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PubMed1977

Mutagenicity of hydroxamic acids for Salmonella typhimurium.

P-Butoxyphenylacethydroxamic acid, benzohydroxamic acid, salicylhydroxamic acid, 2-naphthohydroxamic acid, indole-2-carbohydroxamic acid and benzoylaminoacethydroxamic acid were synthesized, and their mutagenicity for Salmonella typhimurium strains TA98 and TA100 were determined. Except for p-butoxyphenylacethydroxamic acid, all the hydroxamic acids were mutagenic for both strains. The mutagenicity progressed in the following order: 2-naphthohydroxamic acid greater than benzohydroxamic acid and salicylhydroxamic acid greater than benzoylaminoacethydroxamic acid and indole-2-carbohydroxamic acid. The starting materials for the synthesis of these acids including hydroxylamine were not in themselves mutagenic for TA98 and TA100. Thus, while the mutagenicity may require the hydroxamic acid as a whole, the acyl group may determine the mutagenic potency.

Genetic Techniques↗
PubMed1985

A colorimetric method for the determination of hydroxamic acid by iodine oxidation.

A new colorimetric method for the determination of hydroxamic acid is described. Hydroxamic acid was oxidized quantitatively by iodine to produce nitrous acid, which was thereafter determined according to the diazocoupling reaction. This method is sensitive to as little as 5 nmol of hydroxamic acid, and the calibration curve is linear up to 50 nmol. Using this method, acyl-CoAs were determined after conversion to hydroxamic acid by the addition of hydroxylamine. The present method is applicable to the determination of free fatty acids which are activated by acyl-CoA synthetase.

Chemical Phenomena↗
PubMed1987

Hydroxamic acid inhibitors of 5-lipoxygenase.

The hydroxamic acid functionality can be incorporated in a variety of simple molecules to produce potent inhibitors of 5-lipoxygenase. As an example of this, the structure-activity relationships in a series of omega-phenylalkyl and omega-naphthylalkyl hydroxamic acids are presented. Among the features described are the influence of hydrophobicity, aryl substitution, and modifications of the hydroxamate group on enzyme inhibitory potency. To assist in the selection of more potent hydroxamic acid inhibitors, a simple hypothesis about the nature of enzyme-inhibitor binding was devised. In this hypothesis, the structures of compounds were matched to a proposed geometry of arachidonic acid when bound to the enzyme. Compounds that match best without extending into disfavored regions were predicted to be the best inhibitors. Three series of hydroxamates selected according to this approach are described. Within these series are some of the most potent inhibitors of 5-lipoxygenase reported to date.

Arachidonate Lipoxygenases↗
PubMed1985

Inhibition of proliferation and differentiation of mouse erythroleukemia cells by hydroxamic acids.

The effect of several hydroxamic acids on cell growth and differentiation was studied in vitro in cultures of Friend erythroleukemia cells, line F4-6. Terminal differentiation in F4-6 cells can be induced by exposure to a variety of structurally unrelated compounds or to conditions which inhibit cell growth. Hydroxamic acids do not induce erythroid differentiation but interfere with both cell growth of F4-6 cells and the induction of differentiation by DMSO in these cells. DMSO-induced terminal differentiation is inhibited even when F4-6 cells are pretreated for 24 h with hydroxamates followed by removal of the hydroxamates and transfer to fresh medium containing 1% DMSO. Reduction of cell growth by hydroxamates is completely and immediately reversible upon removal. In contrast, the inhibition of DMSO inducibility is not reversible within 24 h. Cell pretreated with hydroxamates for 24 h prior to a 96 h-exposure to DMSO show the same reduction in synthesis of hemoglobin as cells simultaneously exposed to DMSO and hydroxamates.

Animals↗
PubMed1992

Inhibition of urease activity by dipeptidyl hydroxamic acids.

A series of dipeptidyl hydroxamic acids (H-X-Gly-NHOH: X = amino acid residues) was synthesized, and the inhibitory activity against Jack bean and Proteus mirabilis ureases [EC 3.5.1.5] was examined. A number of H-X-Gly-NHOH inhibited Jack bean urease with an I50 of the order of 10(-6) M and inhibited Proteus mirabilis urease with an I50 of the order of 10(-5) M. The inhibition against Jack bean urease was more potent than that with the corresponding aminoacyl hydroxamic acids (H-X-NHOH).

Dipeptides↗
PubMed1997

Pharmacokinetics and antiepileptic activity of valproyl hydroxamic acid derivatives.

PURPOSE: To explore the utilization of seven novel hydroxamic acid derivatives of valproic acid (VPA) as new antiepileptics. METHODS: The study was carried out by investigating the pharmacokinetics of two active compounds in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of valproyl hydroxamic acid and six of its derivatives. RESULTS: Three valproyl hydroxamic acid derivatives: valproyl hydroxamic acid-VPA-HA, N-(1-hydroxyethyl)-valpromide-HEV and N-methoxy valpromide, showed better anticonvulsant activity than VPA at the maximal electroshock (MES) test. The remaining four compounds, O-valproyl-VPA-HA, N-valproyl-O-valproyl-VPA-HA, N-(1-methoxyethyl) valpromide and N-(1,2-dihydroxylpropyl)-valpromide were found to be inactive. Therefore, only the pharmacokinetics of the active compounds VPA-HA and HEV was studied. CONCLUSIONS: In contrast to valpromide (VPD) which is biotransformed to VPA, VPA-HA and HEV were found to be stable in vivo to the biotransformation of the amide to its corresponding acid. VPA-HA and HEV showed improved anticonvulsant activity over VPA because of their greater intrinsic activity and not due to better pharmacokinetic characteristics. This paper discusses the structural requirements for active anticonvulsant valproyl hydroxamic acid derivatives.

Animals↗
PubMed1987

In vivo characterization of hydroxamic acid inhibitors of 5-lipoxygenase.

The hydroxamic acid functionally can be incorporated into simple molecules to produce potent inhibitors of 5-lipoxygenase. The ability of many of these hydroxamates to inhibit leukotriene synthesis in vivo has been measured directly with a rat peritoneal anaphylaxis model. Despite their potent enzyme inhibitory activity in vitro, many orally dosed hydroxamic acids only weakly inhibited leukotriene synthesis in vivo. This discrepancy is attributable at least in part to the rapid metabolism of hydroxamates to the corresponding carboxylic acids, which are inactive against the enzyme. A study of the structural features that affect this metabolism revealed that 2-arylpropionohydroxamic acids are relatively resistant to metabolic hydrolysis. Several members of this class of hydroxamates are described that are orally active inhibitors of leukotriene synthesis.

Administration, Oral↗
PubMed1982

Isolation and characterization of a new hydroxamic acid from Pseudomonas mildenbergii.

A low molecular weight hydroxamic acid was produced by Pseudomonas mildenbergii in iron-deficient media associated with green fluorescent peptides. The chemical structure of this hydroxamic acid has been investigated for comparison to known iron-binding siderophores. The hydroxamic acid was extracted from lyophilized culture media with ethanol and methanol and crystallized as the hydrochloride. The product had a molecular weight of 202.6 and an empirical formula of C9H11O2N X HCl and contained hydroxylamine nitrogen. The infrared, nuclear magnetic resonance, and mass spectral data suggested that the chemical structure was N-methylphenylacetohydroxamic acid. N-Methylphenylacetohydroxamic acid was synthesized, and its melting point, elemental analysis, and molecular weight were identical with those of the natural product. The compound chelated ferric iron, producing a distinctive iron chelate absorption band at 470 nm. Its relationship to the green fluorescent peptides is discussed.

Benzeneacetamides↗
PubMed2026

HDAC inhibition via suberoylanilide hydroxamic acid ameliorates doxorubicin-induced cardiotoxicity.

Anthracycline-induced cardiotoxicity remains a major limitation of cancer therapy, and effective preventive strategies are lacking. Topoisomerase IIb has been implicated as a central driver of this toxicity, suggesting that epigenetic regulators may interfere with the pathological cardiac response. Here, we show that doxorubicin promotes topoisomerase IIb accumulation at cardiomyocyte-specific gene promoters (e.g., Actc1, Myl2, and Myh7) overlapping myocyte enhancer factor 2 binding sites and enhances myocyte enhancer factor 2 -dependent transcription. This response is attenuated by the pan-histone deacetylase inhibitor suberoylanilide hydroxamic acid. Suberoylanilide hydroxamic acid -mediated cardioprotection requires class IIa histone deacetylases, as genetic loss of HDAC4 abolishes its effect. Mechanistically, suberoylanilide hydroxamic acid induces acetylation of the chaperone 14-3-3, disrupting its interaction with HDAC4/5, promoting their nuclear accumulation, and repressing myocyte enhancer factor 2 - driven transcription. In vivo, suberoylanilide hydroxamic acid mitigates doxorubicin-induced cardiotoxicity. These findings identify histone deacetylase inhibition as a cardioprotective repurposing strategy and reveal a mechanistic link between epigenetic regulation and anthracycline-associated cardiotoxicity.

Doxorubicin↗
PubMed1997

Antipsoriatic anthrones with modulated redox properties. 4. Synthesis and biological activity of novel 9,10-dihydro-1,8-dihydroxy-9-oxo-2-anthracenecarboxylic and -hydroxamic acids.

A novel series of carboxylic and hydroxamic acids based on 1,8-dihydroxy-9(10H)-anthracenone were synthesized from 8-hydroxy-1-methoxy-9,10-anthracenedione as the key intermediate and evaluated both in the bovine polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay and in the HaCaT keratinocyte proliferation assay for their enzyme inhibitory and antiproliferative activity, respectively. The most potent inhibitors in both assays were the N-methylated hydroxamic acids 5d-8d with straight chain alkyl spacers. Incorporation of these structural features on the anthracenone pharmacophore resulted in increased inhibitory activity against 5-LO while the antiproliferative activity was retained. In addition, prooxidant properties as measured by deoxyribose degradation and cytotoxicity as assessed by LDH release were largely reduced as compared with the antipsoriatic anthralin. Contrary to anthralin, antioxidant properties were observed as documented by the reactivity of the novel compounds against free radicals and inhibition of lipid peroxidation in model membranes.

Animals↗
PubMed1985

Nitroreductase-dependent mutagenicity of p-nitrophenylhydroxylamine and its N-acetyl and N-formyl hydroxamic acids.

p-Nitrophenylhydroxylamine (NPH) and two hydroxamic acids derived from it were synthesized and subjected to mutagenicity testing in Salmonella typhimurium strains TA98, TA98NR, TA1538 and TA1538NR. In addition, p-dinitrobenzene (DNB), p-nitroaniline (NA) and p-nitroacetanilide (AcNA) were simultaneously examined for mutagenic action against these four tester strains. NPH, its N-acetyl (AcNPH) and N-formyl (FoNPH) derivatives, and also DNB displayed strong mutagenic action to the nitroreductase-containing strains, TA98 and TA1538. NPH was the most potent chemical in this series against both of these strains, while the two hydroxamic acids AcNPH and FoNPH, and also DNB displayed approximately the same degree of mutagenicity. In the nitroreductase-deficient strains, TA98NR and TA1538NR, the mutagenicity of these four compounds was markedly reduced. The necessity for nitroreduction in order to activate these promutagens is fairly certain; however, the lack of mutagenicity of NA and AcNA towards all four tester strains made the interpretation of these data somewhat more complicated. Several possible bioactivation pathways were presented, with one mechanism in particular being proposed. This mechanism requires only that the strong electron-withdrawing nitro group be converted to an electron-donating group by bacterial nitroreductase. Such a mechanism is unique for the bioactivation of nitro aromatics by nitroreductase, since the enzymatic reduction need not produce the intermediary hydroxylamine metabolite.

Acetylation↗