hydroxamic acids followed, in order of decreasing inhibitory power. The inhibition proceeded with time at a comparable rate to fatty acyl hydroxamic acid inhibition. The I50 values of alpha-aminoacyl hydroxamic acids were found to be almost equal to those of the corresponding fatty acyl hydroxamic acids. This fact shows that the alpha-amino group did not affect inhibitory power. However, aspartic-beta-, lysine-, and glutamic-gamma-hydroxamic acids, in descending order, were much less inhibitory, probably due to the presence of a carboxyl or omega-amino group. Furthermore, the pH optimum of the inhibition shifted to lower pH in the presence of a carboxyl group, and to a higher pH in e presence of an amino group. The results suggest that the dissociation of an acidic or a basic group reduces the inhibitory power of hydroxamic acid. Hydroxamic acid inhibits urease activity with strict specificity, excpet for aspartic-beta-hydroxamic acid, which inhibited asparaginase competitively. Hydroxamic acid derivatives of amino acids inhibited not only the urease activity of the Jack Bean, but also that of the caecum and ileum parts of the rat intestine.

Amino Acids↗
PubMed2002

Temporal variation of RAPD-PCR phenotype composition of the grain aphid Sitobion avenae (Hemiptera: Aphididae) on wheat: the role of hydroxamic acids.

Hydroxamic acids (Hx) contained in wheat are active mutagens which play an important role in the defence of the plant against aphids. Random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR) dominant markers were used to assess genetic variability in the aphid Sitobion avenae (Fabricius) in relation to hydroxamic acid levels in their host-plants. Colonies of aphids belonging to a single RAPD-PCR profile were grown on different host-plants differing in their Hx content under greenhouse conditions. The RAPD-PCR phenotypic pattern showed the appearance of two new RAPD-PCR variants after four to five generations of exposure to wheat cv. Chagual (high Hx levels), one after exposure to wheat cv. Huayún (low Hx levels), and none after exposure to oat (lacking Hx). Differential appearance of new RAPD-PCR aphid phenotypes also occurred on field-grown wheat. While the overall phenotypic 'richness' diminished during the season, the number of RAPD-PCR phenotypes decreased on cv. Huayún and increased on cv. Chagual. The preferential appearance in the field and in the greenhouse of new RAPD-PCR phenotypes of S. avenae on cv. Chagual is discussed on the basis of mutagenesis induced by hydroxamic acids and by the products of their transformation within the aphid. Aphid abundance is interpreted in terms of antixenosis and antibiosis by hydroxamic acids. The appearance on cv. Chagual of phenotypes first detected on cv. Huayún was accounted for by intercrop migrations.

Animals↗
PubMed2003

Acidity of hydroxamic acids and amides.

The relatively strong acidity of hydroxamic acids was analyzed by means of isodesmic reactions in which this acid or its anion is formed from simpler precursors. Acidity of amides was analyzed in the same way. Energies of all compounds involved in the reactions were calculated at the B3LYP/AUG-cc-pVTZ//B3LYP/6-311 + G(d,p) level; at this level a good agreement was reached with the sparse experimental data. Interpretation of the results was the same as in the recent discussion of the acidity of carboxylic acids, and the conclusions were similar: both amides and hydroxamic acids are stabilized with respect to simpler reference molecules of amines or N-alkylhydroxylamines, respectively. However, their anions are stabilized still more and are responsible for the acidity. This effect is stronger in hydroxamic acids or amides than in carboxylic acids. The problem of whether it is due to resonance depends on the definition of this term. Semiquantitative comparison suggests that resonance in hydroxamic acids is more important than in amides and still more than in carboxylic acids. The stronger acidity of hydroxamic acids compared to amides is due to the destabilizing inductive effect of the hydroxyl group in the acid molecule, not to any effect in the anion.

Journal Article↗
PubMed1971

Specific inhibition of the cyanide-insensitive respiratory pathway in plant mitochondria by hydroxamic acids.

Hydroxamic acids, R-CONHOH, are inhibitors specific to the respiratory pathway through the alternate, cyanide-insensitive terminal oxidase of plant mitochondria. The nature of the R group in these compounds affects the concentration at which the hydroxamic acids are effective, but it appears that all hydroxamic acids inhibit if high enough concentrations are used. The benzhydroxamic acids are effective at relatively low concentrations; of these, the most effective are m-chlorobenzhydroxamic acid and m-iodobenzhydroxamic acid. The concentrations required for half-maximal inhibition of the alternate oxidase pathway in mung bean (Phaseolus aureus) mitochondria are 0.03 mm for m-chlorobenzhydroxamic acid and 0.02 mm for m-iodobenzhydroxamic acid. With skunk cabbage (Symplocarpus foetidus) mitochondria, the required concentrations are 0.16 for m-chlorobenzhydroxamic acid and 0.05 for m-iodobenzhydroxamic acid. At concentrations which inhibit completely the alternate oxidase pathway, these two compounds have no discernible effect on either the respiratory pathway through cytochrome oxidase, or on the energy coupling reactions of these mitochondria. These inhibitors make it possible to isolate the two respiratory pathways and study their mode of action separately. These inhibitors also enhance an electron paramagnetic resonance signal near g = 2 in anaerobic, submitochondrial particles from skunk cabbage, which appears to be specific to the alternate oxidase and thus provides a means for its assay.

Cyanides↗
PubMed1980

Therapy for urolithiasis by hydroxamic acids. III. Urease inhibitory potency and urinary excretion rate of N-acylglycinohydroxamic acids.

Hydroxamic acid, a potent urease inhibitor, having a high urinary excretion rate is expected to be a therapeutic agent for urolithiasis caused by urea-splitting bacterial infection of the urinary tract. Twenty-one new derivatives of N-aliphatic-acylglycinohydroxamic acids (GHAs) were synthesized, and their inhibitory potencies against the urease activity of sword bean in a phosphate buffer and against the ureolytic activity of Proteus mirabilis in human urine, and their urinary excretion rates in rats were also measured for this purpose I50 values of most of GHAs against the urease activity of sword bean were about 1 to 10 microM and 2-ethyl-n-butyroyl GHA was the most potent inhibitor with the value of 0.79 microM. I50 values of most of the GHAs against the ureolytic activity of Proteus mirabilis were about 5 to 50 microM and n-nonaroyl GHA was the most potent inhibitor with the value of 3.6 microM. 2,2-Dimethylpropionyl GHA had the highest urinary excretion rate with the recovery of 11%. Routes of administration of 2,2-dimethylpropionyl GHA and sex of rats used did not affect the amount of urinary excretion at all. The results in this report suggest that DL 2-methyl-n-butyroyl, 2-ethyl-n-butyroyl and 2,2-dimethylpropionyl GHA are the most hopeful therapeutic agents for urolithiasis among them.

Animals↗
PubMed1999

Apoptosis induction by a novel anti-prostate cancer compound, BMD188 (a fatty acid-containing hydroxamic acid), requires the mitochondrial respiratory chain.

We recently developed a class of novel anti-prostate cancer compounds, cyclic hydroxamates that elicit a potent apoptotic response in many tumor cells cultured in vitro (D.G. Tang et al., Biochem. Biophys. Res. Commun., 242: 380-384, 1998). The lead compound, termed BMD188, induces programmed cell death in a variety of prostate cancer cells in vitro as well as in vivo (L. Li et al., Anticancer Res., 19: 51-70, 1999). BMD188 kills androgen-independent prostate cancer cells as well as prostate cancer cells with a multidrug-resistance phenotype. The apoptotic effect of BMD188 in prostate cancer cells does not depend on cell cycle, p53 status, or its purported target, arachidonate 12-lipoxygenase, but does require caspase activation and seems to involve mitochondria. To synthesize more specific and effective anti-prostate cancer hydroxamic acid compounds, it is important to understand their mechanism(s) of action. In the present study, we studied the role of mitochondrial respiratory chain (MRC) in BMD188-induced apoptosis in androgen-independent prostate cancer PC3 cells and compared its effect with that of staurosporine (STS), a widely used apoptosis inducer. Several lines of evidence indicate that BMD188-induced cell death depends on MRC: (a) the death could be significantly inhibited by several complex-specific respiration inhibitors; (b) respiration-deficient rho0 cells were more resistant than wild-type parent cells to apoptosis induction by BMD188; and (c) BMD188 induced a rapid increase in reactive oxygen species in mitochondria, an up-regulation of cytochrome c oxidase subunits, a biphasic alteration (i.e., an early hyperpolarization, followed by later hypopolarization) in the mitochondrial membrane potential (delta psi(m)), dramatic changes in mitochondrial morphology and distribution prior to caspase activation, and an abnormal proliferation of mitochondria at the ultrastructural level. By contrast, STS-induced PC3 apoptosis seemed not to depend on MRC. Taken together, the data suggest that the MRC represents a functional target for anti-prostate cancer hydroxamates.

Antineoplastic Agents↗
PubMed1999

Generation of nitric oxide and possibly nitroxyl by nitrosation of sulfohydroxamic acids and hydroxamic acids.

Diazeniumdiolates (NONOates) and sulfohydroxamic acids are chemical entities that spontaneously generate nitric oxide (NO) and nitroxyl (HNO), respectively, at physiological pH and temperature. By combining the functional aspects of the NONOates with the hydroxamic acids and sulfohydroxamic acids, hybrid NONOate-type compounds that could theoretically generate nitroxyl or nitric oxide can be rationalized. Although the instability of these compounds, viz., the N-nitrosohydroxamic acids and the N-nitrososulfohydroxamic acids, precluded their chemical characterization by actual isolation, their transient existence was deduced by identification of the products of their decomposition. Thus, treatment of benzohydroxamic acid (BHA) with limiting or excess nitrous acid (from NaNO(2) and H(3)PO(4)) gave rise to quantitative generation of N(2)O, possibly via HNO, based on the limiting reactant. Nitrosation of N-t-butyloxycarbonyl hydroxylamine gave similar results. The organic acid produced from BHA was identified as benzoic acid. No nitric oxide was detected from these reactions. In contrast, treatment of Piloty's acid (benzenesulfohydroxamic acid) and methanesulfohydroxamic acid (MSHA) with nitrous acid under the same conditions as above gave 36% of the theoretical quantity of NO from Piloty's acid and 47% of NO from MSHA, although finite quantities of HNO (measured as N(2)O) were also formed. The organic acid produced from Piloty's acid was identified by reverse-phase HPLC as the redox product, benzenesulfinic acid.

Hydrazines↗
PubMedDate not supplied

Synthesis of N-[tris[2-[[N-(benzyloxy)amino]carbonyl]ethyl]methyl]succinamic acid, trisuccin. Hydroxamic acid derivatives as a new class of bifunctional chelating agents.

In an effort to generate bifunctional chelating agents (BCAs) with improved labeling, conjugation, and biodistribution properties, the synthesis of trisuccin is reported. This new hydroxamate BCA, after synthesis and characterization, was used for conjugation and radiolabeling of monoclonal antibodies with 99mTc. This new class of synthetic BCAs may be useful in the radioimmunodiagnosis and radioimmunotherapy of cancer.

Antibodies, Monoclonal↗
PubMed2000

Metal complexes of salicylhydroxamic acid (H2Sha), anthranilic hydroxamic acid and benzohydroxamic acid. Crystal and molecular structure of [Cu(phen)2(Cl)]Cl x H2Sha, a model for a peroxidase-inhibitor complex.

Stability constants of iron(III), copper(II), nickel(II) and zinc(II) complexes of salicylhydroxamic acid (H2Sha), anthranilic hydroxamic acid (HAha) and benzohydroxamic acid (HBha) have been determined at 25.0 degrees C, I=0.2 mol dm(-3) KCl in aqueous solution. The complex stability order, iron(III) >> copper(II) > nickel(II) approximately = zinc(II) was observed whilst complexes of H2Sha were found to be more stable than those of the other two ligands. In the preparation of ternary metal ion complexes of these ligands and 1,10-phenanthroline (phen) the crystalline complex [Cu(phen)2(Cl)]Cl x H2Sha was obtained and its crystal structure determined. This complex is a model for hydroxamate-peroxidase inhibitor interactions.

Copper↗
PubMed1987

HRP-catalyzed bioactivation of carcinogenic hydroxamic acids. The greater reactivity of glycolyl- versus acetyl-derived hydroxamic acids.

An analysis of the hydroxamic acid oxidation reaction by H2O2 and horseradish peroxidase (HRP) was made with three pairs of hydroxamic acids. Each pair consisted of the aceto- and glycolhydroxamic acid derivatives from one of three different arylhydroxylamines. The parent arylhydroxylamines were the known carcinogens, N-hydroxy-2-aminofluorene and N-hydroxy-4-aminobiphenyl and the noncarcinogen 4-chlorophenyl-hydroxylamine. All the hydroxamic acids appeared to be converted to products that were expected on the basis of the previously-proposed mechanism of this peroxidative reaction. Each acetohydroxamic acid gave the corresponding nitroso compound and O-acetyl ester of the starting material in approximately equal amounts. The glycolhydroxamic acids gave the corresponding nitroso compound and a relatively unstable product that was proposed, by analogy, to be the O-glycolyl ester of the starting material. A comparison of the initial rates of reaction of each hydroxamic acid pair showed that the glycolhydroxamic acid was much more susceptible to the peroxidation reaction than was the corresponding acetohydroxamic acid. The initial rate of the reaction was also highly dependent upon the nature of the aromatic ring in the order fluorene greater than biphenyl greater than 4-chlorophenyl. The relative degree of HRP-catalyzed covalent binding to DNA of the aceto- and glycolhydroxamic acids in the fluorene series was studied and found to parallel the relative rates of reaction of these substrates in the H2O2/HRP system. It was proposed that glycolhydroxamic acids are likely to be more genotoxic than are acetohydroxamic acids when subjected to peroxidative bioactivation conditions.

Biotransformation↗
PubMed2001

Identification of novel potent hydroxamic acid inhibitors of peptidyl deformylase and the importance of the hydroxamic acid functionality on inhibition.

Peptidyl deformylase (PDF) is a metallo protease that catalyzes the removal of a formyl group from the N-termini of prokaryotic prepared polypeptides, an essential step in bacterial protein synthesis. Screening of our compound collection using Staphylococcus aureus PDF afforded a very potent inhibitor with an IC(50) in the low nanomolar range. Unfortunately, the compound that contains a hydroxamic acid did not exhibit antibacterial activity (MIC). In order to address the lack of activity in the MIC assay and to determine what portion of the molecule was responsible for binding to PDF, we prepared several analogues. This paper describes our findings that the hydroxamic acid functionality found in 1 is mainly responsible for the high affinity to PDF. In addition, we identified an alternative class of PDF inhibitors, the N-hydroxy urea 18, which has both PDF and antibacterial activity.

Amidohydrolases↗