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PubMed2003

[Octanhydroxamate of iron: synthesis, analysis and investigation of stability].

Hydroxamic acids are found as chelates in plants, as metabolites of bacteria and funges. Some aerobic microorganisms synthesize hydroxamic acids, which transmit iron from environment to the cells of the plants. Fourteen hydroxamic acids were synthesized and their interaction with iron (II and III) was investigated. The purpose of this investigation was synthesis of hydroxamic acids, creation of stable iron chelate with one of these acids, preparation of the methods of analysis, investigation of the stability of chelate and application for prophylaxis and treatment of iron deficiency anemia. We used octanhydroxamic acid for creation of chelate with iron. The synthesis of this acid was the cheapest and compound with iron appeared stable. Iron chelates after acid hydrolysis were analyzed by quantity of iron (9.8-12.3%). We used complexometric titration method with dinatrium salt of ethylendiamintetraacetic acid without indication for quantitative analysis. Iron (II) chelate is less stable, therefore, we used Fe (III) octanhydroxamate for further investigations. Preliminary trials with rabbits confirm rapid assimilation of iron (III) chelate from gastrointestinal tract and activation of erythropoiesis.

Anemia, Iron-Deficiency↗
PubMed1991

Maize microsomal benzoxazinone N-monooxygenase.

The benzoxazinones occur in hydroxamic acid and lactam forms in maize (Zea mays L.) tissue. The hydroxamic acid forms which possess a N-hydroxyl group are found in the highest concentration while the lactam members which lack the N-hydroxyl group occur in lower concentrations. The hydroxamic acid 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA) has as its lactam counterpart 2-hydroxy-1,4-benzoxazin-3-one (HBOA). An enzyme has been identified in maize microsomal preparations which catalyzes the N-hydroxylation of HBOA to form DIBOA. The enzyme is initially observed in seedlings 2 days after imbibition which coincides with the onset of hydroxamic acid accumulation. The enzyme requires NADPH and is inhibited by sulfhydryl reagents, NADP, cytochrome c, cations, carbon monoxide, and nitrogen gas. The effect of nitrogen can be reversed by exposing the enzyme to air, while the effect of carbon monoxide can be reversed by exposing the enzyme to 450 nanometer light during the incubation period. The apparent K(m) values for HBOA and NADPH are 13 and 5 micromolar, respectively. The pH optimum is 7.5 and the temperature optimum for the enzyme is 35 degrees C. A 450 nanometer absorbance peak is observed when reduced microsomal preparations are exposed to carbon monoxide which in combination with other data presented supports the hypothesis that the enzyme is a cytochrome P-450 dependent N-monooxygenase.

Journal Article↗
PubMed2000

Synthesis of iron-crosslinked hydroxamated alginic acid and its in vitro evaluation as a potential matrix material for oral sustained-release beads.

Hydroxamated alginic acid (HAA) was prepared. The generated semisynthetic polymer was employed in the formation of drug-loaded, iron(III)-crosslinked polymeric beads. Infrared spectroscopy was employed to prove the crosslinking. The degree of hydroxamate substitution was determined by acid-base back titration, and it was found to be ca. 20%. The produced beads were evaluated in vitro as orally administered sustained release drug delivery system. Theophylline, paracetamol, and chlorpheniramine maleate were used as model drugs. The generated beads proved to be successful in prolonging drug release, particularly in the case of theophylline. Iron leaching from the generated beads was minimal (< 0.5% of the entire complexed iron), and took place during passage through the simulated gastric fluid.

Acetaminophen↗
PubMed2002

[Pyrrolo(2,3-c)quinolines and pyrrolo(3,4-d)quinolines--synthesis and investigation of lipoxygenase inhibition].

The Paal-Knorr synthesis of the cyclic hemiketonacetal 4 yields the pyrrole-2,4-dicarboxylic acid diesters 1c and 7 via the cyclic hemiaminals 5 and 6; while the pyrrole-2-carboxylic acid ester 9 is formed from the 1,4-diketon 10. Under reducing conditions 1c and their 4-carboxylic acid 8 give the pyrrolo[3,4-c]quinoline carboxylic acid ester 2a; the cyclic hydroxamic acid 11 and the lactam 12 of the pyrrolo[2,3-c]quinoline type are obtained from compound 9. The isomeric compounds of the pyrrolo[3,4-c]quinoline series 16, 17 and 18, respectively, are synthesized from the pyrroles 14 and 15; the cyclic hemiacetal 13 was used as educt. The tricyclic hydroxamic acids 16 and 17 weakly inhibit the 5-lipoxygenase (IC50 > 10 microM, relating to the formation of LTB4 of human whole blood).

Arachidonate 5-Lipoxygenase↗
PubMed1977

N-phenylglycolhydroxamate production by the action of transketolase on nitrosobenzene.

The incubation of nitrosobenzene with yeast transketolase and D-xylulose 5-phosphate resulted in the production of N-phenylglycolhydroxamic acid. The addition of D-ribose 5-phosphate decreased the amount of hydroxamic acid that was produced. This conversion of nitrosobenzene into the glycollic acid-derived hydroxamic acid was shown to be an enzymic process, and a chemical mechanism for the conversion was proposed.

Hydroxamic Acids↗
PubMed2004

Enhancement of radiation sensitivity of human squamous carcinoma cells by histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors are emerging therapeutic agents with potential for disruption of critical cellular processes in cancer cells. Transcriptional regulation, differentiation, cell cycle arrest, radiation sensitization, and apoptosis have been observed in response to exposure to HDAC inhibitors. In the present study, we observed that several potent HDAC inhibitors, including trichostatin A, suberoylanilide hydroxamic acid, M344 (an analogue of hydroxamic acid), and the cyclic tetrapeptide, depsipeptide (FR90228), modulate cellular responses to ionizing radiation in cells of two human squamous carcinoma lines (SQ-20B and SCC-35), previously characterized as intrinsically resistant to radiation. Also exposure to IC(50) concentrations of these inhibitors, radiation sensitivities were enhanced in both cell lines. Depsipeptide exhibited the greatest effect on SQ-20B cells, decreasing D(0) values from 2.62 Gy to 1.64 Gy. M344 was the most active drug in sensitizing SCC-35 cells, decreasing D(0) values from 1.91 Gy to 1.21 Gy. The mechanisms underlying HDAC inhibitor-induced radiosensitization were further investigated by extending trichostatin A studies to assess cell cycle distributions and levels of apoptosis. Treatment of SQ-20B cells with radiosensitizing concentrations of trichostatin A resulted in cell cycle arrest in G(1) phase (>70%) and inhibition of DNA synthesis. Contrary to previous reports, induction of apoptosis was very low and caspase 3 and 9 were not activated. Taken together, these results implicate G(1) arrest and inhibition of DNA synthesis in the mechanisms underlying radiation sensitization by trichostatin A and support the use of HDAC inhibitors for targeting radioresistant cancers.

Apoptosis↗
PubMedDate not supplied

High stability and high efficiency chemiluminescent acridinium compounds obtained from 9-acridine carboxylic esters of hydroxamic and sulphohydroxamic acids.

A series of hydroxamic acids and sulphohydroxamic acids were prepared and linked to 9-acridinecarboxylic acid through a pseudo-ester function. After N-methylation of the heterocyclic ring, the different compounds were tested for their chemiluminescent properties. Substituents on the hydroxamic functions have shown various effects (steric or electronic) on the luminescence yield or stability of the molecule. The most interesting derivatives were selected in terms of chemical stability and chemiluminescence efficiency. 9-[(N-hydroxysuccinimidyl-4-oxo-4-N-phenylaminobutanoate)N-carb oxylat e]-10-methyl-acridinium (FA6), 9-(N-phenylpivalamide-N-carboxylate)-10-methylacridinium (FA17) and 9-(N-phenylpivalamide N-carboxylate)-10-carboxymethyl-acridinium (FA18) iodomercurates are very promising as chemiluminescent labels. These compounds can be detected at very low levels (10(-16)-10(-17) mol/L) and in our stability evaluation, FA6, FA17 and FA18 showed similar results to the acridinium ester DMAE. Their half-lives at 20 degrees C are greater than 2 weeks.

Acridines↗
PubMed2004

Microbial transformation products of benzoxazolinone and benzoxazinone allelochemicals--a review.

Cyclic hydroxamic acids and lactams are allelochemicals present in the common agricultural crops wheat, rye, and maize. The hydroxamic acids are mainly present in the plants as glucosides. Upon injury or insect attack or when exuded to the soil environment, the hydroxamic acids occur in their unstable agluconic form. In the first step in the transformation of hydroxamic acids, benzoxazolinones are formed spontaneously. It is necessary to elucidate the further microbial transformation of these compounds in the soil environment for a purposeful exploitation of the allelopathic properties of wheat, rye, and maize. In the present paper, the existing knowledge on microbial transformation products of benzoxazolin-2-one (BOA), 6-methoxy-benzoxazolin-2-one (MBOA), and 2-hydroxy-1,4-benzoxazin-3-one (HBOA) was reviewed. Three main groups of transformation products were identified: aminophenoxazinones, malonamic acids, and acetamides. Future research needs concerning the transformation of these chemicals in soil are discussed, when their properties for suppressing weeds and soil-borne diseases are going to be exploited.

Acetamides↗
PubMed1978

Synthesis and antibiotic properties of chloramphenicol reduction products.

Analogs of chloramphenicol were prepared for the first time in which the nitro group was replaced by hydroxylamine, nitroso, hydroxamic acid, methyl hydroxamate, and O-acetyl hydroxamate functional groups. These compounds were tested for antibiotic activity in order to determine whether the antibiotic activity of chloramphenicol is mediated by one or more of these potential metabolites of chloramphenicol. None of these analogs was as active as chloramphenicol against the four test organisms, and two of the compounds were essentially devoid of activity. The significance of these findings with regard to the importance of the nitro group to the biological activity of chloramphenicol is discussed.

Anti-Bacterial Agents↗
PubMed1986

Characterization of anguibactin, a novel siderophore from Vibrio anguillarum 775(pJM1).

Anguibactin, a siderophore produced by cells of Vibrio anguillarum 775 harboring the pJM1 plasmid, has now been isolated from the supernatants of iron-deficient cultures. This iron-reactive material was purified by adsorption onto an XAD-7 resin and subsequent gel filtration on a Sephadex LH-20 column. The resulting neutral compound produced an ion at m/z 348 in mass spectrometry and contained one sulfur, four oxygen, and four nitrogen atoms as determined by elemental analysis. Its strong UV absorbance and blue fluorescence were suggestive of a phenolic moiety. In colorimetric reactions anguibactin behaved like a catechol. The catechol assignment was supported by the appearance of a new absorption band at 510 nm in the ferric complex and by the appearance of peaks at 1,367, 1,447, 1,469, and 1,538 cm-1 in the resonance Raman spectrum. In addition, the infrared spectrum gave evidence of a secondary amide function, but no free carboxylic acid or hydroxamic acid groups were observed. A third iron-ligating group was suggested by the liberation of three protons during iron binding; mass spectrometry of the resulting material yielded a molecular ion characteristic of a 1:1 complex of ferric anguibactin. The purified anguibactin exhibited specific growth-promoting activity under iron-limiting conditions for a siderophore-deficient mutant of V. anguillarum 775(pJM1). A novel structure for anguibactin was indicated by the failure of a large number of known siderophores and synthetic chelators to yield a similar type of specific cross-feeding in the V. anguillarum bioassay.

Bacterial Outer Membrane Proteins↗
PubMed2004

Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells.

Present studies demonstrate that treatment with the histone deacetylases inhibitor LAQ824, a cinnamic acid hydroxamate, increased the acetylation of histones H3 and H4, as well as induced p21(WAF1) in the human T-cell acute leukemia Jurkat, B lymphoblast SKW 6.4, and acute myelogenous leukemia HL-60 cells. This was associated with increased accumulation of the cells in the G(1) phase of the cell cycle, as well as accompanied by the processing and activity of caspase-9 and -3, and apoptosis. Exposure to LAQ824 increased the mRNA and protein expressions of the death receptors DR5 and/or DR4, but reduced the mRNA and protein levels of cellular FLICE-inhibitory protein (c-FLIP). As compared with treatment with Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or LAQ824 alone, pretreatment with LAQ824 increased the assembly of Fas-associated death domain and caspase-8, but not of c-FLIP, into the Apo-2L/TRAIL-induced death-inducing signaling complex. This increased the processing of caspase-8 and Bcl-2 interacting domain (BID), augmented cytosolic accumulation of the prodeath molecules cytochrome-c, Smac and Omi, as well as led to increased activity of caspase-3 and apoptosis. Treatment with LAQ824 also down-regulated the levels of Bcl-2, Bcl-x(L), XIAP, and survivin. Partial inhibition of apoptosis due to LAQ824 or Apo-2L/TRAIL exerted by Bcl-2 overexpression was reversed by cotreatment with LAQ824 and Apo-2L/TRAIL. Significantly, cotreatment with LAQ824 increased Apo-2L/TRAIL-induced apoptosis of primary acute myelogenous leukemia blast samples isolated from 10 patients with acute myelogenous leukemia. Taken together, these findings indicate that LAQ824 may have promising activity in augmenting Apo-2L/TRAIL-induced death-inducing signaling complex and apoptosis of human acute leukemia cells.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Histone deacetylase inhibitors: a novel target of anticancer therapy (review).

Accumulating evidence suggests that the acetylation and deacetylation of histones play significant roles in transcriptional regulation of eukaryotic cells. The balance between acetylation and deacetylation is an important factor in regulating gene expression and is thus linked to the control of cell fate. The histone deacetylase inhibitors (HDIs) including the hydroxamic acids, such as suberoylanilide hydroxamic acid and pyroxamide, the benzamides MS-275 and CI-994 and the butyrate derivative 4-PBA are a new class of anti-neoplastic agents currently being evaluated in clinical trials. Moreover, new synthetic HDIs have been used recently in phase I and II clinical trials. Over the next few years experts believe that as first generation HDIs produce clinical benefits and second generation inhibitors are rationally designed with improved specificity, this class of drugs will emerge as a new way of cancer treatment. The first clinical studies have shown that histone hyperacetylation can be achieved safely in humans and that treatment of cancer with such agents seems to become possible. The use of HDIs, probably in association with classical chemotherapy drugs or in combination with DNA-demethylating agents, could be promising for cancer patients. Further evaluation is needed to establish the clinical activity of combination therapy using HDIs with cytotoxic drugs or differentiation induced agents.

Animals↗
PubMed1990

Synthesis of a new class of 1,4-dihydropyridines having a hydroxamic ester group in position 3 with a potential calcium antagonistic activity.

The synthesis of new 1,4-dihydropyridines having a hydroxamic acid or hydroxamic ester group in position 3 is described. Pharmacological evaluation included calcium antagonistic activity in the guinea pig Taenia coli test and acute toxicity. The compounds had not a calcium antagonistic activity, if compared with other well known DHP utilized as standard, so the pharmacological tests were not furtherly studied.

Animals↗
PubMed1991

Study of reactions induced by hydroxylamine treatment of esters of organic acids and of 3-ketoacids: application to the study of urines from patients under valproate therapy.

Hydroxylamine used at alkaline pH as oximating agent in the search for organic aciduria by gas chromatography/mass spectrometry (GC/MS) induces other chemical reactions. Esters are partially transformed in their corresponding hydroxamic acids. GC/MS characteristics of the trimethylsilylated derivatives of the hydroxamic acids arising from alpha-unsaturated esters are here reported. Their mass spectral fragmentation helps in the recognition of peaks arising from the glucuronides of 2-ene- and probably 2,3'-diene-valproic acid. By heating in the injection port of the gas chromatograph, part of some trimethylsilylated hydroxamic acids are transformed to the corresponding isocyanates by a Lossen-like rearrangement. In addition to the corresponding hydroxamic acids, hydroxylamine treatment of alpha-unsaturated esters forms 2-isoxazolidin-3-ones by intramolecular Michael addition. GC/MS characteristics of the trimethylsilylated derivatives of these compounds are reported. Submitted to hydroxylamine, 3-ketoacids forms 2-isoxazolin-5-ones by cyclization of the oximes after acidification. This explains the existence of two GC peaks observed from urine extracts of patients under valproate therapy, which correspond to two tautomers of 2-isoxazolin-5-one originating from the oximes of the 3-keto-valproic acid.

Gas Chromatography-Mass Spectrometry↗
PubMed1984

Mutagenicity of pyridine- and quinoline-carbohydroxamic acid derivatives.

11 pyridine- and 6 quinoline-carbohydroxamic acids were tested for mutagenicity on Salmonella typhimurium TA100 and TA98. The results are compared with those obtained for benzohydroxamic acid and 4 naphthohydroxamic acids. Most of them were mutagenic on both these tester strains. Of the pyridine derivatives, pyridine-2-carbohydroxamic acid was the most potent mutagen. Quaternarization of the pyridine-ring nitrogen prevented the induction of mutation to a marked extent. Among the quinoline derivatives, quinoline-6-carbohydroxamic acid showed potent mutagenicity similar to that of 2-naphthohydroxamic acid. The present study supports the proposal made previously that the mechanism for mutagenicity of hydroxamic acids involves Lossen rearrangement of the acid conjugates produced by enzymic acylation (or perhaps phosphorylation or sulfation) of the hydroxamic acids, followed by carbamoylation of the target molecule in the cell by the resultant isocyanate. The multiplicity of factors determining the mutagenic potency of hydroxamic acids is discussed.

Hydroxamic Acids↗
PubMed1996

Shedding of the lymphocyte L-selectin adhesion molecule is inhibited by a hydroxamic acid-based protease inhibitor. Identification with an L-selectin-alkaline phosphatase reporter.

Expression of the L-selectin adhesion molecule can be rapidly down-modulated by regulated proteolysis at a membrane-proximal site. The L-selectin secretase has remained undefined, and the secretase activity is resistant to a broad panel of common protease inhibitors. We have developed an L-selectin-alkaline phosphatase reporter, consisting of the ectodomain of human placental alkaline phosphatase fused to the membrane-proximal cleavage, transmembrane, and cytoplasmic domains of L-selectin, to aid in the screening for L-selectin secretase inhibitors. A hydroxamic acid-based metalloprotease inhibitor, KD-IX-73-4, inhibited release of the L-selectin-alkaline phosphatase reporter in a dose-dependent manner. The hydroxamic acid-based peptide was also found to inhibit wild type L-selectin down-regulation from the surfaces of phorbol myristate acetate-activated peripheral blood lymphocytes and phytohemagglutinin-stimulated lymphoblasts. Analysis of the proteolytic cleavage fragments of L-selectin confirmed that KD-IX-73-4 inhibited L-selectin proteolysis. Lymphocyte L-selectin was not down-regulated when co-cultured with formylmethionylleucylphenylalanine-stimulated neutrophils, suggesting that the putative secretase acts in cis with the membrane-bound L-selectin. These results suggest that the L-selectin secretase activity may involve a cell surface, zinc-dependent metalloprotease, although L-selectin shedding is not affected by EDTA and may be related to the recently described activity involved in processing of membrane-bound TNF-alpha.

Alkaline Phosphatase↗
PubMed2005

Crystal structure of a bacterial class 2 histone deacetylase homologue.

Histone deacetylases (HDACs) are among the most promising targets in cancer therapy. However, structural information greatly enhancing the design of HDAC inhibitors as novel chemotherapeutics has not been available on class 2 HDACs so far. Here we present the structure of the bacterial FB188 HDAH (histone deacetylase-like amidohydrolase from Bordetella/Alcaligenes strain FB188) that reveals high sequential and functional homology to human class 2 HDACs. FB188 HDAH is capable to remove the acetyl moiety from acetylated histones. Several HDAC-specific inhibitors, which have been shown to inhibit tumor activity in both pre-clinical models and in clinical trials, also inhibit FB188 HDAH. We have determined the crystal structure of FB188 HDAH at a resolution of 1.6 angstroms in complex with the reaction product acetate, as well as in complex with the inhibitors suberoylanilide hydroxamic acid (SAHA) and cyclopentyle-propionyle hydroxamic acid (CypX) at a resolution of 1.57 angstroms and 1.75 angstroms, respectively. FB188 HDAH exhibits the canonical fold of class 1 HDACs and contains a catalytic zinc ion. The highest structural diversity compared to class 1 enzymes is found in loop regions especially in the area around the entrance of the active site, indicating significant differences among the acetylated proteins binding to class 1 and 2 HDACs, respectively.

Acetates↗
PubMed1978

Cyanide- and hydroxamate-resistant respiration in Neurospora crassa.

Strain inl-89601 of Neurospora crassa respires exclusively by means of the mitochondrial cytochrome chain. The respiration of this strain is entirely inhibited by cyanide or antimycin A, the classical inhibitors of cytochrome chain respiration. When this strain was grown in the presence of chloramphenicol, however, two additional terminal oxidases were detected. One of these oxidases is inhibited by substituted hydroxamic acids and has been described previously. The second oxidase was not inhibited by cyanide or hydroxamic acid but was inhibited by azide in the presence of both cyanide and hydroxamic acid. This azide-sensitive respiration was due to a single respiratory pathway with a Ki for azide of 200 micrometer. A small amount of azide-sensitive respiration was detected in mitochondrial fractions obtained from chloramphenicol-treated cells, and it is likely that the azide-sensitive oxidase is localized in the mitochondrion. The determinants for the azide-sensitive and hydroxamate-sensitive oxidases segregate in a Mendelian manner in crosses and are either unlinked or not closely linked to each other.

Azides↗