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PubMed2003

Squaric acid N-hydroxylamides: synthesis, structure, and properties of vinylogous hydroxamic acid analogues.

The synthesis of squaric acid N-hydroxylamide esters 5 and amides 6 from dimethyl squarate 2a is described. These derivatives are analogues of the naturally occurring iron(III) chelator hydroxamic acid. On the basis of a comparative reactivity study, a concerted retro-Cope mechanism for the formation of the N-hydroxylamide esters 5 by reaction of dimethyl squarate with hydroxylamines is proposed. A preliminary iron(III) binding study of these hydroxamic acid analogues is presented, demonstrating binding of iron(III) to amides 6 in aqueous solutions, while the esters 5 did not show any sign of metal ion binding. 13C NMR spectroscopic data (chemical shift and spin-lattice relaxation time determination) of these and related derivatives delineate the resonance structures predominant in these molecules. The resonance structures of the derivatives rationalize their spectroscopic data, chemical reactivity, and iron(III) binding properties. Single-crystal X-ray structure analyses of squaric acid N-hydroxylamide ester 5b and squaric acid N-hydroxylamide amide 6c confirm their connectivity and provide structural evidence supporting the spectroscopically derived conclusions. The squaric acid N-hydroxylamides are potentially useful in the construction of chemosensors for iron(III).

Binding, Competitive↗
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↗
PubMed2004

Toward an HDAC6 inhibitor: synthesis and conformational analysis of cyclic hexapeptide hydroxamic acid designed from alpha-tubulin sequence.

A cyclic hexapeptide hydroxamic acid inhibitor for HDAC6 has been designed and synthesized on the basis of the facts that alpha-tubulin is the substrate of HDAC6 and of the excellent inhibitory activity of cyclic tetrapeptide hydroxamic acids (CHAPs) for HDACs. Unexpectedly, cyclic hexapeptide hydroxamic acid showed very low HDAC inhibitory activity. To explain the low activity, we have carried out conformation analysis and compared it to the crystal structure of alpha-tubulin. The conformation around the acetylated lysine of the cyclic hexapeptide substrate or the aminosuberate hydroxamic acid [Asu(NHOH)] of cyclic hexapeptide inhibitor is different from that around alpha-tubulin's lysine-40. The difference in the conformation seems to cause some steric hindrance at the capping site resulting in poor binding capacity.

Acetylation↗
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↗
PubMed2004

Chlamydocin-hydroxamic acid analogues as histone deacetylase inhibitors.

Chlamydocin-hydroxamic acid analogues were designed and synthesized as histone deacetylase (HDAC) inhibitors based on the structure and HDAC inhibitory activity of chlamydocin and trichostatin A. Chlamydocin is a cyclic tetrapeptide containing an epoxyketone moiety in the side chain that makes it an irreversible inhibitor of HDAC. We replaced the epoxyketone moiety of chlamydocin with hydroxamic acid to design potent and reversible inhibitors of HDAC. In addition, a number of amino-cycloalkanecarboxylic acids (Acc) are introduced instead of the simple amino-isobutric acid (Aib) for a variety of the series of chlamydocin analogues. The compounds synthesized were tested for HDAC inhibitory activity and the results showed that many of them are potent inhibitors of HDAC. The replacement of Aib residue of chlamydocin with an aromatic amino acid enhances the in vivo and in vitro inhibitory activity. We have carried out circular dichroism and molecular modeling studies on chlamydocin-hydroxamic acid analogue and compared it with the solution structure of chlamydocin.

Animals↗
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↗
PubMed2002

Mechanism of inhibition of the beta-lactamase of Enterobacter cloacae P99 by 1:1 complexes of vanadate with hydroxamic acids.

The class C beta-lactamase of Enterobacter cloacae P99 is competitively inhibited by low concentrations of 1:1 complexes of vanadate and hydroxamic acids. Structure-activity studies indicated that the hydroxamic acid functional group was essential to this inhibition. Both aryl and alkyl hydroxamic acids form inhibitory ternary complexes with vanadate and the enzyme, although, in certain cases of the latter, the inhibition may not be seen because of the low formation constants of the vanadate-hydroxamic acid complex. After all of the vanadate species present in solution had been taken into account, "real" K(i) values for the vanadate complexes could be determined. The K(i) value of the best of the inhibitors that were investigated, the 1:1 complex of vanadate with 4-nitrobenzohydroxamic acid, was 0.48 microM. Kinetics studies showed that the association and dissociation rate constants of this complex with the enzyme were 1.48 x 10(6) s(-1) M(-1) and 0.73 s(-1), respectively; the magnitude of the latter indicates covalent interaction of the complex with the enzyme. (51)V NMR and UV-vis spectra suggest that the structure of the vanadate complex bound to the enzyme may be very similar to that in solution. A (13)C NMR spectrum of the enzyme complex with 4-nitrobenzo[(13)C]hydroxamic acid and vanadate yields a coordination-induced shift (CIS) of 7.74 ppm. This is significantly larger than that of the vanadate complex in free solution (3.62 ppm), suggesting either, somewhat contrary to the (51)V and UV-vis spectra, greater interaction between vanadium and the hydroxamate carbonyl oxygen in the enzyme complex than in free solution or, more likely, polarization of the hydroxamate by interaction, e.g., hydrogen bonding, with the enzyme. Molecular modeling indicates that a pentacoordinated vanadate complex may well be able to snugly occupy the enzyme active site; Asn 152 is suitably placed to hydrogen bond to the hydroxamic acid oxygen atom. The experimental results are in accord with a model whereby the vanadate-hydroxamate-enzyme complex is a moderately good analogue of the transition state of the reaction of the beta-lactamase with phosphonate inhibitors.

Dose-Response Relationship, Drug↗
PubMedDate not supplied

[Inhibitory effect of linoleyl-hydroxamic acid on the oxidation of linoleic acid by 12-lipoxygenase from porcine leukocytes].

Linoleic acid oxidation by 12-lipoxygenase from porcine leukocytes has been studied as affected by linoleyl-hydroxamic acid. Linoleyl-hydroxamic acid has been found to be an effective inhibitor of porcine leucocyte 12-lipoxygenase. Aerobic preincubation of 12-lipoxygenase with 0.1-6 microM of linoleyl-hydroxamic acid led to a time- and dose-dependent inhibition of the enzyme. The inhibitor's concentration able to induce a 50% loss of the enzyme activity with and without 15-min preincubation were 3.5 and 0.65 microM, respectively. Experimental results obeyed a kinetic scheme, which supposed 2 extra substrate molecules bounding with the enzyme-substrate complex in the presence of linoleyl-hydroxamic acid.

Animals↗
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↗
PubMed2005

Hydroxamic acid content and toxicity of rye at selected growth stages.

Rye (Secale cereale L.) is an important cover crop that provides many benefits to cropping systems including weed and pest suppression resulting from allelopathic substances. Hydroxamic acids have been identified as allelopathic compounds in rye. This research was conducted to improve the methodology for quantifying hydroxamic acids and to determine the relationship between hydroxamic acid content and phytotoxicity of extracts of rye root and shoot tissue harvested at selected growth stages. Detection limits for an LC/MS-MS method for analysis of hydroxamic acids from crude aqueous extracts were better than have been reported previously. (2R)-2-beta-D-Glucopyranosyloxy-4-hydroxy-(2H)-1,4-benzoxazin-3(4H)-one (DIBOA-G), 2,4-dihydroxy-(2H)-1,4-benzoxazin-3(4H)-one (DIBOA), benzoxazolin-2(3H)-one (BOA), and the methoxy-substituted form of these compounds, (2R)-2-beta-D-glucopyranosyloxy-4-hydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one (DIMBOA glucose), 2,4-hydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one (DIMBOA), and 6-methoxy-benzoxazolin-2(3H)-one (MBOA), were all detected in rye tissue. DIBOA and BOA were prevalent in shoot tissue, whereas the methoxy-substituted compounds, DIMBOA glucose and MBOA, were prevalent in root tissue. Total hydroxamic acid concentration in rye tissue generally declined with age. Aqueous crude extracts of rye shoot tissue were more toxic than extracts of root tissue to lettuce (Lactuca sativa L.) and tomato (Lycopersicon esculentum Mill.) root length. Extracts of rye seedlings (Feekes growth stage 2) were most phytotoxic, but there was no pattern to the phytotoxicity of extracts of rye sampled at growth stages 4 to 10.5.4, and no correlation of hydroxamic acid content and phytotoxicity (I50 values). Analysis of dose-response model slope coefficients indicated a lack of parallelism among models for rye extracts from different growth stages, suggesting that phytotoxicity may be attributed to compounds with different modes of action at different stages. Hydroxamic acids may account for the phytoxicity of extracts derived from rye at early growth stages, but other compounds are probably responsible in later growth stages.

Herbicides↗