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PubMedDate not supplied

Developmental toxicity of metal chelating agents.

Chelation therapy is the basis for the treatment of metal poisoning. A number of chelating agents have been widely used since the 1950s. Since these agents can be potentially given to a metal-intoxicated pregnant woman, their intrinsic developmental toxicities are a matter of concern. While the embryo/fetal toxic effects of some chelators have been reported to occur at doses higher than those currently given in the medical treatment of metal poisoning, according to experimental data the potential use of other metal antidotes is controversial. In those cases, the benefits and risks of usage should be carefully weighed. The developmental toxicity of known chelators of clinical interest is presented here. Chelating agents were divided according to the following structurally related categories: polyaminocarboxylic acids, chelators with vicinal -SH groups, beta-mercapto-alpha-aminoacids, hydroxamic acids, ortho-hydroxycarboxylic acids, and miscellaneous agents. Since it has been demonstrated that the teratogenic potential of most chelators is, at least in part, due to induced trace element deficiencies, the advisability of mineral supplements during chelation treatment is also discussed.

Abnormalities, Drug-Induced↗
PubMed2004

Human meprin alpha and beta homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors.

Meprin is a zinc endopeptidase of the astacin family, which is expressed as a membrane-bound or secreted protein in mammalian epithelial cells, in intestinal leucocytes and in certain cancer cells. There are two types of meprin subunits, alpha and beta, which form disulphide-bonded homo- and hetero-oligomers. Here we report on the cleavage of matrix proteins by hmeprin (human meprin) alpha and beta homo-oligomers, and on the interactions of these enzymes with inhibitors. Despite their completely different cleavage specificities, both hmeprin alpha and beta are able to hydrolyse basement membrane components such as collagen IV, nidogen-1 and fibronectin. However, they are inactive against intact collagen I. Hence the matrix-cleaving activity of hmeprin resembles that of gelatinases rather than collagenases. Hmeprin is inhibited by hydroxamic acid derivatives such as batimastat, galardin and Pro-Leu-Gly-hydroxamate, by TAPI-0 (tumour necrosis factor alpha protease inhibitor-0) and TAPI-2, and by thiol-based compounds such as captopril. Therapeutic targets for these inhibitors are MMPs (matrix metalloproteases), TACE (tumour necrosis factor alpha-converting enzyme) and angiotensin-converting enzyme respectively. The most effective inhibitor of hmeprin alpha in the present study was the naturally occurring hydroxamate actinonin ( K(i)=20 nM). The marked variance in the cleavage specificities of hmeprin alpha and beta is reflected by their interaction with the TACE inhibitor Ro 32-7315, whose affinity for the beta subunit (IC50=1.6 mM) is weaker by three orders of magnitude than that for the alpha subunit ( K(i)=1.6 microM). MMP inhibitors such as the pyrimidine-2,4,6-trione derivative Ro 28-2653 that are more specific for gelatinases do not bind to hmeprin, presumably due to the subtle differences in the mode of zinc binding and active-site structure between the astacins and the MMPs.

Animals↗
PubMed1997

Improvement of lysine production by analog-sensitive and auxotroph mutants of the acetylene-utilizing bacterium Gordona bronchialis (Rhodococcus bronchialis).

An acetylene utilizing Gordona (Rhodococcus) bronchialis strain, screened for the production of fine chemicals, was found to be capable of producing small amounts of lysine. Attempts to produce amino-acid analog-resistant and/or sensitive mutants and auxotrophs of this strain with increased lysine production were made following UV-irradiation or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) treatment. The bacterium exhibited surprisingly high resistance levels to the aforementioned mutagens which is attributed to highly effective inborn-repair systems. Natural resistance to high levels of S-(2-aminoethyl)-L-cysteine (AEC) (2%) was observed, in contrast with D, L-aspartic acid hydroxamate (AAH), L-lysine hydroxamate (LHX) and beta-fluoropyruvate (FP). A variety of amino-acid analog-resistant (AAHr, LHXr) or analog-sensitive (FPs) mutants were produced following UV-irradiation or MNNG treatment. Similarly, a large number of auxotrophs (68) of different types were also obtained. From these, one FPs mono-auxotroph and two poly-auxotrophs (with at least one requirement for the aspartic acid family) showed an increased lysine production (approximately 1.8 g/L) comparable (4 g/L) to that found in other bacteria capable of utilizing long-chain hydrocarbons (1).

Acetylene↗
PubMed2006

Production, properties and application to biocatalysis of a novel extracellular alkaline phenol oxidase from the thermophilic fungus Scytalidium thermophilum.

Scytalidium thermophilum produces an extracellular phenol oxidase on glucose-containing medium. Certain phenolic acids, specifically gallic acid and tannic acid, induce the expression of the enzyme. Production at 45 degrees C in batch cultures is growth-associated and is enhanced in the presence of 160 microM CuSO4 x 5 H2O and 3 mM gallic acid. The highest enzyme activity is observed at pH 7.5 and 65 degrees C, on catechol. When incubated for 1 h at pH 7 and pH 8, 95% and 86% of the activity is retained. Thermostability decreases gradually from 40 degrees C to 80 degrees C. Estimated molecular mass is c. 83 kDa, and pI is acidic at c. 5.4. Substrate specificity and inhibition analysis in culture supernatants suggest that the enzyme has unique properties showing activity towards catechol; 3,4-dihydroxy-L-phenylalanine (L-DOPA); 4-amino-N, N-diethylaniline (ADA); p-hydroquinone; gallic acid; tannic acid and caffeic acid, and no activity towards L-tyrosine, guaiacol, 2,2'-azino-bis(3-ethyl-benzthiazoline-6-sulphonic acid) (ABTS) and syringaldazine. Inhibition is observed in the presence of salicyl hydroxamic acid (SHAM) and p-coumaric acid. Enzyme activity is enhanced by cetyltrimethylammonium bromide (CTAB) and polyvinylpyrrolidone (PVP), and the organic solvents dimethyl sulfoxide (DMSO) and ethanol. No inhibition is observed in the presence of carbon monoxide. Benzoin, benzoyl benzoin and hydrobenzoin are converted into benzil, and stereoselective oxidation is observed on hydrobenzoin. The reported enzyme is novel due to its catalytic properties resembling mainly catechol oxidases, but displaying some features of laccases at the same time.

Ascomycota↗
PubMed2006

[Thieno[3,4-c]quinoline-4-yl-amines--synthesis and investigation of activity against malaria].

The 4-aryl derivative 3, obtained by Suzuki cross coupling of the methyl 4-bromothiophene-3-carboxylate (2) with 2-nitrophenylboronic acid cyclizes under reductive conditions pH-dependant to yield the tricyclic hydroxamic acid 4 or the lactam 5. The chlorothieno[3,4-c]quinoline 6 was formed by reaction of the lactam 5 with P,P-dichlorophenylphosphinoxide. The amines 7-14 were synthesized from the chloroimine 6. Compounds 7a,b, 8, 9, 10b, 11, 12 and 14a, b were tested for in vitro antimalarial activity using the chloroquine sensitive 3D7 and the chloroquine resistant Plasmodium falciparum strain Dd2. The highest activity were shown by 10b with IC50 values of 130 nM and 50 nM, respectively and by 11 with IC50 values of 190 nM and 44 nM, respectively.

Aminoquinolines↗
PubMed1994

Antiproliferative effect of D-aspartic acid beta-hydroxamate (DAH) on Friend virus-infected erythropoietic progenitor cells.

D-aspartic beta-hydroxamate (DAH), an aspartic acid analog, exerts antitumoral activity on murine leukemia L5178Y, both in vitro and in vivo. In this study, we show that DAH is also active in vivo against Friend virus (FV-P)-induced erythroleukemia, and we report the effects of DAH in vivo an in vitro on FV-P target cells, i.e. the mature erythroid colony-forming cells (CFU-E). DAH treatment (2 g/kg/day) given for 95 days as a single daily i.p. injection to DBA/2 mice either 3 or 12 days following inoculation with a high dose (10(3) plaque-forming units) of FV-P resulted in a marked increase in the mean survival time of treated animals (212 and 191%, respectively). Since FV-P elicits spleen enlargement and polycythemia, we examined the effects of DAH on spleen size, spleen-nucleated cell number, and hematocrit, in normal and FV-P infected mice, at different times in the course of continuous DAH treatments. DAH treatment initiated 3 days after viral infection inhibits the virus-induced splenomegaly, with at day 26 p.i. 1.15 x 10(8) and 12.6 x 10(8) nucleated cells per spleen observed in DAH-treated mice and untreated mice respectively, whereas only 1.03 x 10(8) nucleated cells were observed in uninfected mice. Furthermore, DAH prevents virus-induced polycythemia: on day 26, an hematocrit of 39% was measured in DAH-treated mice as compared to 60% in untreated mice. DAH treatment initiated 12 days after viral infection reduces splenomegaly, the number of nucleated spleen cells and the hematocrit of infected mice. DAH treatment initiated 3 days after viral infection prevents the tremendous increase of CFU-E in the spleen of infected mice: on day 11, the spleen of infected mice contained 4.6 x 10(6) CFU-E, while the spleen of treated mice only contained 26 x 10(3) CFU-E, and on day 26 the spleen CFU-E numbers were 45.4 x 10(6) and 1.5 x 10(6) in untreated and treated infected mice, respectively. In control uninfected mice, DAH treatment induced a transient decrease in spleen CFU-E followed by a rebound phenomenon. In vitro, preincubation with DAH inhibits colony formation by FV-P infected CFU-E, at doses starting at 3 mM, as compared to uninfected CFU-E. These data show that DAH inhibits the expression of the retroviral infection, and appears to preferentially inhibit the proliferation of infected target cells (CFU-E) in vivo.

Animals↗
PubMed2005

Matrix metalloproteinase inhibitors: a review on pharmacophore mapping and (Q)SARs results.

The matrix metalloproteinases (MMPs) are a family of more than 20 enzymes that are intimately involved in tissue remodelling. These zinc-containing endopeptidases consist of several subsets of enzymes, including collagenase, stromelysins and gelatinases and are involved in the degradation of the extracellullar matrix (ECM) that forms the connective material between cells and around tissues. Disease processes associated with the MMPs are generally related to imbalance between the inhibition and activation of MMPs resulting in excessive degradation of the ECM. These indications include osteoarthritis rheumatoid arthritis, tumour metastasis and congestive heart failure. Inhibitors for these enzymes have been developed for the treatment of a starthingly wide array of disease process where matrix remodelling plays a key role. There are three major components to most MMP inhibitors- the zinc binding group ZBG, the peptidic backbone and the pocket occupying side chain. Most MMPs inhibitors are classified according to their ZBG. Inhibitors interactions at active-site zinc plays a critical role in defining the binding mode and relative inhibitor potency. The majority of MMP inhibitors reported in the literature contain an effective zinc binding group (e.g. hydroxamic acid, carboxylic acid, sulfhydryl group) that is either generally substituted with a peptide-like structure that mimics the substrates that they cleave or appended to smaller side chains that may interact with specific subsites (e.g., P1', P2', P3') within the active site. Although carboxylates exhibit weaker zinc binding properties than hydroxamates, they are known to show better oral bioavailability and are less prone to metabolic degradation. The expected loss of binding affinity after replacement of hydroxamates against carboxylates is faced by adequate choice of elongated S1' directed substituents. The need for novel selective MMP inhibitors makes them an attractive target for the QSAR and molecular modelling. 3-D QSAR models were derived using CoMFA, CoMSIA and GRID approaches leading to the identification of binding regions where steric, electronic or hydrophobic effects are important for affinity. Some structural requirements essential for achieving high binding affinity and selectivity are: an acidic unit tightly anchored through four contact points, bidentate chelation of Zn2+, carbonyl groups for hydrogen bonding, more than two extra units for hydrogen bonds, a hydrophobic moiety.

Binding Sites↗
PubMed2003

Synthesis and reactions of 2-substituted ethyl N-alkylmalonylhydroxamic acids.

Alkylation of O-silylated N-alkylmalonylhydroxamic acids provides a method for the synthesis of 2-substituted N-alkylmalonyl hydroxamic acids. The substituent at C-2 does not materially change the chemistry of the alpha-lactam intermediates produced from them. They can be converted to unsymmetric ureas and hydantoins in high yields. The addition of unsaturated substituents at C-2 is used to produce cyclic ureas containing medium rings via RCM reactions.

Journal Article↗
PubMed2001

Intramolecular O-arylation of phenols with phenylboronic acids: application to the synthesis of macrocyclic metalloproteinase inhibitors.

[reaction: see text]. The copper acetate mediated intramolecular O-arylation of phenols with phenylboronic acid pseudopeptides is the key step in the preparation of macrocyclic biphenyl ether hydroxamic acid inhibitors of collagenase 1 and gelatinases A and B. The intramolecular macrocyclization was found to be mild and tolerant of common chemical functionality. This methodology should provide a general route to macrocyclic biphenyl ethers.

Boronic Acids↗
PubMed1982

Mechanism of action of butyryl-CoA dehydrogenase: reactions with acetylenic, olefinic, and fluorinated substrate analogues.

The acetylenic thio ester (3-pentynoyl)pantetheine irreversibly inactivates butyryl-CoA dehydrogenase from Megasphaera elsdenii. The inactivator becomes covalently attached to the protein (0.61 +/- 0.1 mol of 14C-labeled inactivator/mol of enzyme flavin). No modification of the flavin cofactor is seen. The covalent enzyme-inactivator adduct is labile toward base and neutral hydroxylamine. These treatments release 85 +/- 5% of the incorporated 14C label from the protein. Base-catalyzed hydrolysis of the adduct releases 3-oxopentanoic acid (0.6 mol/mol of incorporated inactivator). Treatment with hydroxylamine leads to formation of a hydroxamic acid on the protein (0.64 +/- 0.09 mol/mol of incorporated inactivator). The covalent adduct can be reduced with sodium borohydride with release of 1,3-pentanediol. Hydrolysis of the protein with 6 N HCl after sodium borohydride reduction yields 2-amino-5-hydroxyvaleric acid and proline. We conclude that the inactivator has reacted with the gamma-carboxyl group of a glutamate residue at the enzyme active site. The inactivation proceeds through enzyme-catalyzed rearrangement of the acetylene to an allene, followed by nucleophilic addition of the carboxyl group to the allene. (3-Chloro-3-butenoyl)pantetheine irreversibly inactivates the enzyme in a fashion similar to the acetylenic thio ester and also modifies a glutamate residue. Butyryl-CoA dehydrogenase catalyzes the isomerization of (3-butenoyl)pantetheine to (2-butenoyl)pantetheine. The enzyme catalyzes the elimination of HF from 3-fluoropropionyl-CoA and (3,3-difluorobutyryl)pantetheine. We suggest, that these results together support an oxidation mechanism for butyryl-CoA dehydrogenase which is initiated by alpha-proton abstraction.

Acetylation↗
PubMed1998

Modular fluorescent-labeled siderophore analogues.

Biomimetic analogues 1 of the microbial siderophore (iron carrier) ferrichrome were labeled via piperazine with various fluorescent markers at a site not interfering with iron binding or receptor recognition (compounds 10-12). These iron carriers were built from a tetrahedral carbon symmetrically extended with three strands, each containing an amino acid (G = glycyl, A = alanyl, L = leucyl and P = phenylalanyl) and terminated by a hydroxamic acid, which together define an octahedral iron-binding domain. A fourth exogenous strand provided the site for connecting various fluorescent markers via a short bifunctional linker. Iron(III) titrations, along with fluorescence spectroscopy, generated quenching of fluorescence emission of some of the probes used. The quenching process fits the Perrin model which reinforces the intramolecular quenching process, postulated previously.1 All tested compounds, regardless of their probe size, polarity, or the linker binding them to the siderophore analogue, promote growth of Pseudomonas putida with the same efficacy as the nonlabeled analogues 1, with the added benefit of signaling microbial activity by fluorescence emission. All G derivatives of compounds 10-12 were found to parallel the behavior of natural ferrichrome, whereas A derivatives mediated only a modest iron(III) uptake by P. putida. Incubation of various Pseudomonas strains with iron(III)-loaded G derivatives resulted in the build-up of the labels' fluorescence in the culture medium to a much larger extent than from the corresponding A derivatives. The fluorescence buildup corresponds to iron utilization by the cells and the release of the fluorescent labeled desferrisiderophore from the cell to the media. The fact that the microbial activity of these compounds is not altered by attachment of various fluorescent markers via a bifunctional linker proposes their application as diagnostic tools for detecting and identifying pathogenic microorganisms.

Drug Design↗
PubMed2005

A quantitative structure-activity relationship study on some series of anthranilic acid-based matrix metalloproteinase inhibitors.

A quantitative structure-activity relationship (QSAR) study has been made on four different series of anthranilic acid-based matrix metalloproteinase (MMP) inhibitors, in which two substituted aryl rings, one bearing the hydroxamic acid moiety that binds with the zinc atom of MMPs, are joined through a bridge group of sulfonamide. The QSAR results indicate that the sulfonamide group plays a very important role in the inhibition activity of the inhibitors and that the effectiveness of this sulfonamide group can be increased by the presence at the aryl rings or at the sulfonamide nitrogen itself of nitrogen-containing or some such substituents that can increase the electronic character of the sulfonamide group. The hydrophobic character of the molecules is not found to be of any advantage; rather in most of the cases it is shown to have detrimental effect, suggesting that MMPs provide little opportunity to the inhibitors to have a any hydrophobic interactions with them. On the other hand, polarizability of the molecules has been found to be conducive to activity in some cases. Thus the inhibition mechanism seems to predominantly involve the electronic interactions between the inhibitors and the enzymes.

Matrix Metalloproteinase Inhibitors↗
PubMed1991

Anti-tumoral activity of L and D isomers of aspartic acid beta-hydroxamate on L5178Y leukemia.

D and L isomers of aspartic acid beta-hydroxamate (respectively DAH and LAH) were compared for their in vitro and in vivo activity against the murine leukemia L5178Y and their tolerance in vivo in DBA/2 mice. DAH and LAH displayed comparable cytotoxic activity against L5178Y leukemia in vitro. Death of leukemia cells was observed at concentrations above 1.2 mM for both DAH and LAH. High concentrations of L-asparagine partially reversed the growth-inhibitory effects of DAH and LAH on L5178Y cells for concentrations of DAH and LAH lower than 0.6 mM. Intraperitoneal administration of DAH and LAH to mice showed that the LD10, LD50 and LD90 of DAH was 3- to 4-fold greater for DAH than for LAH. DAH was able to eradicate L5178Y tumors in mice without inducing toxic deaths, whereas LAH at comparable doses killed all the animals treated.

Animals↗
PubMed2004

Phosphoglyceride (PG) crystal deposition disease: a novel acquired disease in which PG crystals are deposited in injured soft tissue and bone with phospholipid metabolism disturbance.

The clinical history and crystal characteristics of three published cases and three new cases of phosphoglyceride (PG) crystal deposition disease of soft tissues and bones were compared. All patients (age range, 51-64 years) were generally healthy without a genetic background of congenital immunodeficiency or lipidosis. Foreign body granulomas grew slowly, predominantly at postoperative or repeat injection lesions. In two cases, crystals were deposited in multiple locations, and in one case, lipophage accumulations were found in the bone marrow. The crystals characteristically dissolved in acetic acid with oxygen gas formation, easily dissolved in alkalis and showed positive staining for PG by the gold hydroxamic acid method. All crystals examined by infrared microscopy, mass spectrometry and X-ray microanalysis showed similar results, supporting the theory that the crystals were PG. Phosphoglyceride deposition disease is a lipid metabolic disorder in which PG crystals are slowly deposited, predominantly in injured soft tissues, forming foreign body granulomas. The diagnosis can be based on histological characteristics. The prognosis is favorable, although some cases showed systemic depositions with repetitions. Lysosomal phosphoglyceride metabolism in macrophages might be affected.

Bone Marrow↗
PubMed1990

An isozyme-selective affinity label for rat hepatic acetyltransferases.

Affinity chromatography of an ammonium sulfate precipitate obtained from rat hepatic cytosol resulted in the separation of two fractions of N-acetyltransferase (NAT) activity. NATI catalyzed the S-acetylcoenzyme A (AcCoA)-dependent acetylation of p-aminobenzoic acid (PABA); NAT II catalyzed the N-hydroxy-2-acetylaminofluorene (N-OH-AAF)-dependent acetylation of 4-amino-azobenzene (AAB) (N,N-acetyltransferase), the AcCoA-dependent acetylation of procainamide (PA), and the N-arylhydroxamic acid N,O-acyltransferase (AHAT) activity that results in the conversion of N-OH-AAF and related hydroxamic acids to electrophilic reactants. 1-(Fluoren-2-yl)-2-propen-1-one (vinyl fluorenyl ketone, VFK) was shown to be a potent and irreversible inactivator of NAT II activities. A 200-fold higher concentration of VFK was required to inactivate NAT I activity than was required for inactivation of NAT II activities. Similar selectivity in the inactivation of the isozymes was observed when experiments were conducted with enzyme preparations that contained both NAT I and NAT II activities. The presence of substrates and products of the NAT II-catalyzed reactions such as AcCoA, 2-acetylaminofluorene (2-AAF), and N-acetyl-4-aminoazobenzene (N-Ac-AAB) protected NAT II from the inactivating effects of VFK, providing evidence that VFK is an active site directed inhibitor (affinity label) of NAT II. Studies with 1-(fluoren-2-yl)-2-propan-1-one (EFK), an analogue of VFK in which the alpha, beta-unsaturated vinyl ketone group of VFK has been replaced with an ethyl ketone group, demonstrated that the conjugated ketone of VFK is required for inactivation of enzyme activity. The results of these studies suggest that agents such as VFK should have utility as probes of acetyltransferase multiplicity and in the investigation of the active site topography of the enzymes.

Acetylation↗
PubMed1998

Transformation of monomorphic Trypanosoma brucei bloodstream form trypomastigotes into procyclic forms at 37 degrees C by removing glucose from the culture medium.

African trypanosomes have been shown previously to undergo efficient transformation from bloodstream forms to procyclic (insect dwelling) forms in vitro by adding citrate and/or cis-aconitate to the culture medium and lowering incubation temperature to 27 degrees C. In this paper, it is shown that strain 427 monomorphic bloodstream forms of Trypanosoma brucei grown in axenic culture at 37 degrees C can be transformed to procyclic forms by simply replacing the glucose carbon source in the culture medium with glycerol. The removal of glucose from the medium results in the loss of the variant surface glycoprotein, the acquisition of cell surface procyclic acidic repetitive protein, the synthesis of procyclic-specific glycosylphosphatidylinositol precursors and the acquisition of substantial resistance to salicyl hydroxamic acid and glycerol within 72 h. A procyclic-specific cytoskeletal protein, known to be a marker of the late stage of transformation, is fully expressed by 96 h but full trans-sialidase activity appears only after 18-30 days. The transformation process described here is slower and less efficient than that previously described for monomorphic trypanosomes, using citrate and/or cis-aconitate and temperature shift as triggers. However, the separation of the transformation process from these stimuli is significant and the effects of glucose deprivation described here may reflect some of the events that occur in vivo in the tsetse fly midgut, where glucose levels are known to be very low.

Animals↗
PubMed1993

Inhibition of dynorphin converting enzymes from human spinal cord by N-peptidyl-O-acyl hydroxylamines.

Two cysteine proteinases, cleaving dynorphins A and B to enkephalins, were isolated from the human spinal cord. These enzymes were found to be competitively inhibited by a new class of synthetic inhibitors: N-peptidyl-O-acyl hydroxylamines. The most potent (Ki < 20 microM) were the N-terminally protected peptides Z-Phe-Phe-NHO-Ma and Boc-Phe-Gly-NHO-Bz, both containing hydrophobic amino acids at the P2 position. N-Peptidyl-O-acyl hydroxylamines were converted in water solution to the corresponding hydroxamic acids and no cleavage of the peptide bond within the inhibitor sequence was observed after prolonged incubation with the enzymes. It is anticipated that these synthetic compounds may serve as potential pharmacological tools for in vitro studies on dynorphin processing.

Amino Acid Sequence↗