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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↗
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↗
PubMed1985

Mutagenicity of some monoaromatic hydroxamic acids.

The mutagenicity of some monoaromatic hydroxamic acids was tested in the presence and absence of rat liver S-9 with Salmonella typhimurium tester strains TA98 and TA100. Of the five N-(chlorophenyl)-substituted hydroxamic acids and seven N-arylformohydroxamic acids tested, 2 of the first and 4 of the latter series were mutagenic to both strains upon metabolic activation. None of the four N-acetyl-type hydroxamic acids was mutagenic to either strain, even upon activation. Because some of the N-acetyl-derived hydroxamic acids were inactive, whereas the same aromatic nucleus possessing a formyl group displayed significant activity, a consideration of the nature of the aryl group in hydroxamic acid mutagenicity is important.

Animals↗
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↗
PubMed2004

[Research advance in cyclic hydroxamic acids, main allelochemicals of Zea mays].

The research advance in cyclic hydroxamic acids was reviewed in this paper. Cyclic hydroxamic acids are the important natural products of cereal crops. They and their respective derivatives are the constitutive compounds of a wide variety of gramineous plants and few dicot plants. They have structural diversity and different natural occurrences. Because of their phytotoxic properties, cyclic hydroxamic acids show a great variety of biological activities. They are the defensive agents against plant diseases, pests, nematodes and other plants. The distribution of cyclic hydroxamic acids in Zea mays and their variation in relation to the age were focused on in the paper. In Zea mays, there are structural diversity of cyclic hydroxamic acids and related benzoxazolinones. DIMBOA (1,4-benzoxazin-3(4H)-ones) is the most abundant derivative in Zea mays. The content of cyclic hydroxamic acids is strongly cultivar-dependent in Zea mays. Hydroxamic acids are not present in seeds. After germination, the level of DIMBOA increases, and the maximum level occurs in young seedlings a few days after germination. DIMBOA exists in all parts of plants, and its concentration is generally higher in shoots than in roots. In all stages, the young leaves of Zea mays have relatively high content of DIMBOA. The concentrations of these hydroxamic acids are highly dependent on environmental growth conditions. Under UV-light and water deficiencies, the levels of hydroxamic acids in plant increase rapidly. Cyclic hydroxamic acids exuded by Zea mays root can be quantitatively analyzed by HPLC. Supplying iron can significantly increase the exudation of DIMBOA from Zea mays root.

Benzoxazines↗