Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “HYDROXAMIC ACID”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 667 records · Page 37Linked to original sources
PubMedDate not supplied

Modification of 6-aminopenicillanic acid derivatives.

In order to prepare intermediate for further transformation of penicillins), and to obtain new derivatives with enlarged spectrum of biological activity some semi-synthetic phenoxyalkanepenicillins were subjected to the esterification, amidation and hydroxyamidation reactions. Hydroxyamidation i.e. synthesis of corresponding penicilline-hydroxamic acids was a complex reaction depending on the structure of hydroxylamine used. The two-directional reaction course, with beta-lactam bond splitting, was specific for unsubstituted hydroxylamine only. A number of new penicilline hydroxamic acids and N-methoxypenicilline amides, with intact and cleaved beta-lactam ring were synthesized.

Methods↗
PubMed1998

Detoxification of Benzoxazolinone Allelochemicals from Wheat by Gaeumannomyces graminis var. tritici, G. graminis var. graminis, G. graminis var. avenae, and Fusarium culmorum.

The ability of phytopathogenic fungi to overcome the chemical defense barriers of their host plants is of great importance for fungal pathogenicity. We studied the role of cyclic hydroxamic acids and their related benzoxazolinones in plant interactions with pathogenic fungi. We identified species-dependent differences in the abilities of Gaeumannomyces graminis var. tritici, Gaeumannomyces graminis var. graminis, Gaeumannomyces graminis var. avenae, and Fusarium culmorum to detoxify these allelochemicals of gramineous plants. The G. graminis var. graminis isolate degraded benzoxazolin-2(3H)-one (BOA) and 6-methoxy-benzoxazolin-2(3H)-one (MBOA) more efficiently than did G. graminis var. tritici and G. graminis var. avenae. F. culmorum degraded BOA but not MBOA. N-(2-Hydroxyphenyl)-malonamic acid and N-(2-hydroxy-4-methoxyphenyl)-malonamic acid were the primary G. graminis var. graminis and G. graminis var. tritici metabolites of BOA and MBOA, respectively, as well as of the related cyclic hydroxamic acids. 2-Amino-3H-phenoxazin-3-one was identified as an additional G. graminis var. tritici metabolite of BOA. No metabolite accumulation was detected for G. graminis var. avenae and F. culmorum by high-pressure liquid chromatography. The mycelial growth of the pathogenic fungi was inhibited more by BOA and MBOA than by their related fungal metabolites. The tolerance of Gaeumannomyces spp. for benzoxazolinone compounds is correlated with their detoxification ability. The ability of Gaeumannomyces isolates to cause root rot symptoms in wheat (cultivars Rektor and Astron) parallels their potential to degrade wheat allelochemicals to nontoxic compounds.

Journal Article↗
PubMed1999

Glucuronidation of benzidine and its metabolites by cDNA-expressed human UDP-glucuronosyltransferases and pH stability of glucuronides.

Although glucuronidation is considered a necessary step in aromatic amine-induced bladder cancer, the specific enzymes involved are not known. This study assessed the capacity of five different human recombinant UDP-glucuronosyltransferases expressed in COS-1 cells to glucuronidate benzidine, its metabolites and 4-aminobiphenyl. [(14)C]UDP-glucuronic acid was used as co-substrate. UGT1A1, UGT1A4 and UGT1A9 each metabolized all of the aromatic amines. UGT1A9 exhibited the highest relative rates of metabolism with preference for the two hydroxamic acids, N-hydroxy-N-acetylbenzidine and N-hydroxy-N,N'-diacetylbenzidine. UGT1A9 metabolized 4-aminobiphenyl approximately 50% faster than benzidine or N-acetylbenzidine. UGT1A4 N-glucuronidated N'-hydroxy- N-acetylbenzidine at the highest relative rate compared with the other transferases. UGT1A6 was effective in metabolizing only four of the eight aromatic amines tested. UGT1A1 demonstrated more extensive metabolism of the hydroxamic acid, N-hydroxy-N,N'-diacetylbenzidine, and the ring oxidation product, 3-OH-N,N'-diacetylbenzidine, than it did for the other six amines. UGT2B7 was the only product of the UGT2 gene family examined and it metabolized all the aromatic amines at similar low relative levels compared with a preferred substrate, 4-OH-estrone. The K(m) values for N-acetylbenzidine metabolism by UGT1A1 and UGT1A4 were 0.37 +/- 0.14 and 1.8 +/- 0.4 mM, respectively. The O-glucuronide of 3-OH-N,N'-diacetylbenzidine was not hydrolyzed during a 24 h 37 degrees C incubation at either pH 5. 5 or 7.4. Likewise, the O-glucuronide of 3-OH-benzidine was stable at pH 7.4, with 52% remaining at pH 5.5 after 24 h. These results suggest the following relative ranking of transferase metabolism: UGT1A9 > UGT1A4 > > UGT2B7 > UGT1A6 approximately UGT1A1. The relative pH stability of O-glucuronides is consistent with a role in detoxification and excretion of aromatic amines, while the acid lability of N-glucuronides is consistent with delivery of these amines to the bladder epithelium for activation, resulting in DNA adducts which may lead to mutations.

Base Sequence↗
PubMed2000

Structure-activity relationships and pharmacokinetic analysis for a series of potent, systemically available biphenylsulfonamide matrix metalloproteinase inhibitors.

A series of biphenylsulfonamide derivatives of (S)-2-(biphenyl-4-sulfonylamino)-3-methylbutyric acid (5) were prepared and evaluated for their ability to inhibit matrix metalloproteinases (MMPs). For this series of compounds, our objective was to systematically replace substituents appended to the biphenyl and alpha-position of 5 with structurally diverse functionalities to assess the effects these changes have on biological and pharmacokinetic activity. The ensuing structure-activity relationship (SAR) studies showed that biphenylsulfonamides substituted with bromine in the 4'-position (11c) significantly improved in vitro activity and exhibited superior pharmacokinetics (C(max), t(1/2), AUCs), relative to compound 5. Varying the lipophilicity of the alpha-position by replacing the isopropyl group of 11c with a variety of substituents, in general, maintained potency versus MMP-2, -3, and -13 but decreased the oral systemic availability. Subsequent evaluation of its enantiomer, 11c', showed that both compounds were equally effective MMP inhibitors. In contrast, the corresponding hydroxamic acid enantiomeric pair, 16a (S-isomer) and 16a' (R-isomer), stereoselectivity inhibited MMPs. For the first time in this series, 16a' provided nanomolar potency against MMP-1, -7, and -9 (IC(50)'s = 110, 140, and 18 nM, respectively), whereas 16a was less potent against these MMPs (IC(50)'s = 24, 78, and 84 microM, respectively). However, unlike 11c, compound 16a' afforded very low plasma concentrations following a single 5 mg/kg oral dose in rat. Subsequent X-ray crystal structures of the catalytic domain of stromelysin (MMP-3CD) complexed with inhibitors from closely related series established the differences in the binding mode of carboxylic acid-based inhibitors (11c,c') relative to the corresponding hydroxamic acids (16a,a').

Animals↗
PubMed2005

Biotransformation of 2-benzoxazolinone to 2-amino-(3H)-phenoxazin-3-one and 2-acetylamino-(3H)-phenoxazin-3-one in soil.

An alternative to the use of synthetic pesticides is to exploit the natural defense chemicals produced by cereals. An important class of allelochemicals is cyclic hydroxamic acids and related benzoxazolinones. A prolonged degradation experiment of the allelochemical compound from rye 2-benzoxazolinone (BOA) was carried out for up to 90 d at 15 degrees C at three different concentration levels, 3, 3000, and 30,000 nmol BOA g soil(-1), respectively, in a sandy loam soil. Two main degradation products, 2-amino-(3H)-phenoxazin-3-one (APO) and 2-acetylamino-(3H)-phenoxazin-3-one (AAPO), were identified and quantified by LC-ESI-MS-MS. The half-life of BOA increased with higher levels of BOA added to the soil. Half-lives of BOA, APO, and AAPO were determined by fitting a single first-order model to the degradation data. Half-life of BOA was determined to be 0.6 d in the 3 nmol BOA g soil(-1) treatment. Half-lives of BOA, APO, and AAPO were 3.1, 2.7, and 2.1 d, respectively, in the 3000 nmol BOA g soil(-1) treatment. In the 30,000 nmol BOA g soil(-1) treatment, the half-lives were 31 d for BOA and 45 d for APO. The microbial community structure was not affected by addition of BOA to the soil as investigated by analysis of signature fatty acids. The results suggest that the exploitability of BOA for crop protection is dependent on the existing concentration of BOA in the soil and the timing of incorporation of hydroxamic acid synthesizing crops into the soil.

Agriculture↗
PubMed1989

Spermexatin and spermexatol: new synthetic spermidine-based siderophore analogues.

Syntheses of hexanediamine-based dihydroxamate (Hexamate), spermidine-based trihydroxamate (Spermexatins), and spermidine-based mixed siderophore analogues (Spermexatols) are described. Key intermediates include the N-hydroxysuccinimide esters of various hydroxamic acids, e.g., malonohydroxamate, succinohydroxamate, and glutarohydroxamate. These intermediates were synthesized, characterized, and incorporated as the ligating chains on spermidine. Also, mixed iron chelating compounds (Spermexatols) with both catechol and hydroxamic acid side chains were synthesized. The reagent carbobenzoxyimidazole was employed to distinguish between the primary and secondary amino groups of spermidine. The ability of these iron chelators to stimulate microbial growth is also described.

Iron Chelating Agents↗
PubMed2005

Spectral and theoretical studies of N-p-(ethylbenzene)thiobenzohydroxamic acid metal chelates.

The preparation of N-p-(ethylbenzene)thiobenzohydroxamic acid chelates with several metal ions and their spectral properties are described in this paper. This is followed by a theoretical study of metal complexes of some thiohydroxamic acids, as well as the prepared chelates. The electronic properties of the metal complexes are discussed. The experimental and theoretical electronic spectra are also compared. A possible reason for the smaller pKa values of thiohydroxamic acid complexes than those of the corresponding hydroxamic acids is given.

Chelating Agents↗
PubMed1993

Identification of the thyrotropin-releasing-hormone-degrading ectoenzyme as a metallopeptidase.

A time-dependent inhibition of the thyrotropin-releasing-hormone (TRH)-degrading ectoenzyme (EC 3.4.19.-) from rat brain by the metal-complexing agents imidazole, NaCN, EDTA and 1,10-phenanthroline could be demonstrated. In contrast, the inhibition by the non-chelating analogues 4,7- and 1,7-phenanthroline was not time-dependent. At a concentration of 100 microM EDTA the enzymic activity decreased by 50% only after pretreatment for 6 h. It could be restored by addition of Zn2+, Ni2+ and Co2+ but not by other transition metal ions and also not by Ca2+ and Mg2+. Without pretreatment, the enzyme was activated by Co2+ and inhibited by Cu2+, Cd2+ and Hg2+ in a time-dependent manner, but remained unaffected by Ni2+ and Mn2+, as well as by Ca2+ and Mg2+. Compatible with the His-Glu-Xaa-Xaa-His consensus sequence of most zinc-containing metallopeptidases, chemical modification studies with carbodiimide revealed the presence of an essential acidic amino acid residue, probably located at the active site of the enzyme. The catalytically active metal ion could be exchanged for 65Zn and the enzyme could be effectively inhibited by L-pyroglutamyl hydroxamic acid, the chelating derivative of the TRH cleavage product pyroglutamic acid. The TRH-degrading ectoenzyme thus classifies as a member of the zinc-dependent metallopeptidase family.

Aminopeptidases↗
PubMed1977

Determination of ibuproxam and its metabolites in the plasma and urine of rats.

The metabolism of 2-(4-isobutylphenyl)-propio-hydroxamic acid (ibuproxam, Ibudros), a new molecule with anti-inflammatory, antipyretic and analgesic activity was studied by its administration orally and rectally to the rat. The analysis, carried out with gas chromatographic method and thin-layer chromatography, showed that the drug is present in blood as 2-(4-isobutylphenyl)-propionic acid (ibuprofen), an anti-inflammatory drug which is commonly used and the metabolites of which are already known. Using the same methods, it was observed that only a few traces of the hydroxamic acid appear in the urines of rats treated with ibuproxam, whilst the ibuprofen metabolite is absent. Therefore, we conclude that the drug ibuproxam changes rapidly into ibuprofen, following afterwards the same known metabolic process as the latter drug.

Animals↗
PubMed1986

Proteoglycan- and collagen-degrading enzymes from human interleukin 1-stimulated chondrocytes from several species: proteoglycanase and collagenase inhibitors as potentially new disease-modifying antiarthritic agents.

Human IL-1-stimulated chondrocytes derived from rabbit, bovine, and human articular cartilage produce proteoglycan- and collagen-degrading enzymes. These studies demonstrate that the biological activity of IL-1 is not species specific. Several thiol, carboxyalkyl, and hydroxamic acid peptide inhibitors showed differential effects. The thiols were equipotent inhibitors of both the collagen- and proteoglycan-degrading enzymes whereas the carboxyalkyls appear to inhibit solely the proteoglycan-degrading enzyme(s). The hydroxamic acid peptides, the most potent inhibitors, appear to be more active against the proteoglycan-degrading enzymes. These synthetic inhibitors of proteoglycan- and/or collagen-degrading enzymes may represent a new class of disease-modifying antiarthritic agents.

Animals↗
PubMed2005

Histone deacetylase inhibitors.

Histones are small basic proteins that, by complexing wtih DNA, form the nucleosome core. Repetitive units of this nucleosome led to the chromatin in which all the human genome is packaged. Histones can be in one of the two antagonist forms, acetylated or deacetylated, equilibrium regulated by the corresponding enzymes, histone acetylases and histones deacetylases (HDACs). Inhibition of HDACs represents a new strategy in human cancer therapy since these enzymes play a fundamental role in regulating gene expression and chromatin assembly. They are potent inducers of growth arrest, differentiation and apoptosis of tumor cells. A wide variety of HDACs of both natural and synthetic origin has been reported. Except depsispeptide FK228, natural HDACs (trichostatin (TSA), depudecin, trapoxins, apicidins) as well as sodium butyrate, phenylbutyrate and suberoyl anilide hydroxamic acid (SAHA), while effective in vivo, are inefficient due to instability and low retention. Subsequently, synthetic analogs isolated from screening libraries (oxamflatin, scriptaid) were discovered as havind a common structure with TSA and SAHA: an hydroxamic acid zinc-binding group linked via a spacer (5 or 6 CH2) to a hydrophobic group. Design of a second generation of HDACs was based upon these data affording potent HDACs such as LAQ824 and PDX101 currently under phase I clinical trials. Simultaneously, synthetic benzamide-containing HDACs were reported and two of them, MS-275 and CI-994, have reached phase II and I clinical trials, respectively.

Drug Design↗
PubMed1996

Iron chelates bind nitric oxide and decrease mortality in an experimental model of septic shock.

The hydroxamic acid siderophore ferrioxamine B [FeIII(HDFB)+] and the iron complex of diethylenetri-aminepentaacetic acid [FeIII(DTPA)2-] protected mice against death by septic shock induced by Corynebacterium parvum + lipopolysaccharide. Although FeIII(DTPA)2- was somewhat more effective than FeIII(HDFB)+, the iron-free ligand H4DFB+ was significantly more effective than DTPA. The hydroxamic acid chelator has a much higher iron affinity than the amine carboxylate, allowing for more efficient formation of the FeIII(HDFB)+ complex upon administration of the iron-free ligand. Electrochemical studies show that FeIII(DTPA)2- binds NO stoichiometrically upon reduction to iron(II) at biologically relevant potentials to form a stable NO adduct. In contrast, FeIII(HDFB)+ is a stable and efficient electrocatalyst for the reduction of NO to N2O at biologically relevant potentials. These results suggest that the mechanism of protection against death by septic shock involves NO scavenging and that particularly effective drugs that operate a low dosages may be designed based on the principle of redox catalysis. These complexes constitute a new family of drugs that rely on the special ability of transition metals to activate small molecules. In addition, the wealth of information available on siderophore chemistry and biology provides an intellectual platform for further development.

Animals↗
PubMed1994

Fragments of human fibroblast collagenase: interaction with metalloproteinase inhibitors and substrates.

On purification, active human fibroblast collagenase breaks down by an autolytic mechanism into two major forms (M(r) 22,000 and M(r) 27,000) and one minor form (M(r) 25,000). The ability of human collagenase to bind to the tissue inhibitor of metalloproteinases (TIMP) and to TIMP-2 resides mainly in the active site area of the 22,000 M(r) N-terminal domain of the molecule, but the 27,000 M(r) C-terminal domain also has a role in stabilizing these interactions. The 22,000 M(r) fragment is able to form a complex with TIMP and TIMP-2 which is stable to gel filtration in a similar manner to the whole molecule, but no such complexes are formed by the 27,000 M(r) fragment. Complex formation with the whole molecule is prevented by EDTA and by 1,10-phenanthroline demonstrating the importance of the active site; additionally TIMP and TIMP-2 will compete with a reversibly bound peptide hydroxamic acid inhibitor for the active site. The inhibition of enzyme activity by TIMP and TIMP-2 is less pronounced in the 22,000 M(r) fragment when compared to the whole molecule and a similar effect is seen with the peptide hydroxamic acid inhibitor and also with alpha 2-macroglobulin, suggesting a role for the C-terminal domain in interacting with these inhibitors. Whole molecule collagenase and the 27,000 M(r) fragment bind to type 1 collagen-Sepharose while the 22,000 M(r) fragment exhibits no such binding, suggesting that the C-terminal domain has an important role in the binding of enzyme to substrate.

Binding Sites↗
PubMed2003

Iron chelation properties of an extracellular siderophore exochelin MN.

The coordination chemistry of an extracellular siderophore produced by Mycobacterium neoaurum, exochelin MN (ExoMN), is reported along with its pK(a) values, Fe(III) and Fe(II) chelation constants, and aqueous solution speciation as determined by spectrophotometric and potentiometric titration techniques. Exochelin MN is of particular interest as it can efficiently transport iron into pathogenic M. leprae, which is responsible for leprosy, in addition to its own parent cells. The Fe(III) coordination properties of ExoMN are important with respect to understanding the Fe(III) acquisition and uptake mechanism in pathogenic M. leprae, as the siderophores from this organism are very difficult to isolate. Exochelin MN has two hydroxamic acid groups and an unusual threo-beta-hydroxy-l-histidine available for Fe(III) chelation. The presence of threo-beta-hydroxy-l-histidine gives rise to a unique mode of Fe(III) coordination. The pK(a) values for the two hydroxamic acid moieties, the histidine imidazole ring and the alkylammonium groups on ExoMN, correspond well with the literature values for these moieties. Proton-dependent Fe(III)- and Fe(II)-ExoMN equilibrium constants were determined using a model involving sequential protonation of the Fe(III)- and Fe(II)-ExoMN complexes. These data were used to develop a model whereby deprotonation reactions on the surface of the complex in the second coordination shell result in first coordination shell isomerization. The overall formation constants were calculated: log beta(110) = 39.12 for Fe(III)-ExoMN and 16.7 for Fe(II)-ExoMN. The calculated pFe value of 31.1 is one of the highest among all siderophores and their synthetic analogues and indicates that ExoMN is thermodynamically capable of removing Fe(III) from transferrin. The E(1/2) for the Fe(III)ExoMN/Fe(II)ExoMN(-) couple was determined to be -595 mV from quasi-reversible cyclic voltammograms at pH = 10.8, and the pH-dependent E(1/2) profile was used to determine the Fe(II)-ExoMN protonation constants.

Ferric Compounds↗
PubMedDate not supplied

Covalent binding of N-hydroxy-N-acetyl-2-aminofluorene and N-hydroxy-N-glycolyl-2-aminofluorene to rat hepatocyte DNA: in vitro and cell-suspension studies.

Two 2-aminofluorene-derived hydroxamic acids that differ only in the nature of the N-acyl group were examined for their relative abilities to undergo covalent binding to nucleic acids. Studies of the bioactivation of N-hydroxy-N-acetyl-2-aminofluorene (N-OH-AAF) and N-hydroxy-N-glycolyl-2-aminofluorene (N-OH-GAF) were conducted with hepatocyte suspensions and subcellular fractions prepared from male Sprague-Dawley rats. Both hydroxamic acid substrates displayed equal binding to both DNA and RNA after incubations with hepatocyte suspensions. The extent of binding of each substrate was approximately the same for DNA and RNA. Investigations with subcellular fractions revealed some major differences between the probable mechanisms by which the two substrates were covalently bound to exogenous DNA. In agreement with the prior literature reports, N-OH-AAF was extensively bound to DNA through the action of cytosol enzymes, including both N,O-acyltransferase and sulfotransferase. The microsomal enzyme fraction also catalyzed binding to DNA, and this process was completely inhibited by paraoxon. The covalent binding of N-OH-GAF to DNA was catalyzed by cytosol enzymes to a significant extent only in the presence of 3'-phosphoadenosine-5'-phosphosulfate, which suggests the action of sulfotransferase. Covalent binding of N-OH-GAF to DNA was minimal through the action of cytosolic N,O-acyltransferase, which confirms our earlier observation that N-OH-GAF is a potent suicide inhibitor of this enzyme. The microsomal fraction catalyzed the binding of N-OH-GAF to DNA at a rate that was about twice that observed for N-OH-AAF.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Comparative effect of chemical structure of chlorinated N-hydroxy-N-acyl-aminobiphenyl ethers and their related compounds on rat liver cytosol-catalyzed transacylation.

Studies of structure-transacylation relationships for a series of acylhydroxamic acids of chlorinated biphenyl ethers and their related compounds by rat liver N-arylacylhydroxamic acid-dependent N-acyltransferase (AHNAT) are described. In the transacylation of 4-aminoazobenzene catalyzed by AHNAT, 4-substituents (chloro, phenoxy, and mono-, di-, and trichlorophenoxy groups) of N-phenylacetohydroxamic acid enhanced the ability of the unsubstituted hydroxamic acid to serve as acetyl donors. As to the number of chlorines in the phenoxy group, the activity increased with decreasing number from three to zero. Of the monochlorophenoxy compounds, the 4'-chloro compound was the most effective acetyl donor. In 3-substituents (chloro and phenoxy groups) of N-phenylacetohydroxamic acid, the 3-chloro compound was an effective acetyl donor similarly to the 4-chloro compound, whereas the 3-phenoxy compound was 48% as active as the 4-phenoxy compound. None of 2-substituted N-phenylacetohydroxamic acids examined showed transacetylation activity. As to the effect of acyl group structure on the activity, N-propionyl, N-glycoloyl, and N-formyl derivatives of the 4-(4'-chlorophenoxy) compound were only 4, 2, and 0% as active as the corresponding acetyl compound, respectively. Esterification of the N-arylacetohydroxamic acid decreased the activity; O-acetyl, O-methyl, O-glucosyl, and O-glucuronosyl derivatives of the 4-(4'-chlorophenoxy) compound were 35, 7, 0, and 0% as active as the corresponding N-hydroxy compound, respectively.

Acetyltransferases↗
PubMed2005

Design and synthesis of phthalimide-type histone deacetylase inhibitors.

Several hydroxamic acid derivatives with a substituted phthalimide group as a linker and/or cap structure, prepared during structural development studies based on thalidomide, were found to have histone deacetylase (HDAC)-inhibitory activity. Structure-activity relationship studies indicated that nature of the substituent introduced at the phthalimide nitrogen atom, introduction of a hydroxamic acid structure, and distance between the N-hydroxyl group and the cap structure are important for HDAC-inhibitory activity.

Enzyme Inhibitors↗
PubMedDate not supplied

Investigations of the N-hydroxylation of 3'-hydroxyacetanilide, a non-hepatotoxic positional isomer of acetaminophen.

The hydroxamic acid of 3'-hydroxyacetanilide (AMAP) was synthesized to test the hypothesis that different reactive metabolites of AMAP and acetaminophen account for similarities in covalent binding of the two positional isomers to hepatic proteins, but for differences in their ability to cause hepatotoxicity. N-OH-AMAP was found to be a relatively stable hydroxamic acid, but it was not detected as a metabolite of AMAP formed in vitro by mouse liver microsomes or in urine of mice administered AMAP. Therefore, metabolites other than N-OH-AMAP must be responsible for covalent binding observed with AMAP to mouse liver proteins.

Acetaminophen↗