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At least 397 records · Page 22Linked to original sources
PubMed2006

Stereoselective synthesis of orthogonally protected alpha-methylnorlanthionine.

[reaction: see text] As the unusual amino acid norlanthionine (nor-Lan) has previously been incorporated into cyclic peptide analogues of the ring C of lantibiotic nisin, we report here the stereoselective synthesis of the new (S,R)- and (R,R)-alpha-methylnorlanthionines (alpha-Me-nor-Lan). The orthogonally protected derivatives of these compounds have also been prepared. The key step in the synthesis of these bisamino acids was the S(N)2 opening reaction of the corresponding cyclic sulfamidates with the SH group of appropriately protected l-cysteine derivatives.

Alanine↗
PubMed1999

Grafting of aliphatic and aromatic probes on bovine serum albumin: influence on its structural and physicochemical characteristics.

Bovine serum albumin was chosen as a model protein to study the effect of the functionalization of the epsilon-NH2 of lysine residues with different carbon chains on the physical properties of proteins. Thus, BSA has been acylated and sulfonylated by means of anhydrides and sulfonyl chlorides, respectively. The secondary structures of modified BSA, studied by far-UV CD, showed very slight changes except after sulfamidation. However, near-UV CD and intrinsic fluorescence spectra revealed important conformational perturbations for proteins bearing long carbon chains. Furthermore, the binding of an apolar probe (ANS) to BSA revealed an improvement of surface hydrophobicity after modification. Meanwhile, Scatchard plot results indicate that only 20% of the hexanoyl carbon chains lie at the surface of the proteins. Solvent conditions should influence the exposure of these chains and consequently the surface hydrophobicity of proteins.

Acylation↗
PubMed2004

Low-temperature sealed tube combustion of gaseous, liquid and solid organic compounds for 13C/12C and 14C analysis.

A new, low-temperature sealed tube technique for combustion of organic carbon prior to subsequent off-line isotope analysis is proposed. Complete oxidation is achieved with potassium peroxodisulfate and silver permanganate as oxidants at temperatures not exceeding 500 degrees C. The combustion of gaseous (methane), solid (cane sugar, vanilla, N-thiazolyl-2-sulfamide, ascorbic acid, phenanthrene, thiourea, polyethylenefilm, tetrafluoropolyethylene, polyetheretherketone, graphite, and Suwannee River Fulvic Acid), and liquid (tetrachloroethene, toluene, and oil) model compounds and international standards was tested. A 24 h combustion at 500 degrees C was sufficient for complete oxidation in all cases. The time required for complete oxidation of Suwannee River Fulvic Acid, typical of refractory freshwater dissolved organic carbon, as a function of combustion temperature was 2 h at 500 degrees C, 6 h at 400 degrees C, and 24 h at 300 degrees C. Preparation of saline solution parallels of cane sugar, vanilla, N-thiazolyl-2-sulfanilamide, and ascorbic acid gave consistent results. For reproducible delta13C analyses using a Thermoquest MAT 252 MS, a minimum of 5 microg C had to be combusted. Reliable 14C results, measured at an accelerator mass spectrometer facility, were obtained from coal and from cane sugar combusted for 24 h at 500 degrees C by the proposed method.

Carbon↗
PubMed2006

Carbonic anhydrase inhibitors. N-cyanomethylsulfonamides--a new zinc binding group in the design of inhibitors targeting cytosolic and membrane-anchored isoforms.

A series of N-cyanomethyl aromatic sulfonamides and bis-sulfonamides was prepared by reaction of arylsulfonyl halides with aminoacetonitrile. The obtained derivatives incorporated various aryl moieties, such as 4-halogeno/alkyl/aryl/nitro-substituted-phenyl, pentafluorophenyl or 2-naphthyl. Moderate inhibitory activity was detected for some compounds against the cytosolic human isoform II of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA II, with inhibition constants of 90, 180 and 560n M for the 4-nitrophenyl-, 4-iodophenyl- and pentafluorophenyl-N-cyanomethylsulfonamides, respectively. Other derivatives acted as weak inhibitors of isoforms hCA I (KIs of 720 nM-45 microM), hCA II (KIs of 1000-9800 nM) and hCA IX (KIs of 900-10200 nM). Thus, the N-cyanomethylsulfonamide zinc binding group is less effective than the sulfonamide, sulfamate or sulfamide ones for the design of effective CA inhibitors.

Carbonic Anhydrase Inhibitors↗
PubMed1991

Synaptic concentration of dopamine in the mouse striatum in relationship to the kinetic properties of the dopamine receptors and uptake mechanism.

The concentration of dopamine (DA) in the synaptic cleft in the mouse striatum in vivo was estimated from the competition between the synaptic DA and the 3H-labelled DA D2 receptor agonists N-n-propylnorapomorphine (NPA) or N,N-diethyl-N'-[(3 alpha, 4a alpha, 10 beta)-1,2,3,4,4a,5,10,10a-octahydro- 7-hydroxyl-1-propyl-3-benzo (g) quinolinyl]sulfamide (Sandoz 205-501) injected intravenously in tracer doses. Knowing the inhibitor constant for DA in inhibiting the binding of these receptor agonists in vitro, attempts were made to calculate the changes in the synaptic DA concentration from the changes in the in vivo binding of the receptor agonists evoked by various pharmacological agents. Inhibiting the firing of the dopaminergic neurons by gamma-butyrolactone (GBL) increased the binding of the receptor agonists corresponding to a decrease in the synaptic DA concentration of 55 +/- 2 nM in the experiments with [3H]Sandoz 205-501 and 48 +/- 3 nM in the experiments with tracer doses of [3H]NPA. These values may therefore approximate the normal DA concentration in the synaptic cleft in the mouse striatum. With this technique it was also possible to determine the synaptic concentration of NPA by its competition with [3H]Sandoz 205-501 for the DA D2 receptors in the striatum of GBL-treated mice in vivo. To compare the estimated synaptic concentration of DA with the affinity of DA to D1 and D2 receptors and to the DA transporter in the mouse striatum the kinetic parameters were determined at 37 degrees C in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoquinolines↗
PubMed1999

Molecular and biochemical characterization of VEB-1, a novel class A extended-spectrum beta-lactamase encoded by an Escherichia coli integron gene.

A clinical isolate, Escherichia coli MG-1, isolated from a 4-month-old Vietnamese orphan child, produced a beta-lactamase conferring resistance to extended-spectrum cephalosporins and aztreonam. In a disk diffusion test, a typical synergistic effect between ceftazidime or aztreonam and clavulanic acid was observed along with an unusual synergy between cefoxitin and cefuroxime. The gene for VEB-1 (Vietnamese extended-spectrum beta-lactamase) was cloned and expressed in E. coli JM109. The recombinant plasmid pRLT1 produced a beta-lactamase with a pI of 5.35 and conferred high-level resistance to extended-spectrum (or oxyimino) cephalosporins and to aztreonam. Vmax values for extended-spectrum cephalosporins were uncommonly high, while the affinity of the enzyme for ceftazidime and aztreonam was relatively low. blaVEB-1 showed significant homology at the DNA level with only blaPER-1 and blaPER-2. Analysis of the deduced protein sequence showed that VEB-1 is a class A penicillinase having very low levels of homology with any other known beta-lactamases. The highest percentage of amino acid identity was 38% with PER-1 or PER-2, two uncommon class A extended-spectrum enzymes. Exploration of the genetic environment of blaVEB-1 revealed the presence of gene cassette features, i.e., (i) a 59-base element associated with blaVEB-1; (ii) a second 59-base element just upstream of blaVEB-1, likely belonging to the aacA1-orfG gene cassette; (iii) two core sites (GTTRRRY) on both sides of blaVEB-1; and (iv) a second antibiotic resistance gene 3' of blaVEB-1, aadB. blaVEB-1 may therefore be the first class A extended-spectrum beta-lactamase that is part of a gene cassette, which itself is likely to be located on a class 1 integron, as sulfamide resistance may indicate. Furthermore, blaVEB-1 is encoded on a large (> 100-kb) transferable plasmid found in a Klebsiella pneumoniae MG-2 isolated at the same time from the same patient, indicating a horizontal gene transfer.

Amino Acid Sequence↗
PubMed2000

Characterization of VIM-2, a carbapenem-hydrolyzing metallo-beta-lactamase and its plasmid- and integron-borne gene from a Pseudomonas aeruginosa clinical isolate in France.

Pseudomonas aeruginosa COL-1 was identified in a blood culture of a 39-year-old-woman treated with imipenem in Marseilles, France, in 1996. This strain was resistant to beta-lactams, including ureidopenicillins, ticarcillin-clavulanic acid, cefepime, ceftazidime, imipenem, and meropenem, but remained susceptible to the monobactam aztreonam. The carbapenem-hydrolyzing beta-lactamase gene of P. aeruginosa COL-1 was cloned, sequenced, and expressed in Escherichia coli DH10B. The deduced 266-amino-acid protein was an Ambler class B beta-lactamase, with amino acid identities of 32% with B-II from Bacillus cereus; 31% with IMP-1 from several gram-negative rods in Japan, including P. aeruginosa; 27% with CcrA from Bacteroides fragilis; 24% with BlaB from Chryseobacterium meningosepticum; 24% with IND-1 from Chryseobacterium indologenes; 21% with CphA-1 from Aeromonas hydrophila; and 11% with L-1 from Stenotrophomonas maltophilia. It was most closely related to VIM-1 beta-lactamase recently reported from Italian P. aeruginosa clinical isolates (90% amino acid identity). Purified VIM-2 beta-lactamase had a pI of 5.6, a relative molecular mass of 29.7 kDa, and a broad substrate hydrolysis range, including penicillins, cephalosporins, cephamycins, oxacephamycins, and carbapenems, but not monobactams. As a metallo-beta-lactamase, its activity was zinc dependent and inhibited by EDTA (50% inhibitory concentration, 50 microM). VIM-2 conferred a resistance pattern to beta-lactams in E. coli DH10B that paralleled its in vitro hydrolytic properties, except for susceptibility to ureidopenicillins, carbapenems, and cefepime. bla(VIM-2) was located on a ca. 45-kb plasmid that in addition conferred resistance to sulfamides and that was not self-transmissible either from P. aeruginosa to E. coli or from E. coli to E. coli. bla(VIM-2) was the only gene cassette located within the variable region of a novel class 1 integron, In56, that was weakly related to the bla(VIM-1)-containing integron. VIM-2 is the second carbapenem-hydrolyzing metalloenzyme characterized from a P. aeruginosa isolate outside Japan.

Amino Acid Sequence↗
PubMed1996

Dual-component excitatory amino acid-mediated responses in trigeminal motoneurons and their modulation by serotonin in vitro.

1. Intracellular recordings were made from guinea pig trigeminal motoneurons in brain stem slices. Monosynaptic excitatory postsynaptic potentials (EPSPs) were evoked in trigeminal motoneurons by focal stimulation of the mesencephalic nucleus of V (Mes V), a region containing cell bodies of primary afferent fibers of jaw muscle spindle and periodontal receptor origin. 2. The presence of N-methyl-D,L-aspartate (NMDA) and non-NMDA excitatory amino acid receptors (EAAs) was determined by iontophoretic application of NMDA and (+/-)-alpha-amino-3-hydroxy methylisoxazole-4-propionic acid (AMPA) from multi-barreled micropipettes. Application of either agonist in normal Mg(2+)-containing extracellular solutions produced a membrane depolarization or inward current from resting potential in current-or voltage-clamp modes, respectively. However, the voltage and current responses to NMDA and AMPA differed in their dependence on initial membrane potential. In voltage clamp between -70 and -50 mV, the peak current response to NMDA application increased whereas the response to AMPA application decreased as a function of holding potential. 3. Mes-V-induced synaptic potentials were examined for the presence of NMDA and non-NMDA components in extracellular solutions devoid of Mg2+. In the presence of DL-2-amino-5-phosphonopentanoic acid (30 microM), the peak amplitude and half-amplitude duration were decreased 52 and 36% (n = 2), respectively, compared with control. In the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10-15 microM), a specific non-NMDA antagonist, the mean decrease in evoked synaptic potential amplitude was 55% (n = 5), but the half-amplitude duration increased by a mean of 63% (n = 5). 4. The non-NMDA component of the evoked EPSP obtained in the presence of DL-2-amino-5-phosphonovaleric acid showed a linear decrease in peak amplitude as a function of holding potential. In contrast, the NMDA EPSP component obtained in the presence of CNQX increased in peak amplitude as a function of holding potential between -70 and -40 mV. The increase in EPSP peak amplitude was abolished by removal of Mg2+ from the extracellular media. 5. Bath application of serotonin (5-HT) (50-100 microM) increased the peak NMDA and non-NMDA EPSP components by 31% (n = 10) and 23% (n = 8), respectively, while producing a mean increase in half-amplitude duration of 67 and 88%, respectively. Concomitantly, 5-HT increased input resistance by approximately 40% and produced a membrane depolarization. 6. In the presence of tetrodotoxin, 5-HT enhanced both iontophoretic NMDA and AMPA voltage responses. In cells voltage clamped between -60 and -70 mV in Mg(2+)-free solutions, iontophoretic NMDA and AMPA peak currents were enhanced 27 and 32%, respectively, by 5-HT. 7. The enhancement of the iontophoretic NMDA and non-NMDA responses was mimicked by (+/-)-1-(2,5-dimethyoxy-4-iodophenyl)-2- aminopropane HCL and blocked by 3-[2-[4-(fluorobenzoyl)-1-piperdinyl]-2,4 (1H,3H)-quinazolinedione-tartrate and N'-[(8a)-1,6-dimethylergolin-8-yl]-N,N-dimethyl-sulfamide hydrochloride, suggesting 5-HT2 receptor involvement. 8. The results demonstrate that trigeminal motoneurons possess both NMDA and non-NMDA receptors that are activated during Mes-V-induced synaptic transmission. The data suggest that EAA-mediated responses in trigeminal motoneurons are substrates for modulation by 5-HT via changes in membrane resistance and modulation of the EAA-induced synaptic current.

Animals↗
PubMed2000

Placental transfer of pyrimethamine studied in an ex vivo placental perfusion model.

Pyrimethamine is used as and anti-infectious agent because of its antifolate properties. Its action is synergistic with that of dapsone and sulfamides on Toxoplasma gondii. The goal of the present study was to evaluate the placental transfer of pyrimethamine in an ex vivo model of perfused human placental cotyledon at term. Human placentas were perfused according to the slightly modified method of Schneider. The pyrimethamine fetal transfer rate was approximately 30%, while cotyledon clearance was about 1.8 ml/min. The placental transfer of pyrimethamine seems to be independent of the maternal concentrations of pyrimethamine, suggesting passive diffusion mechanisms or a nonsaturable active transport at the tested concentrations.

Female↗
PubMed1984

Detection of drug-dependent IgG antibodies with antiplatelet activity by the antiglobulin consumption assay.

Drug-induced thrombocytopenia is a common acquired hemorrhagic disorder. In this study 32 patients with drug-induced thrombocytopenia were examined with the antiglobulin consumption assay. Platelet-associated IgG was elevated in 19 of 20 patients that were analyzed. An increase in serum platelet bindable IgG was observed in 24 subjects after the addition of various drugs (acetylsalicylic acid, noraminopyrine, antibiotics, sulfamides, digoxin, heparin and chenodeoxycholic acid). These findings are significant for the presence of drug-dependent platelet antibodies.

Adolescent↗
PubMed1974

Sanfilippo A syndrome: sulfamidase deficiency in cultured skin fibroblasts and liver.

The Sanfilippo A syndrome is an autosomal recessive mucopolysaccharidosis characterized clinically by severe mental retardation and biochemically by storage in tissue and excretion in urine of excessive amounts of heparan sulfate. Since sulfamide groups are present in heparan sulfate, a sulfamidase deficiency could explain the impaired degradation of this polysaccharide. To investigate the enzymic basis of this disease, assays for sulfamidase were performed. Extracts of cultured fibroblasts and post-mortem liver were prepared by suspension of tissues in acetate: NaCl buffer, pH 4.5, containing Triton X-100 (Rohm and Haas Co., Philadelphia, Pa.), sonication, and centrifugation at 10,000 g. The supernatant fluid was incubated with [(35)S]-N-sulfated heparin. The release of inorganic sulfate after 18 h of incubation was determined by chromatography on Sephadex G-25. The liver and fibroblast extracts of patients with the Sanfilippo A syndrome showed a deficiency of sulfamidase. The quantity of heparan sulfate in fibroblasts derived from patients with Sanfilippo A, Hurler's and Hunter's diseases was found to be 7-10%, while it was about 1.25% of the total glycosaminoglycans in fibroblasts of normal controls.

Fibroblasts↗
PubMed2002

Resistance profiles of cyclic and linear inhibitors of HIV-1 protease.

Resistance to anti-HIV protease drugs is a major problem in the design of AIDS drugs with long-term efficacy. To identify structural features associated with a certain resistance profile, the inhibitory properties of a series of symmetric and asymmetric cyclic sulfamide, cyclic urea and linear transition-state analogue inhibitors of HIV-1 protease were investigated using wild-type and mutant enzyme. To allow a detailed structure-inhibition analysis, enzyme with single, double, triple and quadruple combinations of G48V, V82A, 184V and L90M substitutions was used. Kinetic analysis of the mutants revealed that catalytic efficiency was 1-30% of that for the wild-type enzyme, a consequence of reduced kcat in all cases and an increased KM for all mutants except for the G48V enzyme. The overall structure-inhibitory profiles of the cyclic compounds were similar, and the inhibition of the V82A, 184V and G48V/L90M mutants were less efficient than of the wild-type enzyme. The greatest increase in Ki was generally observed for the 184V mutant and least for the G48V/L90M mutant, and additional combinations of mutations did not result in improved inhibition profiles for the cyclic compounds. An extended analysis of additional mutants, and including a set of linear compounds, showed that the profile was unique for each compound, and did not reveal any general structural features associated with a certain inhibition profile. The effects of structural modifications in the inhibitors, or of mutations, were not additive and they differed depending on their context. The results demonstrate the difficulties in predicting resistance, even for closely related compounds, and designing compounds with improved resistance profiles.

Drug Resistance, Viral↗
PubMed2006

A perspective on quantitative structure-activity relationships and carbonic anhydrase inhibitors.

Carbonic anhydrases (CAs, EC 4.2.1.1) are wide-spread enzymes, present in mammals in at least 15 different isoforms. The 12 catalytically active isoforms play important physiological and pathophysiological functions and are strongly inhibited by aromatic/heterocyclic sulfonamides, sulfamides and sulfamates, among others. The catalytic and inhibition mechanisms of these enzymes are understood in great detail, and this greatly helped the design of potent inhibitors, some of which possess important clinical applications as antiglaucoma drugs, or in the management of some neuromuscular disorders. A recent discovery is connected with the involvement of CAs and their sulfonamide inhibitors in cancer: many potent CA inhibitors were shown to inhibit the growth of several tumour cell lines in vitro and in vivo, thus constituting interesting leads for developing novel antitumour therapies. The field of quantitative structure-activity relationship (QSAR), formalised by Hansch and others in the early 1960s, is the discovery of empirical relationships between the chemical structure of drugs and their biological activity. The emphasis is on empirical. Extending a QSAR to drugs other than those used to formulate it is always a new hypothesis, and although these extensions are often successful, it should be no cause for surprise if they break down in particular cases. With CA, as with other targets, the descriptor variables that have been used include topological indices, physical properties such as solvent partition coefficients and Hammett constants from reaction rate studies, and quantum theoretical parameters, such as orbital energies, atomic charges, polarisabilities and recently the orientation of nodes in pi-orbitals. This review deals only with the physical and quantum theoretical descriptors.

Animals↗
PubMed2005

Neuropeptide-derived antimicrobial peptides from invertebrates for biomedical applications.

Since the beginning of the 20th century, important medicinal progress has led medical doctors to think that the end of devastating epidemics has arrived. In 1930, the discovery of sulfamides and penicillin opened a wide area of applications able to fight against bacterial infections. However, almost all antibiotics were baffled by the great ability to adaptation of bacteria (1) and the emergence of new bacterial agents, discovered with up-dated technologies. The living world is perpetually in co-evolution and since more than 3 billion years, bacteria have developed resistance mechanisms to overcome external aggressions. Thus, in the middle of the 80th century, multi-resistant bacteria appeared and disseminated out from hospitals. In this context, researches have been developed in order to find new antimicrobial substances to destroy such new types of bacteria. Thus, several groups have turned their focus on invertebrates, which co-evoluad with human and have appeared on the planet since a long time. Evidence of new families of antimicrobial substances isolated from invertebrates different to the classical cationic peptide family i.e. dipeptides and anionic peptides been given. Moreover, these molecules are also present in human and may serve in the innate immune response as an important survival strategy.

Animals↗
PubMed2006

Chloroquine resistance reversal agents as promising antimalarial drugs.

The development and spread of resistance to antimalarial drugs poses a severe and increasing public health threat. Failures of prophylaxis or treatment with quinolines, hydroxynaphthoquinones, sesquiterpene lactones, antifolate drugs and sulfamides are involved in a return malaria-related morbidity and mortality. Resistance is associated with a decrease in accumulation of drugs into the vacuole, which results from a reduced uptake of the drug, an increased efflux or a combination of both. A number of candidate genes in P. falciparum have been proposed to be involved in antimalarial resistance, each concerned in membrane transport. Weaker or stronger associations are seen in P. falciparum between the resistance to quinolines or artemisinin derivatives and codon changes in Pfmdr1, a gene which encodes Pgh-1, an ortholog of one of the P-glycoproteins expressed in multi-drug resistant human cancer cells (ABC transporter). Further analysis has revealed a new gene, Pfcrt, encoding a PfCRT protein, which resembles an anion channel. Codon changes found in the Pfcrt sequence in drug resistant isolates could facilitate the drug efflux through a putative channel. It has been proposed that the reversal of quinoline resistance by verapamil is due to hydrophobic binding to the mutated PfCRT protein. Several compounds have demonstrated in the past decade a promising capability to reverse the antimalarial drug resistance in vitro in parasite isolates, in animal models and in human malaria. These drugs belong to different pharmacological classes such as calcium channel blockers, tricyclic antidepressants, antipsychotic calmodulin antagonists, histamine H1-receptor antagonists, analgesic and antipyretic drugs, non-steroidal anti-inflammatory drugs, and to different chemical classes such as synthetic surfactants, alkaloids from plants used in traditional medicine, pyrrolidinoaminoalkanes and anthracenic derivatives. Here we summarize the progress made in biochemical and genetic basis of antimalarial resistance, emphasizing the recent developments on drugs, which interfere with trans membrane proteins involved in drug efflux or uptake.

Animals↗
PubMed2006

New zinc binding motifs in the design of selective carbonic anhydrase inhibitors.

The carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous zinc enzymes which catalyze a very simple physiological reaction, the interconversion between carbon dioxide and the bicarbonate ion, and are involved in physiological and pathological processes. The different isozymes have been considered as important targets for inhibitors with clinical applications. Several sulfonamide carbonic anhydrase inhibitors (CAIs) were used for decades as diuretics, anti-glaucoma, anti-epileptic, anti-ulcer agents, or as drugs for treating other neurological/neuromuscular disorders, whereas presently several such agents still find wide applications in therapy, mainly as topically acting anti-glaucoma drugs, anti-cancer, or anti-obesity agents. Although sulfonamides were considered the moiety par excellence to coordinate the catalytic zinc and for designing potent CAIs, in recent years related functional groups such as sulfamate, sulfamide and others have proven to be successful in the design of selective CAIs. The present review will deal with these different zinc binding functions recently reported in literature.

Binding Sites↗