Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Hydroxamic Acids”

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 757 records · Page 42Linked to original sources
PubMed2004

Modulation of pro- and anti-apoptotic factors in human melanoma cells exposed to histone deacetylase inhibitors.

Valproic acid (VPA, 2-propylpentanoic acid) is an established drug in the long-term therapy of epilepsy. Recently, VPA was demonstrated to inhibit histone deacetylases (HDACs) class I enzyme at therapeutically relevant concentrations, thereby, mimicking the prototypical histone deacetylase inhibitors, tricostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA). In the present study, we investigated the cellular effects of VPA, TSA and SAHA on four human melanoma cell lines (WM115, WM266, A375, SK-Mel28) with particular reference to the modulation of regulators of apoptosis, including Bcl-2, BclXL, Mcl-1, Apaf-1, BclXs, NOXA, TRAIL-R1, TRAIL-R2, caspase 8, and survivin). Firstly, we found that VPA induced apoptosis in two of the four human melanoma cell lines, while both TSA and SAHA exhibited an antiproliferative and apoptotic effects in all four cell lines, a different expression of Bcl-2 and BclX(L/S) occurred. On the other hand, SAHA and VPA modulated differently pro- and anti-apoptotic factors. In particular, the treatment with VPA enhanced the level of expression of survivin only in VPA-resistant cell lines, whereas down-regulation of survivin was induced by VPA and SAHA in VPA-sensitive cells. In the latter, since activation of caspase 8 was documented, a receptor-mediated apoptosis was suggested. Taken together, our results suggest that HDAC inhibitors may represent a promising therapeutic strategy to treat melanoma.

Apoptosis↗
PubMed2004

A new amidohydrolase from Bordetella or Alcaligenes strain FB188 with similarities to histone deacetylases.

The full-length gene encoding the histone deacetylase (HDAC)-like amidohydrolase (HDAH) from Bordetella or Alcaligenes (Bordetella/Alcaligenes) strain FB188 (DSM 11172) was cloned using degenerate primer PCR combined with inverse-PCR techniques and ultimately expressed in Escherichia coli. The expressed enzyme was biochemically characterized and found to be similar to the native enzyme for all properties examined. Nucleotide sequence analysis revealed an open reading frame of 1,110 bp which encodes a polypeptide with a theoretical molecular mass of 39 kDa. Interestingly, peptide sequencing disclosed that the N-terminal methionine is lacking in the mature wild-type enzyme, presumably due to the action of methionyl aminopeptidase. Sequence database searches suggest that the new amidohydrolase belongs to the HDAC superfamily, with the closest homologs being found in the subfamily assigned acetylpolyamine amidohydrolases (APAH). The APAH subfamily comprises enzymes or putative enzymes from such diverse microorganisms as Pseudomonas aeruginosa, Archaeoglobus fulgidus, and the actinomycete Mycoplana ramosa (formerly M. bullata). The FB188 HDAH, however, is only moderately active in catalyzing the deacetylation of acetylpolyamines. In fact, FB188 HDAH exhibits significant activity in standard HDAC assays and is inhibited by known HDAC inhibitors such as trichostatin A and suberoylanilide hydroxamic acid (SAHA). Several lines of evidence indicate that the FB188 HDAH is very similar to class 1 and 2 HDACs and contains a Zn(2+) ion in the active site which contributes significantly to catalytic activity. Initial biotechnological applications demonstrated the extensive substrate spectrum and broad optimum pH range to be excellent criteria for using the new HDAH from Bordetella/Alcaligenes strain FB188 as a biocatalyst in technical biotransformations, e.g., within the scope of human immunodeficiency virus reverse transcriptase inhibitor synthesis.

Amidohydrolases↗
PubMed1981

Effects of partial hepatectomy and dietary phenobarbital on liver and mammary tumorigenesis by two N-hydroxy-N-acylaminobiphenyls in female CD rats.

The objective of this study was to investigate the induction of liver tumors by arylhydroxamic acids. The potential involvement of sulfate conjugation was minimized by the administration of a N-hydroxy-4-acylaminobiphenyl to female CD rats. This experimental design provided for the exposure of a target organ that has only a low capacity for activation of hydroxamic acids by sulfate conjugation, with a carcinogen that does not induce tumors in liver that possess a high sulfotransferase activity. A single dose of the N-formyl or N-acetyl derivatives of N-hydroxy-4-aminobiphenyl was given i.p. at 0.4 mmol/kg body weight to 34-day-old animals. In attempts to amplify the hepatocarcinogenic potential of the compounds, partial hepatectomy 24 hr before the chemical injection and subsequent long-term treatment with phenobarbital in the diet were carried out. For comparative purposes, other animals were subjected to three additional partial hepatectomies subsequent to the carcinogen administration instead of the phenobarbital treatment. The experiments were terminated 64 weeks after injection. Both the N-formyl and N-acetyl derivatives of N-hydroxy-4-aminobiphenyl, in conjunction with partial hepatectomy and subsequent treatment of dietary phenobarbital, induced a high incidence of neoplastic nodules and gamma-glutamyltranspeptidase-positive foci in the liver. Only one hepatocellular carcinoma was observed in each treatment group. Repeated partial hepatectomies enhanced the yield of gamma-glutamyltranspeptidase-positive foci but were ineffective in producing neoplastic nodules. In addition to the liver lesions, mammary tumors were also induced. Importantly, an inhibitory effect of the subsequent administration of phenobarbital was observed on mammary tumor formation, possibly because of alterations in hormone metabolism resulting from the induction of microsomal enzymes by phenobarbital, which resulted in a decreased promoting effect. There was no difference in the tumorigenicity of the formyl and acetyl derivatives in these experiments.

Aminobiphenyl Compounds↗
PubMed1999

Isolation and partial characterization of an extracellular low-molecular mass component with high phenoloxidase activity from Thermoascus aurantiacus.

An extracellular low-molecular mass component (LMMC) with catalytic properties was isolated from liquid cultures containing wheat bran of ascomycete thermophilic Thermoascus aurantiacus. The partially purified LMMC showed very high activity with typical phenoloxidase substrates in the absence of hydrogen peroxide at acidic pH (2.8). However, in this pH range, the phenoloxidase (PO) activity was quickly lost. The LMMC showed a high optimum temperature (80 degrees C) and an elevated thermostability. The molecular mass of the component estimated by gel filtration chromatography was 530 Da. IR and 1H- and 13C-NMR spectra indicated the presence of hydroxamic acid moiety. Qualitative determination of metal ions by several techniques revealed the presence of mainly iron associated with this structure. Iron may be the responsible for the ability for catalyze oxidation reactions, such as o-dianisidine oxidation, by the LMMC. These results suggested the existence of a hydroxamate-type metal-binding component, most likely hydroxamate siderophore. In addition, the chrome azurol S (CAS) universal assay for noncomplexed siderophores detection revealed the production of these compounds by T.aurantiacus in solid and liquid media.

Ascomycota↗
PubMed2003

The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571.

Interactions between the proteasome inhibitor bortezomib and histone deacetylase inhibitors (HDIs) have been examined in Bcr/Abl+ human leukemia cells (K562 and LAMA 84). Coexposure of cells (24-48 hours) to minimally toxic concentrations of bortezomib + either suberoylanilide hydroxamic acid (SAHA) or sodium butyrate (SB) resulted in a striking increase in mitochondrial injury, caspase activation, and apoptosis, reflected by caspases-3 and -8 cleavage and poly(adenosine diphosphate-ribose) polymerase (PARP) degradation. These events were accompanied by down-regulation of the Raf-1/mitogen-induced extracellular kinase (MEK)/extracellular signal-related kinase (ERK) pathway as well as diminished expression of Bcr/Abl and cyclin D1, cleavage of p21CIP1 and phosphorylation of the retinoblastoma protein (pRb), and induction of the stress-related kinases Jun kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Transient transfection of cells with a constitutively active MEK construct significantly protected them from bortezomib/SAHA-mediated lethality. Coadministration of bortezomib and SAHA resulted in increased reactive oxygen species (ROS) generation and diminished nuclear factor kappa B (NF-kappa B) activation; moreover, the free radical scavenger L-N-acetylcyteine (LNAC) blocked bortezomib/SAHA-related ROS generation, induction of JNK and p21CIP1, and apoptosis. Lastly, this regimen potently induced apoptosis in STI571 (imatinib mesylate)-resistant K562 cells and CD34+ mononuclear cells obtained from a patient with STI571-resistant disease, as well as in Bcr/Abl- leukemia cells (eg, HL-60, U937, Jurkat). Together, these findings raise the possibility that combined proteasome/histone deacetylase inhibition may represent a novel strategy in leukemia, including apoptosis-resistant Bcr/Abl+ hematologic malignancies.

Antineoplastic Agents↗
PubMed2007

Development and validation of high-performance liquid chromatography-tandem mass spectrometry assay for 6-(3-benzoyl-ureido)-hexanoic acid hydroxyamide, a novel HDAC inhibitor, in mouse plasma for pharmacokinetic studies.

A liquid chromatography/tandem mass spectrometric method for the quantification of 6-(3-benzoyl-ureido)-hexanoic acid hydroxyamide (EX-2), a novel histone deacetylase (HDAC) inhibitor, in mouse plasma was developed to support in-house pharmacokinetic (PK) studies in the lead optimization stage. In order to determine the PK parameters for EX-2 in comparison to other HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA), PXD-101 and LBH-589, which are currently in different stages of clinical trials, research-grade bio-analytical method validations were carried out for EX-2 and these reference HDAC inhibitors, which were synthesized by in-house medicinal chemists. The components of validation consisted of specificity, extraction efficiency, signal-response of calibration standards, lower limit of quantification, autosampler stability and accuracy and precision of quality control samples. The validated LC/MS/MS methods were accurate and precise. The calibration curve ranged from 1 to 1600 ng/mL for all the analytes. The methods developed were used to quantify EX-2 and other HDAC inhibitors in mouse plasma obtained from pharmacokinetic studies. The results suggest that EX-2 has better PK parameters compared with the reference drugs and is a promising drug development candidate.

Animals↗
PubMed2005

Identification of phosphodiesterase-1 and 5 dual inhibitors by a ligand-based virtual screening optimized for lead evolution.

We identified new lead candidates which showed potent dual inhibition against phosphodiesterase-1 and 5 by a ligand-based virtual screening optimized for lead evolution. This virtual screening method, consisting of classification and regression tree analysis using 168 2-center pharmacophore descriptors and 12 macroscopic descriptors, demonstrated a high predictive ability for bioactivity of new chemical compounds. The obtained lead candidates were structurally diverse, although only the structure-activity relationship data of hydroxamic acid derivatives were used to configure the prediction model for the virtual screening.

Drug Evaluation, Preclinical↗
PubMed2005

Ternary ligand-zinc-hydroxamate complexes.

Because of the importance of the hydroxamic acid functional group in zinc protease inhibitors, we have measured the stability constants of the ternary complex LMG, where L is series of tridentate and tetradentate ligands containing amino, carboxylate, pyridyl, and/or imidazolyl groups as enzyme models and G is the guest molecule, acetohydroxamate or N-methylacetohydroxamate. All measurements were determined by pH titration which gave reproducible and reasonable results. A general correlation between binding of LMG and that of LM showed ligands that strongly chelated zinc gave less LMG formation. Surprisingly, no correlation was observed between ligand charge and LMG formation even though the guest, acetohydroxamate, is anionic. The pH value of the maximum formation of the ternary complex is also correlated to the acidity of zinc-bound water; more acidic zinc-bound water results in a maximum ternary complex formation at lower pH value.

Binding Sites↗
PubMed1998

Screening system for urease inhibitors using 13C-NMR.

Urease inhibitors are candidate drugs to treat infection with the human pathogen, Helicobacter pylori, which produces a potent urease [urea amidohydrolase; EC 3.5.1.5]. We developed a screening system based on 13C-NMR measurement of the time course of decrease in the signal of 13C-urea in the presence of urease. The effect on urease activity of known inhibitors, hydroxamic acids, L-ascorbic acid, 2,2'-dipyridyl disulfide and ninhydrin, was speedily and conveniently measured by this method.

Binding, Competitive↗
PubMed1999

Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors.

Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression. HDACs are involved in cell-cycle progression and differentiation, and their deregulation is associated with several cancers. HDAC inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have anti-tumour effects, as they can inhibit cell growth, induce terminal differentiation and prevent the formation of tumours in mice models, and they are effective in the treatment of promyelocytic leukemia. Here we describe the structure of the histone deacetylase catalytic core, as revealed by the crystal structure of a homologue from the hyperthermophilic bacterium Aquifex aeolicus, that shares 35.2% identity with human HDAC1 over 375 residues, deacetylates histones in vitro and is inhibited by TSA and SAHA. The deacetylase, deacetylase-TSA and deacetylase-SAHA structures reveal an active site consisting of a tubular pocket, a zinc-binding site and two Asp-His charge-relay systems, and establish the mechanism of HDAC inhibition. The residues that make up the active site and contact the inhibitors are conserved across the HDAC family. These structures also suggest a mechanism for the deacetylation reaction and provide a framework for the further development of HDAC inhibitors as antitumour agents.

Amino Acid Sequence↗
PubMed1990

Analogues of N-hydroxy-4-acetylaminobiphenyl as substrates and inactivators of hamster hepatic acetyltransferases.

1. A series of analogues of N-hydroxy-4-acetylaminobiphenyl (1, N-OH-AAB) has been synthesized and evaluated in vitro as substrates and inactivators of hamster hepatic N,N-acetyltransferase (N,N-AT) activity. The analogues of 1 are N-arylhydroxamic acids in which an atom or small functional group has been incorporated between the phenyl rings of 1. 2. The structural and molecular properties of the atoms between the two phenyl rings had little influence on the ability of the compounds to serve as acetyl donors in the N-arylhydroxamic acid-dependent transacetylation of 4-aminoazobenzene (AAB) catalysed by N,N-AT. An exception was the SO2 analogue (6) which was inactive. 3. All of the compounds except 6 were mechanism-based inactivators (suicide inhibitors) of hamster hepatic N,N-AT. The inhibition of N,N-AT by the hydroxamic acids was irreversible. The properties of the atom or functional group between the phenyl rings had a substantial influence on the relative effectiveness of the compounds as inactivators of N,N-AT. trans-N-Hydroxy-4-acetylaminostilbene (N-OH-AAS, 7) was the most potent and effective mechanism-based inactivator among the compounds studied. The ketone analogue (2) was the least effective among the compounds that exhibited inactivating activity. 4. The presence of the nucleophile cysteine in the incubation mixtures reduced the extent of inactivation of N,N-AT by 1 and by the ether (4) analogue but had little effect on the inactivation caused by 7. The inactivation of N,N-AT by N-OH-AAS (7) does not appear to involve electrophiles that are released from the active site and subsequently become covalently bound to the enzyme.

Acetylation↗
PubMed1971

Effect of serine hydroxamate on the growth of Escherichia coli.

The structural analogue of l-serine, l-serine hydroxamate, inhibited the growth of Escherichia coli K-12. Of the other amino acid hydroxamates tested, only l-lysine hydroxamate reduced the rate of growth. Inhibition of growth by l-serine hydroxamate was rapidly reversed by the addition of l-serine to the bacterial culture or by removal of the analogue by filtration. The reversal of inhibition was specific for l-serine. l-Alanine, glycine, or adenine had no effect on an inhibited culture. No evidence for active transport of the analogue was obtained.

Adenine↗
PubMed1977

Inhibition of fructose-1,6-bisphosphate aldolase from rabbit muscle and Bacillus stearothermophilus.

Phosphoglycollohydroxamic acid and phosphoglycollamide are inhibitors of rabbit muscle fructose-1,6-bisphosphate aldolase. The binding dissociation constants determined by enzyme inhibition and protein fluorescence quenching suggest that two distinct enzyme inhibitor complexes may be formed. The binding dissociation constants of the two inhibitors to Bacillus stearothermophilus cobalt (II) fructose-1,6-bisphosphate aldolase have also been determined. The hydroxamic acid is an exceptionally potent inhibitor (Ki = 1.2 nM) probably due to direct chelation with Co(II) at the active site. The inhibition, however, is time-dependant and the association and dissociation constants have been estimated. Ethyl phosphoglycollate irreversibly inhibits rabbit muscle fructose-1,6-bisphosphate aldolase in the presence of sodium borohydride, presumably by forming a stable secondary amine through the active-site lysine reside. A new condensation assay for fructose-1,6-bisphosphate aldolases has been developed which is more sensitive than currently used assay procedures.

Animals↗
PubMed2006

Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci.

Vorinostat (suberoylanilide hydroxamic acid) is the prototype of a family of hybrid polar compounds that can induce growth arrest in transformed cells and shows promise for the treatment of cancer. Vorinostat specifically binds to and inhibits the activity of histone deacetylases resulting in acetylation of nucleosomal histones and an activation of gene transcription. Because histone deacetylases modulate chromatin structure and gene expression, both of which can influence radioresponse, this study was designed to examine the capacity of Vorinostat to influence radiation response in human tumor cells and investigate the mechanism underlying these interactions. Vorinostat induced hyperacetylation of histone H4 in a dose-dependent manner. We tested its ability to radiosensitize three human tumor cell lines (A375, MeWo, and A549) using clonogenic cell survival assays. Clonogenic cell survival assay showed that Vorinostat significantly radiosensitized all three tumor cell lines, substantially reducing the surviving fraction at 2 Gy. We examined potential mechanisms that may contribute to the enhanced radiation response induced by Vorinostat. Vorinostat and radiation alone did not induce apoptosis in the melanoma cell line. However, enhanced apoptosis was observed when cells were exposed to both Vorinostat and radiation, suggesting that Vorinostat renders tumor cells more susceptible to radiation-induced apoptosis. Results from DNA damage repair analysis in cultured A375 cells showed that Vorinostat had a strong inhibitory effect on the nonhomologous end joining pathway after radiation. A detailed examination of the involvement of the DNA repair pathway following Vorinostat treatment showed that Vorinostat reduced the expression of the repair-related genes Ku70, Ku80, and Rad50 in A375 cells as detected by Western blot analysis. We also examined gamma-H2AX phosphorylation as a predictive marker of radiotherapy response to Vorinostat and observed that the combination of Vorinostat and radiation caused a prolongation of expression of DNA repair proteins such as gamma-H2AX. Overall, we conclude that Vorinostat enhances tumor radioresponse by multiple mechanisms that may involve antiproliferative growth inhibition and effects on DNA repair after exposure to radiation.

Acetylation↗
PubMed1979

Studies on the formation of N6-hydroxylysine in cell-free extracts of Aerobacter aerogenes 62-1.

We have investigated conditions optimal for the conversion of L-lysine to its N6-hydroxy derivative by partially purified cell-free extracts of Aerobacter aerogenes 62-1. The enzyme system was highly specific to L-lysine: the D-isomer and, the N2- or N6-derivatives of lysine, and alpha-amino acids were not hydroxylated. Most of the latter compounds had little effect onthe hydroxylation of L-lysine. However, -l-glutamic acid and L-glutamine enhanced the hydroxylation, with half-maximal activation achieved at 100 micrometers concentration of the effector. The Km values for pyruvate and L-(+)-lactate (compounds known to stimulate N-hydroxylysine formation) were found to be approx. 100 micrometers. The data show that N-hydroxylation of the amino acid precedes acylation in the biosynthesis of hydroxamic acid in A. aerogenes 62-1.

Antimetabolites↗
PubMed1998

Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: an examination of the subsite pocket.

The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an alpha-branched alkyl group is critical for the binding toward DeltaMT1, while the introduction of a bulky group at the alpha-position of hydroxamic acid seems to diminish the activity against DeltaMT1. Summation of the data on the sensitivity of DeltaMT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of DeltaMT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against DeltaMT1 over MMP-1, but no selectivity between DeltaMT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.

Amino Acid Sequence↗
PubMed1986

S.E.M. study of urease-induced crystalluria in the presence of hydroxamic derivatives.

The effect of 3 hydroxamic acid derivatives on urease-induced crystalluria was studied in vitro. Acetohydroxamic acid is more effective than salicylhydroxamic and gentisohydroxamic acids in inhibiting the kinetic of urease enzymatic reaction and in retarding the formation of struvite and apatite. Crystal deposits studied by scanning electron microscope (S.E.M.) and X-ray microanalysis indicated that acetohydroxamic acid favours the formation of large crystals of struvite, and less aggregation is observed. Salicyl and gentiso derivatives favour the formation of brushite together with struvite and apatite.

Apatites↗
PubMed1979

Metabolic activation of arylhydroxamic acids by N-O-acyltransferase of rat mammary gland.

The lactating mammary glands of rats contain an arylhydroxamic acid N,O-acyltransferase that catalyzes the formation of arylamine-substituted nucleic acid on incubation with N-hydroxy-N-2-acetylaminofluorene or N-hydroxy-N-4-acetylaminobiphenyl and transfer RNA. The acyltransferase activity migrates as a single component with a molecular weight of 28,000 on gel filtration on Sephadex G-100. Acyltransferase activities of the lactating mammary glands of Sprague-Dawley animals are approximately twice those of the less susceptible Fischer strain as determined by assay with either hydroxamic acid. The fluorene substrate was 15 times as efficient as the biphenyl compound in promoting adduct formation. Ribosomal RNA adducts formed in vivo after administration of N-hydroxy-N-2-acetylaminofluorene were consistent with an acyltransferase mechanism of activation in that the adducts did not retain the acetyl group.

Acyltransferases↗