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PubMed2000

Metal complexes of salicylhydroxamic acid (H2Sha), anthranilic hydroxamic acid and benzohydroxamic acid. Crystal and molecular structure of [Cu(phen)2(Cl)]Cl x H2Sha, a model for a peroxidase-inhibitor complex.

Stability constants of iron(III), copper(II), nickel(II) and zinc(II) complexes of salicylhydroxamic acid (H2Sha), anthranilic hydroxamic acid (HAha) and benzohydroxamic acid (HBha) have been determined at 25.0 degrees C, I=0.2 mol dm(-3) KCl in aqueous solution. The complex stability order, iron(III) >> copper(II) > nickel(II) approximately = zinc(II) was observed whilst complexes of H2Sha were found to be more stable than those of the other two ligands. In the preparation of ternary metal ion complexes of these ligands and 1,10-phenanthroline (phen) the crystalline complex [Cu(phen)2(Cl)]Cl x H2Sha was obtained and its crystal structure determined. This complex is a model for hydroxamate-peroxidase inhibitor interactions.

Copper↗
PubMed1987

HRP-catalyzed bioactivation of carcinogenic hydroxamic acids. The greater reactivity of glycolyl- versus acetyl-derived hydroxamic acids.

An analysis of the hydroxamic acid oxidation reaction by H2O2 and horseradish peroxidase (HRP) was made with three pairs of hydroxamic acids. Each pair consisted of the aceto- and glycolhydroxamic acid derivatives from one of three different arylhydroxylamines. The parent arylhydroxylamines were the known carcinogens, N-hydroxy-2-aminofluorene and N-hydroxy-4-aminobiphenyl and the noncarcinogen 4-chlorophenyl-hydroxylamine. All the hydroxamic acids appeared to be converted to products that were expected on the basis of the previously-proposed mechanism of this peroxidative reaction. Each acetohydroxamic acid gave the corresponding nitroso compound and O-acetyl ester of the starting material in approximately equal amounts. The glycolhydroxamic acids gave the corresponding nitroso compound and a relatively unstable product that was proposed, by analogy, to be the O-glycolyl ester of the starting material. A comparison of the initial rates of reaction of each hydroxamic acid pair showed that the glycolhydroxamic acid was much more susceptible to the peroxidation reaction than was the corresponding acetohydroxamic acid. The initial rate of the reaction was also highly dependent upon the nature of the aromatic ring in the order fluorene greater than biphenyl greater than 4-chlorophenyl. The relative degree of HRP-catalyzed covalent binding to DNA of the aceto- and glycolhydroxamic acids in the fluorene series was studied and found to parallel the relative rates of reaction of these substrates in the H2O2/HRP system. It was proposed that glycolhydroxamic acids are likely to be more genotoxic than are acetohydroxamic acids when subjected to peroxidative bioactivation conditions.

Biotransformation↗
PubMed2001

Identification of novel potent hydroxamic acid inhibitors of peptidyl deformylase and the importance of the hydroxamic acid functionality on inhibition.

Peptidyl deformylase (PDF) is a metallo protease that catalyzes the removal of a formyl group from the N-termini of prokaryotic prepared polypeptides, an essential step in bacterial protein synthesis. Screening of our compound collection using Staphylococcus aureus PDF afforded a very potent inhibitor with an IC(50) in the low nanomolar range. Unfortunately, the compound that contains a hydroxamic acid did not exhibit antibacterial activity (MIC). In order to address the lack of activity in the MIC assay and to determine what portion of the molecule was responsible for binding to PDF, we prepared several analogues. This paper describes our findings that the hydroxamic acid functionality found in 1 is mainly responsible for the high affinity to PDF. In addition, we identified an alternative class of PDF inhibitors, the N-hydroxy urea 18, which has both PDF and antibacterial activity.

Amidohydrolases↗
PubMed1982

Inhibition of leucine aminopeptidase by amino acid hydroxamates.

Amino acid hydroxamates are strong competitive inhibitors of leucine aminopeptidase from porcine kidney. The side chain specificity for inhibition correlates well with substrate specificity. L-Leucine hydroxamate (Ki = 14 microM) protects the enzyme from inactivation by EDTA and is presumed to be a bidentate ligand of the zinc at the active site. A substituted beta-mercaptoketone which may bind in a similar way is also a potent inhibitor (Ki = approximately 1 microM). The binding of these inhibitors suggests a mechanism for this enzyme in which a zinc-bound hydroxide ion participates in concerted proton-transfer processes, while the coordination and charge field at the zinc atom remain unchanged.

Amino Acids↗
PubMed2005

Antimicrobial activity of some hydroxamic acids.

Several hydroxamic acids, viz., N-benzyl-N'-hydroxysuccinamide (BHS), poly[alpha,beta-(N-hydroxy)-DL-aspartamide] (PHA), poly[alpha,beta-(N-hydroxy-N-methyl-DL-aspartamide)] (PMHA) and poly[alpha,beta-(N-hydroxy)-DL- aspartamide]/poly[alpha,beta-(N-2-hydroxyethyl)-DL-aspartamide] (PHA-PHEA 1:1) were prepared and screened for their antimicrobial activity. Ten Gram-positive and 7 Gram-negative species of bacteria, 5 Candida species, 4 dermatophyte species and 3 mould species were used in tests. Compound showed no antimicrobial activity on any of the tested microorganisms. Other compounds showed a narrow spectrum of antibacterial activity, but no antifungal activity.

Anti-Infective Agents↗
PubMed1992

Inhibition of human skin fibroblast collagenase, thermolysin, and Pseudomonas aeruginosa elastase by peptide hydroxamic acids.

The hydroxamic acid HONHCOCH2CH(i-Bu)CO-L-Trp-NHMe, isomer 6A (GM 6001), inhibits human skin fibroblast collagenase with Ki of 0.4 nM using the synthetic thiol ester substrate Ac-Pro-Leu-Gly-SCH(i-Bu)CO-Leu-Gly-OEt at pH 6.5. The other isomer, 6B, which has the opposite configuration at the CH2CH(i-Bu)CO alpha-carbon atom, has a Ki of 200 nM for this enzyme. GM 6001 is one of the most potent inhibitors of human skin fibroblast collagenase yet reported. GM 6001 has a Ki of 20 nM against thermolysin and Pseudomonas aeruginosa elastase. Isomer 6B has a Ki of 7 nM against thermolysin and 2 nM against the elastase. 6A and 6B are the most potent hydroxamate inhibitors reported for these bacterial enzymes. The pattern of inhibition for all three enzymes suggests that isomer 6A is the (R,S) compound, stereochemically analogous to the L,L-dipeptide, and isomer 6B is the (S,S) compound, analogous to the DL-dipeptide. The tolerance of the D configuration by thermolysin and the elastase allows these inhibitors to discriminate between the human and bacterial enzymes simply by inversion of configuration at the CH2CH(i-Bu)CO alpha-carbon atom. Substitution of the potential metal liganding groups carboxylate and hydrazide for the hydroxamate group yields much weaker inhibitors for all three enzymes.

Fibroblasts↗
PubMed1978

Studies on the mechanism of inhibition of redox enzymes by substituted hydroxamic acids.

Substituted primary hydroxamic acids were found to inhibit the catalytic activity of a number of redox enzymes. The inhibition was not related to the nature of the metal-active site of the enzyme nor to the nature of the oxygen-containing substrate. Two easily available enzymes, mushroom tyrosinase (monophenol,dihydroyphenylalanine:oxygen oxidoreductase, EC 1.14.18.1) and horseradish peroxidase (donor:hydrogen-peroxide oxidoreductase, EC 1.11.1.7), which were potently inhibited by hydroxamic acids, were chosen for more detailed study. A kinetic analysis of the inhibitory effects on the partially purified tyrosinase of mushroom (Agaricus bispora) revealed that inhibition was reversible and competiitive with respect to reducing substrate concentration, but was not competitive with respect to molecular oxygen concentration. A spectrophotometric and EPR study of the binding of salicylhydroxamic acid to horseradish peroxidase revealed that his hydroxamic acid was bound to the enzyme in the same manner as a typical substrate, hydroquinone. Spectroscopic and thermodynamic measurements of the binding reactions suggested that this binding site is close, to but, not directly onto, the heme group of the enzyme. From these results it is concluded that the mode of inhibition of hydroxamic acid need not be, as generally supposed, by metal chelation, and mechanisms involving either hydrogen bonding at the reducing substrate binding site or the formation of a charge transfer complex between hydroxamic acid and an electron-accepting group in the enzyme are considered to be more feasible. The relevance of these findings to deductions on the nature of other hydroxamic acid-inhibitable systems is discussed.

Basidiomycota↗
PubMed2003

Protease inhibitors: synthesis of bacterial collagenase and matrix metalloproteinase inhibitors incorporating succinyl hydroxamate and iminodiacetic acid hydroxamate moieties.

A series of succinyl hydroxamates/bishydroxamates as well as a new structural type of matrix metalloproteinase (MMP)/bacterial protease (BP) inhibitors, incorporating iminodiacetic (IDA) hydroxamate/bishydroxamate moieties, has been synthesized and tested for interaction with four vertebrate proteases, MMP-1, MMP-2, MMP-8 and MMP-9, and a BP, the collagenase isolated from Clostridium histolyticum (ChC). The new derivatives generally showed inhibition constants in the range of 8-62 nM against the five proteases mentioned above.

Clostridium↗
PubMed2003

Simple one-flask method for the preparation of hydroxamic acids.

[reaction: see text] A one-step conversion of carboxylic acids to hydroxamic acids under very mild conditions is described. This simple and efficient method has been applied for the synthesis of enantiopure hydroxamate of alpha-amino acids and peptides.

Carboxylic Acids↗
PubMed1983

Stereospecificity of amino acid hydroxamate inhibition of aminopeptidases.

Hydroxamates of amino acids and aliphatic acids are effective inhibitors of Aeromonas proteolytica amino-peptidase (EC 3.4.11.10) and of both the cytosolic (EC 3.4.11.1) and microsomal (EC 3.4.11.2) aminopeptidases of swine kidney. Cytosolic leucine aminopeptidase and the Aeromonas enzyme were inhibited to a greater extent by D isomers than by the L enantiomorphs, manganese-activated kidney cytosolic leucine aminopeptidase being inhibited 10 times more effectively by D-leucine and D-valine hydroxamic acids than by the L isomers. The D isomers of these two compounds inhibited Aeromonas aminopeptidase to an even greater extent with Ki values of 2 X 10(-9) and 5 X 10(-9), respectively, whereas the corresponding L isomers were bound 150 times less tightly. With the Aeromonas enzyme, a comparison of inhibition by racemic mixtures with that of the corresponding L isomers indicated that in all cases the contribution of the D isomer was predominant. Isocaproic hydroxamic acid inhibited this enzyme equally well as L-leucine hydroxamic acid, indicating that the amino group orientation in the D isomer contributes to the binding efficacy. Swine kidney microsomal aminopeptidase was also inhibited by D isomers of leucine and valine hydroxamic acids but in contrast to the other two enzymes, the inhibition was 10-fold less than that observed for the corresponding L isomers. Cytosolic leucine aminopeptidase with either 6 g atoms of zinc per mol or 12 g atoms of zinc per mol was inhibited only slightly by any of the hydroxamic acid compounds; evidently enzyme-bound manganese (or magnesium) is specific for hydroxamate binding to this aminopeptidase.

Aeromonas↗
PubMed2004

The metalla-Pinner reaction between Pt(IV)-bound nitriles and alkylated oxamic and oximic forms of hydroxamic acids.

The nitrile ligands in the platinum(IV) complexes trans-[PtCl4(RCN)2] (R=Me, Et, CH2Ph) and cis/trans-[PtCl4(MeCN)(Me2SO)] are involved in a metalla-Pinner reaction with N-methylbenzohydroxamic acid (N-alkylated form of hydroxamic acid, hydroxamic form; F1), PhC(=O)N(Me)OH, to achieve the imino species [PtCl4[NH=C(R)ON(Me)C(=O)Ph]2 (1-3) and [PtCl4[NH=C(Me)ON(Me)C(=O)Ph](Me2SO)] (7), respectively. Treatment of trans-[PtCl4(RCN)2] (R=Me, Et) and cis/trans-[PtCl4(MeCN)(Me2SO)] with the O-alkylated form of a hydroxamic acid (hydroximic form), i.e. methyl 2,4,6-trimethylbenzohydroximate, 2,4,6-(Me3C6H2)C(OMe)=NOH (F2A), allows the isolation of [PtCl4[NH=C(R)ON=C(OMe)(2,4,6-Me3C6H2)]2] (5, 6) and [PtCl4[NH=C(Me)ON=C(OMe)(2,4,6-Me3C6H2)](Me2SO)] (8), correspondingly. In accord with the latter reaction, the coupling of nitriles in trans-[PtCl4(EtCN)2] with methyl benzohydroximate, PhC(OMe)=NOH (F2B), gives [PtCl4[NH=C(Et)ON=C(OMe)Ph]2] (4). The addition proceeds faster with the hydroximic F2, rather than with the hydroxamic form F1. The complexes 1-8 were characterized by C, H, N elemental analyses, FAB+ mass-spectrometry, IR, 1H and 13C[1H] NMR spectroscopies. The X-ray structure determinations have been performed for both hydroxamic and hydroximic complexes, i.e. 2 and 6, indicating that the imino ligands are mutually trans and they are in the E-configuration.

Journal Article↗
PubMed1967

Hydroxamic acids in nature.

The hydroxamic acid bond occurs in products from fungi, yeast, bacteria, and plants. The -CON(OH)-bond arises by oxidation of a free or bound amino group in a unit structure which is often closely related to conventional amino acids. Products are known with one, two, or three hydroxamic acid groups per molecule. The chemistry of the ferrichrome type compounds, which are ferric trihydroxamate-containing peptides, has been worked out in detail and includes a complete crystallographic analysis of the ferrichrome A molecule. The trihydroxamates form potent complexes with ferric ion, called siderochromes, and these are believed to play a role in the metabolism of the metal ion in microorganisms. The actual physiological activity observed ranges from that of growth factor, antibiotic, antibiotic antagonist, tumor inhibitor or cell-division factor. The precise molecular mechanism whereby these substances exert their potent beological activity remains to be elucidated.

Anti-Bacterial Agents↗