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PubMed2002

Chemistry and mechanism of urease inhibition.

Studies on enzyme inhibition remain an important area of pharmaceutical research since these studies have led to the discoveries of drugs useful in a variety of physiological conditions. The enzyme inhibitors can interact with enzymes and block their activity towards natural substrates. Urease inhibitors have recently attracted much attention as potential new anti-ulcer drugs. Ironically, urease was the first enzyme crystallized but its mechanism of action is still largely misunderstood. This chapter therefore reviews comprehensive developments in the field of urease inhibitors. Inhibitors of urease can be broadly classified into two categories: (1) active site directed (substrate-like), (2) mechanism-based directed. We present here the examples of selected inhibitors along with their mechanisms of action to characterize their mode of urease inhibition. The observations that urease due to its high substrate (urea) specificity can only bind to a few inhibitors with a similar binding mode as urea is also discussed. Several non-covalent interactions including hydrogen bonds and hydrophobic contacts stabilize the enzyme-inhibitor complex. Regardless of the class of compound, it is reported that only a few functional groups with electronegative atoms such as oxygen, nitrogen and sulfur act either as bidentate (mostly), tridentate (rarely), or as ligand-chelator to form octahedral complexes with two slightly distorted octahedral Ni ions of the enzyme. Bulky groups attached to the pharmacophore were found to decrease the activity of inhibitors, since the lack of a bulky attachment makes it easier for urease inhibitors to enter the substrate-binding pocket as well as avoid unfavorable steric interactions with amino acid residues in its vicinity. This review is intended to provide highlights of the inhibition of urease by hydroxamic acids (HXAs), phosphorodiamidates (PPDs), imidazoles, phosphazene and related compounds. These compounds are compared to previously reported urease inhibitors for the catalytic models proposed for urease activity. The differences in inhibition of urease activities from plants and of bacterial origin by various inhibitors and physiological implications of urease inhibition are discussed.

Abietanes↗
PubMedDate not supplied

N-glycolylhydroxamic acids: an improved synthetic method and the in situ generation and intramolecular rearrangement of N-acetoxy-N-glycolyl-2-aminofluorene.

A new and improved method for the synthesis of glycolylhydroxamic acids is described. The two-step method involves acylation of arylhydroxylamines with acetoxyacetyl chloride, followed by saponification of the ester bond to give the desired products. The conversion of hydroxamic acids to their thallous salts followed by subsequent acetylation with acetyl chloride to give N-acyloxy esters is described. During the course of this investigation, it was observed that the N-acetoxy ester of an N-glycolylhydroxamic acid was highly unstable and underwent a novel O----O acyl migration. This facile rearrangement reaction was studied for the case of N-acetoxy-N-glycolyl-2-aminofluorene (N-OAc-GAF), which gave N-hydroxy-N-(acetoxyacetyl)-2-aminofluorene (N-OH-AcAAF) as the sole product of this rearrangement. HPLC was used to investigate this reaction and included the assignment of an HPLC peak to be due to N-OAc-GAF. A competition study employed the amide N-glycolyl-2-aminofluorene (GAF) and demonstrated the absence of intermolecular transfer of the N,O-acyl (acetyl) group of N-OAc-GAF. The mechanism for the probable intramolecular rearrangement reaction is presented, along with a consideration of the possible significance it might have for the toxicity of glycolylhydroxamic acids.

Hydroxamic Acids↗
PubMed1976

Comparative stability of cephalosporins in aqueous solution: kinetics and mechanisms of degradation.

The acidic, neutral, and alkaline degradations of six therapeutically useful cephalosporins (cephalothin, cephaloridine, cephaloglycin, cephalexin, cephradine, and cefazolin), 7-amino-cephalosporanic acid, 7-aminodeacetoxycephalosporanic acid, and some 7-substituted derivatives were followed by high-pressure liquid chromatographic, UV spectrometric, iodometric, and hydroxamic acid assays. The pH-rate profiles were determined at 35 degrees and mu = 0.5. The acidic degradation pathway for the 3-acetoxymethyl and 3-pyridinylmethyl derivatives was the specific hydrogen-ion-catalyzed hydrolysis of the beta-lactam bonds. The beta-lactam hydrolyses of these antibiotics exhibited half-lives of about 25 hr at pH 1.0 and 35 degrees. The acetyl functions of 3-acetoxymethylcephalosporins were hydrolyzed eight times faster than their beta-lactam moieties to yield the corresponding deacetyl intermediates, which were rapidly converted to the lactones. Deacetoxycephalosporins were fairly acid stable; e.g., cephalexin and cephradine were about 25 times more stable than cephalothin, cephaloridine, and cephaloglycin and about 180 times more stable than ampicillin at pH 1.0. In the neutral degradation of 3-acetoxymethyl compounds, the competitive reactions of the direct water attack and intramolecular catalysis by the side-chain amido upon the beta-lactams were proposed. The pH-rate profiles near pH 8 for cephaloglycin, cephalexin, and cephradine could be explained by the intramolecular-nucleophilic attack of the side-chain alpha-amino group upon the beta-lactam carbonyls to produce diketopiperazine-type compounds. The reactivity of the cephalosporins in the hydroxideion-catalyzed degradation was influenced significantly by the C-3 methylene substituents.

Cephalosporins↗
PubMed2006

Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells.

Histone deacetylase (HDAC) inhibitors have shown cytotoxicity as single agents in preclinical studies for multiple myeloma (MM) cells. LBH589 is a novel hydroxamic acid derivative that at low nanomolar concentrations induces apoptosis in MM cells resistant to conventional therapies via caspase activation and poly-(ADP-ribose) polymerase (PARP) cleavage. Significant synergistic cytotoxicity was observed with LBH589 in combination with bortezomib against MM cells that were sensitive and resistant to dexamethasone (Dex), as well as primary patient MM cells. LBH589 at low nanomolar concentrations also induced alpha-tubulin hyperacetylation. Aggresome formation was observed in the presence of bortezomib, and the combination of LBH589 plus bortezomib induced the formation of abnormal bundles of hyeracetylated alpha-tubulin but with diminished aggresome size and apoptotic nuclei. These data confirm the potential clinical benefit of combining HDAC inhibitors with proteasome inhibitors, and provide insight into the mechanisms of synergistic anti-MM activity of bortezomib in combination with LBH589.

Boronic Acids↗
PubMed1976

Nalpha-acetylfusarinines: isolation, characterization, and properties.

The isolation, purification, and structural elucidation of a new group of naturally occurring hydroxamic acids are described. These compounds are produced by an unidentified species of Penicillium when grown on iron deficient medium. They are closely related structurally to the fusarinines, whose basic structure contains Ndelta-(cis-5-hydroxy-3-methylpent-2-enoyl)-Ndelta-hydroxy-L-ornithine, but the alpha-amino groups in the new compounds are protected by Nalpha acetyl groups. The most complex of the compounds is N,N',N"-triacetylfusarinine C, or N,N'N"-triacetylfusigen, a cyclic triester composed of three molecules on Nalpha-acetylfusarinine. The trimer has growth factor activity for Arthrobacter JG-9 about equal to fusarinine C itself. The monohydroxamate, Nalpha-acetylfusarinine, is more active than the trimer. The greater chemical stability of these compounds compared to the unacetylated fusarinines reconciles the utilization of otherwise unstable amino acid esters as iron transport agents.

Drug Stability↗
PubMed1985

DNA repair synthesis induced by N-hydroxyurea, acetohydroxamic acid, and N-hydroxyurethane in primary rat hepatocyte cultures: comparative evaluation using the autoradiographic and the bromodeoxyuridine density-shift method.

N-Hydroxyurea and two structurally related compounds, acetohydroxamic acid and N-hydroxyurethane, were investigated for their potential to induce DNA repair synthesis in primary rat hepatocyte cultures. Repair was determined as repair replication by means of the bromodeoxyuridine density-shift method and, in the same cell preparations, as unscheduled DNA synthesis (UDS) by autoradiography. For all 3 compounds, a clear concentration-dependent induction of DNA repair replication could be demonstrated. Interpretation of the UDS data, however, depended on the mode whereby the results were evaluated. Expression of the results as net grains per nucleus after subtraction of cytoplasmic from nuclear grain counts yielded statistically significant increases over the control values for all compounds. In contrast, no significant changes of the nuclear labeling were obtained when nuclear and cytoplasmic grain counts were plotted separately. These findings demonstrate that the two modes to present UDS data may lead to different conclusions, a consequence of the uncertainty regarding the origin and importance of the cytoplasmic background. The observation that both hydroxyurea and the structurally related compounds acetohydroxamic acid and N-hydroxyurethane induce DNA repair in primary hepatocyte cultures suggests that metabolism-dependent genotoxicity may be a common property of aliphatic hydroxamic acids.

Animals↗
PubMed1975

Conversion of nitrosobenzene to N-phenylacetohydroxamic acid by yeast pyruvate decarboxylase.

In the presence of yeast enzyme concentrate or purified yeast pyruvate decarboxylase, nitrosobenzene was converted in part to N-phenylacetohydroxamic acid. This transformation had to be catalyzed by the enzyme, since the incubation of nitrosobenzene with the cofactor of pyruvate decarboxylase did not produce the hydroxamic acid. Similar incubations conducted with phenylhydroxylamine did not yield any detectable amounts of N-phenylacetohydroxamic acid.

Carboxy-Lyases↗
PubMed1983

Photo-oxidation of Jack bean urease in the presence of methylene blue.

Photo-oxidation of Jack bean urease was performed in the presence of a low concentration of methylene blue, which led to the complete loss of the enzymatic activity. The inactivation was more remarkable in an alkaline region than in an acidic region and prevented by the addition of histidine or methionine. Amino acid analysis of the oxidized enzyme revealed that the number of histidine residues had decreased to 73% that of the native enzyme, but the numbers of other amino acid residues were not significantly affected. Benzohydroxamic acid, a specific urease inhibitor, protected the active site of the enzyme against photo-oxidation. On the other hand, oxidation of the enzyme decreased its binding ability with caprylo- and benzohydroxamic acid to one-third. These results suggest that histidine residues are modified by photo-oxidation and are essential to both the enzymatic activity and the binding ability with hydroxamic acid.

Fabaceae↗
PubMed1970

Rhodotorulic acid from species of Leucosporidium, Rhodosporidium, Rhodotorula, Sporidiobolus, and Sporobolomyces, and a new alanine-containing ferrichrome from Cryptococcus melibiosum.

An examination of 142 strains within 19 genera of yeasts and yeastlike organisms for formation of hydroxamic acids in low-iron culture showed production of hydroxamates by two unclassified strains and by 52 strains among the genera Aessosporon (3 of 3 strains), Cryptococcus (1 of 43), Leucosporidium (3 of 11), Rhodosporidium (4 of 4), Rhodotorula (27 of 39), Sporidiobolus (2 of 2), and Sporobolomyces (12 of 13). Crystalline rhodotorulic acid was isolated in amounts sufficient to account for most or all of the measured hydroxamate in culture supernatants of 16 strains representative of the five last-mentioned hydroxamate-producing genera. A new alanine-containing ferrichrome was isolated from one strain of Cryptococcus melibiosum. Rhodotorulic acid was a major metabolic product of many of the positive strains when grown in low-iron media, and iron was shown to repress its synthesis and excretion into the culture medium. The taxonomic significance of production of hydroxamic acids is described in connection with the position of these yeast species in the subclass Heterobasidiomycetidae.

Alanine↗
PubMed2006

Inhibitors of the FEZ-1 metallo-beta-lactamase.

Metallo-beta-lactamases (MBLs) catalyze the hydrolysis of beta-lactams including penicillins, cephalosporins and carbapenems. Starting from benzohydroxamic acid (1) structure-activity studies led to the identification of selective inhibitors of the FEZ-1 MBL, e.g., 2,5-substituted benzophenone hydroxamic acid 17 has a K(i) of 6.1+/-0.7microM against the FEZ-1 MBL but does not significantly inhibit the IMP-1, BcII, CphA or L1 MBLs.

Enzyme Inhibitors↗
PubMed1997

Angiotensin-converting enzyme secretase is inhibited by zinc metalloprotease inhibitors and requires its substrate to be inserted in a lipid bilayer.

Mammalian angiotensin-converting enzyme (ACE; EC 3.4.15.1) is one of several proteins that exist in both membrane-bound and soluble forms as a result of a post-translational proteolytic processing event. For ACE we have previously identified a metalloprotease (secretase) responsible for this proteolytic cleavage. The effect of a range of structurally related zinc metalloprotease inhibitors on the activity of the secretase has been examined. Batimastat (BB94) was the most potent inhibitor of the secretase in pig kidney microvillar membranes, displaying an IC50 of 0.47 microM, whereas TAPI-2 was slightly less potent (IC50 18 microM). Removal of the thienothiomethyl substituent adjacent to the hydroxamic acid moiety or the substitution of the P2' substituent decreased the inhibitory potency of batimastat towards the secretase. Several other non-hydroxamate-based collagenase inhibitors were without inhibitory effect on the secretase, indicating that ACE secretase is a novel zinc metalloprotease that is realted to, but distinct from, the matrix metalloproteases. The full-length amphipathic form of ACE was labelled selectively with 3-trifluoromethyl-3-(m-[125I]iodophenyl)diazirine in the membrane-spanning hydrophobic region. Although trypsin was able to cleave the hydrophobic anchoring domain from the bulk of the protein, there was no cleavage of full-length ACE by a Triton X-100-solubilized pig kidney secretase preparation when the substrate was in detergent solution. In contrast, the Triton X-100-solubilized secretase preparation released ACE from pig intestinal microvillar membranes, which lack endogenous secretase activity, and cleaved the purified amphipathic form of ACE when it was incorporated into artificial lipid vesicles. Thus the secretase has an absolute requirement for its substrate to be inserted in a lipid bilayer, a factor that might have implications for the development of cell-free assays for other membrane protein secretases. ACE secretase could be solubilized from the membrane with Triton-X-100 and CHAPS, but not with n-octyl beta-D-glucopyranoside. Furthermore trypsin could release the secretase from the membrane, implying that like its substrate, ACE, it too is a stalked integral membrane protein.

Affinity Labels↗
PubMed1975

Beta-Ketoacyl-acyl carrier protein synthetase. Characterization of the acyl-enzyme intermediate.

Beta-Ketoacyl-acyl carrier protein (ACP) synthetase catalyzes the condensation reaction of fatty acid synthesis in Escherichia coli. The homogeneous enzyme reacts with hexanoyl-CoA to form hexanoyl-enzyme which was isolated and characterized. Hexanoyl-enzyme contains 2 mol of hexanoate/mol of enzyme (molecular weight 66,000); it is liable at alkaline pH, and it reacts with neutral hydroxylamine to form hexanoyl hydroxamic acid. Hexanoate was cleaved from the enzyme when hexanoyl-enzyme was subjected to performic acid oxidation. These properties indicate that hexanoyl-enzyme is a thioester. Studies of the circular dichroism spectra of fully acylated and nonacylated forms of the enzyme indicated that the secondary structure of the enzyme is relatively unperturbed by the presence of the hexanoyl groups. An alpha helical content of 65% was estimated for the enzyme from the circular dichroism spectrum. Hexanoyl-enzyme is active in both partial reactions that comprise the beta-ketoacyl-ACP synthetase reaction; it reacts with ACP to form hexanoyl-ACP and with malonyl-ACP to form beta-ketooctanoyl-ACP. Although the hexanoate of hexanoyl-enzyme is transferred very rapidly to ACP, the physiological acceptor in this reaction, it is also transferred very slowly to CoA, dithiothreitol, and 2-mercaptoethanol, indicating that the enzyme can react nonspecifically with a number of unrelated mercaptans.

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase↗
PubMed2006

Design and evaluation of hydroxamate derivatives as metal-mediated inhibitors of a protein tyrosine kinase.

Protein tyrosine kinases use two Mg(2+) ions as cofactors in catalysis, one as the ATP-Mg complex (M1) and the other as an essential activator (M2). The M2-binding site has high affinity for transition metal cations such as cobalt and zinc. Taking advantage of this high affinity, we examined hydroxamates as metal-mediated inhibitors against C-terminal Src kinase (Csk), a protein tyrosine kinase. Of a small group of amino acid hydroxamates, tyrosine and phenylalanine hydroxamates inhibited Csk activity only in the presence of Co(2+). Four classes of phenylalanine and tyrosine hydroxamate derivatives were synthesized and evaluated as metal-mediated inhibitors of Csk, leading to improved inhibition and a better understanding of the structure-activity relationships. This study suggests that hydroxamates may serve as a general scaffold for developing metal-mediated inhibitors against protein tyrosine kinases. To the best of our knowledge, this is the first report of designing metal-mediated inhibitors against a protein tyrosine kinase by targeting a metal binding site.

Cations, Divalent↗
PubMed2003

The discovery of NVP-LAQ824: from concept to clinic.

The natural products trapoxin B and trichostatin A, as well as the novel marine natural product psammaplin A (PSMA) were found in a cell-based screen for compounds that induced the expression of the cyclin dependent kinase inhibitor p21(waf1). The mechanism of p21(waf1) induction for these compounds was via histone deacetylase (HDAC) inhibition. Of these compounds, PSMA was of interest because of its novel structure, but the physiological stability of it, and its analogs was poor. Thus, a directed medicinal chemistry effort was undertaken to prepare analogs of the simple HDAC inhibitor dimethylaminobenzamidylcaprylic hydroxamate (DBCH), which led to chromenone amide 9. This compound was efficacious in the HCT116 colon xenograft assay, but was difficult to formulate in pharmaceutically acceptable vehicles. In parallel with these efforts, a screen of the Novartis compound archive for novel HDAC inhibitors uncovered the cinnamyl hydroxamic acid NVP-LAK974. This compound had good enzyme and cellular potency, but poor efficacy in vivo. A systematic structural exploration of cinnamyl hydroxamates based on NVP-LAK974 was undertaken with the goal of finding a novel, well-tolerated and efficacious HDAC inhibitor. Several derivatives were found to be efficacious in the xenograft assay. Of those compounds, NVP-LAQ824 distinguished itself due to its tolerability, efficacy and potency. Based, in part, on these properties, NVP-LAQ824 is currently undergoing human clinical trials as a novel anti-cancer agent.

Animals↗
PubMed2005

Alkyl-substituted polyaminohydroxamic acids: a novel class of targeted histone deacetylase inhibitors.

The reversible acetylation of histones is critical for regulation of eukaryotic gene expression. The histone deacetylase inhibitors trichostatin (TSA, 1), MS-275 (2) and suberoylanilide hydroxamic acid (SAHA, 3) arrest growth in transformed cells and in human tumor xenografts. However, 1-3 suffer from lack of specificity among the various HDAC isoforms, prompting us to design and synthesize polyaminohydroxamic acid (PAHA) derivatives 6-21. We felt that PAHAs would be selectively directed to chromatin and associated histones by the positively charged polyamine side chain. At 1 microM, compounds 12, 15 and 20 inhibited HDAC by 74.86, 59.99 and 73.85%, respectively. Although 20 was a less potent HDAC inhibitor than 1, it was more potent than 2, more effective as an initiator of histone hyperacetylation, and significantly more effective than 2 at re-expressing p21Waf1 in ML-1 leukemia cells. On the basis of these results, PAHAs 6-21 represent an important new chemical class of HDAC inhibitors.

Acetylation↗
PubMed2001

2-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)- and 2-(2,2-dioxo-1,4-dihydro-2H-2lambda6-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides as potent and selective peptide deformylase inhibitors.

Potent, selective, and structurally new inhibitors of the Fe(II) enzyme Escherichia coli peptide deformylase (PDF) were obtained by rational optimization of the weakly binding screening hit (5-chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid hydrazide (1). Three-dimensional structural information, gathered from Ni-PDF complexed with 1, suggested the preparation of two series of related hydroxamic acid analogues, 2-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-N-hydroxy-acetamides (A) and 2-(2,2-dioxo-1,4-dihydro-2H-2lambda(6)-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides (B), among which potent PDF inhibitors (37, 42, and 48) were identified. Moreover, two selected compounds, one from each series, 36 and 41, showed good selectivity for PDF over several endoproteases including matrix metalloproteases. However, these compounds showed only weak antibacterial activity.

Amidohydrolases↗
PubMed1999

The pool of fatty acids covalently bound to platelet proteins by thioester linkages can be altered by exogenously supplied fatty acids.

The goals of this investigation were, first, to develop a chemical strategy to identify and quantitate the mass of fatty acid which is covalently bound to proteins by thioester linkage in unactivated platelets, and, second, to determine whether exogeneously added fatty acids can alter the fatty acid composition of thioester bound fatty acids. Studies with radiolabeled fatty acids cannot identify and quantitate the actual fatty acids bound to proteins because they permit analysis of only the radiolabeled fatty acids added and their metabolites. Therefore, in the absence of metabolic labeling by radiolabeled fatty acids, we isolated the thioester-linked fatty acids from platelet proteins using hydroxylamine at neutral pH to form fatty acid hydroxamates. The hydroxamates were subsequently converted to fatty acid methyl esters by acid methanolysis for quantitation by gas chromatography-mass spectrometry. Using platelet specimens from 14 subjects, 74% of the fatty acid recovered from the unactivated platelet proteins as thioester linked was palmitate. Importantly, however, 22% was stearic acid, and oleate was 4% of the total thioester bound fatty acid. There was minimal variability (2.6-fold at maximum) between the subjects in the amount of the thioester-linked palmitate and thioester-linked stearate. However, there was substantial variability (>100-fold at maximum) between subjects in the amount of thioester-linked oleate. We also demonstrated that incubation of platelets with exogenous fatty acids can alter the profile of fatty acids bound to platelet proteins by thioester linkages. Incubation of platelets with 100 microM palmitate for 3 h increased the amount of thioester-linked palmitate by up to 26%, and incubation of platelets with 100 microM stearate increased the amount of thioester-linked stearate up to 30%. In support of the observation that radiolabeled fatty acids other than palmitate were shown to be capable of binding to platelet proteins by thioester linkage, our results indicate that the fatty acids actually bound to unactivated platelet proteins include a significant amount of stearate, and variable amounts of oleate, as well as palmitate. In addition, the data show that palmitate and stearate can be increased, as a percentage of total protein-bound fatty acid, by incubation with exogenous palmitate and stearate, respectively.

Blood Platelets↗