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PubMed2002

[Benzo(f)furo(3,4-c)(2,7)naphthyridines from furo(3,4-b)pyridines].

The pyridines 5, obtained by dehydrogenation of the 4-(2-nitrophenyl)-1,4-dihydropyridine lactones 4, give the tetracycles 6 and 7 by reduction of the nitro group with zinc/ammonium chloride followed by ring closure. Irradiation of the compounds 4 with UV-A light leads to the 4-(2-nitrosophenyl)pyridines 8. During the reaction of 8 with conc. hydrochloric acid the nitroso group cyclizes with the 5-acyl group yielding the chloro substituted tetracycles 9 and 10. The hydroxamic acids 6 and 9 are deoxygenated by phosphorus trichloride to yield the lactames 11, while O-acetylation with acetic anhydride affords 12. Phosphorus trichloride reduces the N-oxides 7 and 10 to the bases 13. Using the reaction with acetic anhydride the acetates 14 are formed by Boekelheide-transformation. Alcaline saponification of 14 gives the alcohols 15.

Antimalarials↗
PubMed2002

Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors.

A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood.

ADAM Proteins↗
PubMed1983

Respiration of Gametangia of the Aquatic Phycomycete Allomyces macrogynus: Inhibition by Cyanide or Antimycin and Salicylhydroxamic Acid or Propyl Gallate.

Gametangia of the aquatic phycomycete Allomyces macrogynus have a cyanide- and antimycin A-insensitive respiration, which is sensitive to salicylhydroxamic acid (alternative respiration). Propyl gallate is also an inhibitor of this alternative pathway, and propyl gallate is more efficient than hydroxamic acid. Gametangial respiration is insensitive to propyl gallate, but propyl gallate sensitivity is gradually established when the gametangia are titrated with cyanide. Carbonyl cyanide m-chlorophenyl hydrazone stimulates the cyanide-sensitive respiration and engages the alternative sensitive respiration. Sodium azide inhibits both the alternative and the cyanide-sensitive respiration, but the cyanide-sensitive respiration is inhibited 10 times more efficiently than the alternative respiration. Rotenone inhibits the total respiration and the propyl gallate-insensitive respiration by 33% and the cyanide-insensitive respiration by 43%.The kinetic results reported here are discussed with respect to the models of de Troostembergh and Nyns (1977 Arch Int Physiol Biochem 85:404-406; 1978 Eur J Biochem 53:423-432) and of Bahr and Bonner (1973 J Biol Chem 248:3446-3450) for the partitioning of electrons between cyanide-insensitive and propyl gallate-insensitive respiration. The results reported here do not agree with the model of de Troostembergh and Nyns.

Journal Article↗
PubMed1986

Identification of nucleic acid adducts from trans-4-acetylaminostilbene.

It has been proposed that trans-4-acetylaminostilbene (AAS) is an initiator for tumor formation in rat liver and that the metabolically formed hydroxamic acid ester ultimately reacts with nucleic acids in vivo. We have now studied the generation of a major adduct in vitro. trans-4-N-Acetoxy-N-acetylaminostilbene (N-acetoxy-AAS) was reacted with guanosine at pH 7.5 and reaction products were separated by chromatography on Sephadex LH-20 and RP18 HPLC. The major adduct isolated consists of four isomers which have been tentatively identified by mass- and 1H-NMR spectroscopy as (S,S)- and (R,R)-guanosine-N2,beta-N3,alpha-N-acetylaminobibenzyl and the respective regio isomers guanosine-N2,alpha-N3,beta-N-acetylaminobibenzyl. These adducts are formed in a ratio of 9:9:1:1. Under acidic conditions (pH 2) the ribose moiety is removed and two regio isomeric base adducts are formed in the ratio 9:1. Results to be published indicate that the adducts are also formed in vivo in rat liver RNA and DNA.

Animals↗
PubMed2006

Structure and membrane affinity of new amphiphilic siderophores produced by Ochrobactrum sp. SP18.

The coastal alpha-proteobacterium Ochrobactrum sp. SP18 produces a suite of three citrate-derived, cell-associated amphiphilic siderophores, ochrobactins A-C. The ochrobactins are composed of a citric acid backbone amide-linked to two lysine residues. Each epsilon-amine of lysine is hydroxylated and acylated forming two hydroxamic acid moieties. One of the acylated appendages of each ochrobactin is (E)-2-decenoic acid. The other acylated appendages for ochrobactins A-C are (E)-2-octenoic acid, octanoic acid and (E)-2-decenoic acid, respectively. The ferric ochrobactin complexes are photoreactive in UV light, producing an oxidized ligand with loss of 46 mass units that can still coordinate Fe(III). The relative partitioning of the apo-ochrobactins, Fe(III) ochrobactins and Fe(III) photoproducts into 1,2-dimyristoyl-sn-glycero-3-phosphocholine vesicles is presented. The ochrobactins are the first example of aerobactin-based siderophores with two fatty acid appendages produced in a suite with varying acyl appendage lengths.

Acetylation↗
PubMed2004

Zn2+-chelating motif-tethered short-chain fatty acids as a novel class of histone deacetylase inhibitors.

Among various classes of histone deacetylase (HDAC) inhibitors, short-chain fatty acids exhibit the least potency, with IC(50) in the millimolar range. We rationalized that this weak potency was, in part, attributable to their inability to access the zinc cation in the HDAC active-site pocket, which is pivotal to the deacetylation catalysis. We thus explored the structural optimization of valproate, butyrate, phenylacetate, and phenylbutyrate by coupling them with Zn(2+)-chelating motifs (hydroxamic acid and o-phenylenediamine) through aromatic omega-amino acid linkers. This strategy has led to a novel class of Zn(2+)-chelating, motif-tethered, short-chain fatty acids that exhibited varying degrees of HDAC inhibitory potency. One hydroxamate-tethered phenylbutyrate compound, N-hydroxy-4-(4-phenylbutyrylamino)benzamide (HTPB), displayed nanomolar potency in inhibiting HDAC activity. Exposure of several cancer cell lines to HTPB at the submicromolar level showed reduced cell proliferation accompanied by histone hyperacetylation and elevated p21(WAF/CIP1) expression, which are hallmark features associated with intracellular HDAC inhibition.

Acetylation↗
PubMed1989

Inhibition of aminopeptidases by aminophosphonates.

More than 30 aminophosphonates were synthesized to probe how the structural changes introduced into the phosphonic acid analogue of leucine, a potent inhibitor of cytosolic leucine aminopeptidase (Giannousis & Bartlett, 1987), affect their ability to inhibit cytosolic (EC 3.4.11.1) and microsomal (EC 3.4.11.2) aminopeptidases. Although most of the compounds studied were found to exert only a modest competitive inhibitory effect, nearly every modification of the structure of the phosphonic acid analogue of leucine was reflected in a marked difference in the affinities of these compounds for the two enzymes. [1-Amino-2-(N-alkylamino)ethyl]phosphonic acids are effective inhibitors of the microsomal enzyme, acting in a time-dependent manner. Kinetic data obtained for these inhibitors correspond to the mechanism for a biphasic slow-binding inhibition process: E + I in equilibrium E* in equilibrium E*I, in which the slow initial isomerization of the enzyme is followed by the fast formation of enzyme-inhibitor complex. The most effective inhibitor of this type was [1-amino-2-(N-cyclohexylamino)ethyl]phosphonic acid, which has a Ki value of 0.87 microM toward the microsomal aminopeptidase--a value that can be considered as equipotent with bestatin and with leucinal and hydroxamic acids, the strongest known nonpeptide inhibitors of this enzyme.

Aminopeptidases↗
PubMed2004

The activity of antiepileptic drugs as histone deacetylase inhibitors.

PURPOSE: Valproic acid (VPA), one of the widely used antiepileptic drugs (AEDs), was recently found to inhibit histone deacetylases (HDACs). HDAC inhibitors of a wide range of structures, such as hydroxamic acids, carboxylic acids, and cyclic tetrapeptides, have various effects on transformed and nontransformed cells, including neuromodulation and neuroprotection. The aim of this study was to assess comparatively the activity of traditional and newer AEDs as HDAC inhibitors. METHODS: After incubation of HeLa cells with the tested AEDs, histone hyperacetylation was assessed by immunoblotting with an antibody specific to acetylated histone H4. Direct HDAC inhibition by AEDs was estimated by using HeLa nuclear extract as an HDACs source and an acetylated lysine substrate. RESULTS: We found that in addition to VPA, topiramate (TPM) inhibited HDACs with apparent Ki values of 2.22 +/- 0.67 mM. Although levetiracetam (LEV) had no direct effect on HDACs, its major carboxylic acid metabolite in humans, 2-pyrrolidinone-n-butyric acid (PBA), inhibited HDACs with Ki values of 2.25 +/- 0.78 mM. The AEDs LEV, phenobarbital, phenytoin, carbamazepine, ethosuximide, gabapentin, and vigabatrin did not inhibit HDACs. The compounds that directly inhibited HDACs also induced the accumulation of acetylated histone H4 in HeLa cells. The effects of TPM and PBA on histone acetylation were significant at 0.25 mM and 1 mM, respectively. CONCLUSIONS: We found that in addition to VPA, the newer AED TPM and the major metabolite of LEV, PBA, are able to induce histone hyperacetylation in human cells, although with lower potencies than VPA.

Acetylation↗
PubMed2006

Investigation of solid surfaces modified by Langmuir-Blodgett monolayers using sum-frequency vibrational spectroscopy and X-ray photoelectron spectroscopy.

Langmuir-Blodgett (LB) monomolecular layers of alkylhydroxamic acids and alkylphosphonic acids on copper and iron substrates have been studied by X-ray photoelectron spectroscopy (XPS) and sum-frequency vibrational spectroscopy. According to the XPS results, the structures of the hydroxamic acid and phosphonic acid Langmuir-Blodgett films are very similar: the thickness of the layer of the hydrocarbon tails is typically 1.9-2.1 nm, while the layer of headgroups is about 0.3-0.35 nm thick. The tilt angle of the carbon chains is estimated to be 20-30 degrees with respect to the sample surface normal, and the molecules are connected to the substrate via their headgroups. Analysis of the P 2p and N 1s lines indicates the presence of deprotonated headgroups. The substrate Cu 2p line includes a component which can be assigned to Cu(2+) ions in a thin Cu(OH)(2) layer. The deposition of LB layers led to significant decrease of the hydroxide-related signal, which indicates that binding of the headgroups to the surface is accompanied by the elimination of water molecules. The sum-frequency spectra also clearly indicate that well-ordered monolayers can be formed by the Langmuir-Blodgett technique. Since the non-resonant background from the metal substrates renders the analysis of the spectra more difficult, model system samples on glass were prepared. It was found that the alkyl chains of the adsorbed acids predominantly adopt the all-trans conformation and form an ordered structure. Upper limits for the mean tilt angle of the terminal methyl groups are approximately 10-20 degrees.

Journal Article↗
PubMed2000

[The reaction mechnism for formation of a 9-hydroxy-beta-carbolin-4-carboxylic acid from the nifedipine analogue biscyanoethyl ester].

The 3-tert-butyl-5-methyl-1,4-dihydropyridine(DHP)-dicarboxylate 5 reacts with trifluoroacetic acid (TFA) by elimination of the tert-butylester group yielding the 1,4-DHP 6. Irradiation of 6 by UV-A-light affords the corresponding pyridine 7 and the cyclic hydroxamic acid 10. The 2-cyanoethyl-1,4-DHP-carboxylate 13, obtained from the 3-tert-butyl-5-(2-cyanoethyl)-1,4-DHP-dicarboxylate 12 by treating with TFA, reacts with sodium hydroxide solution to give the title compound 3.

Carbolines↗
PubMed1999

Binding of salicylhydroxamic acid and several aromatic donor molecules to Arthromyces ramosus peroxidase, investigated by X-ray crystallography, optical difference spectroscopy, NMR relaxation, molecular dynamics, and kinetics.

The X-ray crystal structure of the complex of salicylhydroxamic acid (SHA) with Arthromyces ramosus peroxidase (ARP) has been determined at 1.9 A resolution. The position of SHA in the active site of ARP is similar to that of the complex of benzhydroxamic acid (BHA) with ARP [Itakura, H., et al. (1997) FEBS Lett. 412, 107-110]. The aromatic ring of SHA binds to a hydrophobic region at the opening of the distal pocket, and the hydroxamic acid moiety forms hydrogen bonds with the His56, Arg52, and Pro154 residues but is not asscoiated with the heme iron. X-ray analyses of ARP-resorcinol and ARP-p-cresol complexes failed to identify the aromatic donor molecules, most likely due to the very low affinities of these aromatic donors for ARP. Therefore, we examined the locations of these and other aromatic donors on ARP by the molecular dynamics method and found that the benzene rings are trapped similarly by hydrophobic interactions with the Ala92, Pro156, Leu192, and Phe230 residues at the entrance of the heme pocket, but the dihedral angles between the benzene rings and the heme plane vary from donor to donor. The distances between the heme iron and protons of SHA and resorcinol are similar to those obtained by NMR relaxation. Although SHA and BHA are usually considered potent inhibitors for peroxidase, they were found to reduce compound I and compound II of ARP and horseradish peroxidase C in the same manner as p-cresol and resorcinol. The aforementioned spatial relationships of these aromatic donors to the heme iron in ARP are discussed with respect to the quantum chemical mechanism of electron transfer in peroxidase reactions.

Binding Sites↗
PubMed2006

Synthesis of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives of potential anti-inflammatory activity.

A series of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives 4-10 were synthesized by rearrangement of 4-(3-pyridyl)-hydrazono-2-phenyl-2-oxazolin-5-one 3 in the presence of different nucleophiles to afford derivatives 4, 7, and 8, while hydroxamic acid derivative 6 was prepared from reaction of methyl ester 4 with hydroxylamine hydrochloride. Semicarbazide 9 and thiosemicarbazide 10, derivatives of the 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid, were synthesized via hydrazide 8 with potassium cyanate and appropriate isothiocyanate, respectively. The structures of the synthesized compounds were confirmed by elemental analyses, IR, (1)H-NMR, and mass spectra. The results of the anti-inflammatory activity of the synthesized derivatives showed that most of the tested compounds 4-10 showed significant inhibition against carrageenan-induced rat paw edema in albino rats. Derivatives 4 and 8 showed promising results and were found to be equipotent or more potent than Indomethacin and Celecoxib as reference drugs at two dose levels, 5 and 10 mg/kg, and they have no ulcerogenic activity.

Animals↗
PubMed1991

The design, synthesis and study of siderophore-antibiotic conjugates. Siderophore mediated drug transport.

The use of conjugates of microbial iron chelators (siderophores) and antibiotics for illicit transport of antibiotics into cells is a potentially powerful method for the rational design of therapeutic agents. The structural complexity of most natural siderophores has impeded progress in this area. Described here are the design, syntheses and preliminary biological studies of several siderophore-beta-lactam antibiotic conjugates. Both hydroxamic-acid-based and catechol-based conjugates with and without amino acid spacers to carbacephalosporins were synthesized and demonstrated to be effective inhibitors of Escherichia coli X580. Mutant selection was noted for each class of conjugates. Mutants selected from exposure of the E. coli to the hydroxamate conjugates were susceptible to the catechol conjugates and vice versa. Combinations of hydroxamate- and catechol-carbacephalosporin conjugates were most effective inhibitors of E. coli X580.

Anti-Bacterial Agents↗
PubMed2006

A series of novel, potent, and selective histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy and the first generation HDAC inhibitors are currently in clinical trials. A structurally novel series of HDAC inhibitors based on the natural cyclic tetrapeptide Apicidin is described. Selected screening of the sample collection looking for L-2-amino-8-oxodecanoic acid (L-Aoda) derivatives identified a small acyclic lead molecule 1 with the unusual ketone zinc binding group. SAR studies around this lead resulted in optimization to potent, low molecular weight, selective, non-hydroxamic acid HDAC inhibitors, equipotent to current clinical candidates.

Amides↗
PubMed1995

Isolation, purification and structure of exochelin MS, the extracellular siderophore from Mycobacterium smegmatis.

The extracellular siderophore from Mycobacterium smegmatis, exochelin MS, was isolated from iron-deficiently grown cultures and purified to > 98% by a combination of ion-exchange chromatography and h.p.l.c. The material is unextractable into organic solvents, is basic (pI = 9.3-9.5), has a lambda max at 420 nm and a probable Ks for Fe3+ of between 10(25) and 10(30). Its structure has been determined by examination of desferri- and ferri-exochelin and its gallium complex. The methods used were electrospray-m.s. and one- and two-dimensional (NOESY, DQF-COSY and TOCSY) 1H n.m.r. The constituent amino acids were examined by chiral g.l.c analysis of N-trifluoroacetyl isopropyl and N-pentafluoropropionyl methyl esters after hydrolysis, and reductive HI hydrolysis, of the siderophore. The exochelin is a formylated pentapeptide: N-(delta-N-formyl,delta N-hydroxy-R-ornithyl) -beta-alaninyl-delta N-hydroxy-R-ornithinyl-R-allo-threoninyl-delta N-hydroxy-S-ornithine. The linkages involving the three ornithine residues are via their delta N(OH) and alpha-CO groups leaving three free alpha-NH2 groups. Although there are two peptide bonds, these involve the three R (D)-amino acids. Thus the molecule has no conventional peptide bond, and this suggests that it will be resistant to peptidase hydrolysis. The co-ordination centre with Fe3+ is hexadenate in an octahedral structure involving the three hydroxamic acid groups. Molecular modelling shows it to have similar features to other ferric trihydroxamate siderophores whose three-dimensional structures have been established. The molecule is shown to have little flexibility around the iron chelation centre, although the terminal (Orn-3) residue, which is not involved in iron binding except at its delta N atom, has more motional freedom.

Amino Acid Sequence↗
PubMed1987

Some properties and subcellular distribution of acyl-coenzyme A: retinol acyltransferase activity in rat testes.

The present study was conducted to examine esterification of retinol by testicular microsomes. The microsomes were isolated from rat testes and were incubated under varying assay conditions with [3H]retinol. [3H]Retinylpalmitate was identified by reversed-phase high-performance liquid chromatography as an esterified product. The rate of esterification was increased by the addition of a fatty acyl-CoA. Coenzyme A esters of oleic, palmitic and stearic acids were equally effective substrates for retinol esterification. A 17-fold increase was observed in the presence of palmitoyl-CoA when microsomes had been pretreated with hydroxylamine, a reagent that reacts with coenzyme A thioesters to form hydroxamic acids. The esterifying activity was stimulated by the addition of dithiothreitol (4 mM) and fatty acid-free bovine serum albumin (1 mg/ml). The optimal concentrations for retinol and palmitoyl-CoA were 40 microM and 30-40 microM, respectively. The enzyme activity was inhibited by p-hydroxymercuribenzoate, sodium taurocholate and 5,5'-dithiobis-(2-nitrobenzoic acid), but not by EDTA. The enzyme activity was highest in microsomes (36%). However, some activity was present in mitochondria (29%). These results clearly show the presence of a fatty acyl-CoA: retinol acyltransferase that catalyzes the esterification of retinol in rat testes.

Acyltransferases↗
PubMed1978

Decomposition of 2,4-Dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one in Aqueous Solutions.

Cyclic hydroxamic acids present in some species of Gramineae have been reported to be important in resistance of these plants to fungi and insects. Since the nonglucosylated forms of these acids are unstable in aqueous solution, in vitro methods for the measurement of their antibiotic properties have been difficult. Kinetics of the decomposition of 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one (DIMBOA), the major hydroxamate in corn (Zea mays L.) extracts, were studied in buffered aqueous solutions from pH 5 to 7.5 at temperatures from 20 to 80 C. Kinetics were apparently first order under all conditions tested; energies of activation (24 to 28 kcal/mol) were nearly pH-independent. DIMBOA decomposed rapidly (half-life = 5.3 hours at 28 C, pH 6.75) relative to the time required for many procedures which have been used to demonstrate the biological activity of DIMBOA. The rate of disappearance of inhibitory activity of DIMBOA toward Erwinia carotovora was indistinguishable from the rate of decomposition of DIMBOA. Contrary to reports, yields of 6-methoxy-2-benzoxazolinone (MBOA) were not quantitative. Gas-liquid chromatography analytical procedures were developed for quantitation of trimethylsilyl and acetyl derivatives of MBOA. As measured by ultraviolet spectroscopy and/or gas-liquid chromatography, conversion of DIMBOA to MBOA ranged from 40 to 75% of theoretical in aqueous buffers, bacterial growth medium, and ethyl acetate extracts of corn tissue resuspended in buffer. Yields varied with temperature, pH, and constituents in the medium.

Journal Article↗
PubMed1992

5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease.

The unique role of the enzyme 5-lipoxygenase (5-LO) in the production of leukotrienes (LTs) makes it a likely target for biochemical manipulation. The rationale for using 5-LO inhibitors for the treatment of inflammatory bowel disease (IBD) is based on the increased generation of LTs in the inflamed mucosa, LTB4 being the most potent chemotactic and chemokinetic metabolite of arachidonic acid. Furthermore, conventional drugs, such as corticosteroids, sulphasalazine, and 5-aminosalicylic acid, inhibit LT production and specific 5-LO inhibition accelerates healing in animal models of acute colitis. The compounds identified as 5-LO inhibitors can be divided into antioxidants, substrate-analogous, and a large miscellaneous group of inhibitors, where hydroxamic acids are potent and more selective inhibitors of 5-LO. The benzothiophene hydroxyurea, zileuton, is the first selective 5-LO inhibitor evaluated for the treatment of patients with IBD. An 800-mg oral dose of zileuton was shown to reduce LTB4, but not prostaglandin E2, concentrations by 75-85% in rectal dialysates from patients with active ulcerative colitis. The clinical efficacy of zileuton 800 mg b.i.d. has also been tested in a randomized, double-blind, placebo-controlled trial in similar patients. Zileuton significantly improved the symptom scores and the histology score, but not the sigmoidoscopy score, compared to pretreatment conditions and with response to placebo, the beneficial effects being most pronounced in patients not receiving concomitant sulphasalazine treatment. The mean inhibition of LTB4 in the target tissue of inflammation was 70%. The proof that any putative 5-LO inhibitor is blocking LT production is an important stage in assessing any such drug. The main disadvantage of existing new LT inhibitors relates to the high potency of LTs, and unless a higher level of inhibition can be achieved, endogenous LTs may still be present in sufficient amounts to produce their effects.

Adrenal Cortex Hormones↗