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PubMed2000

Liquid chromatography tandem mass spectrometric quantitation of sulfamethazine and its metabolites: direct analysis of swine urine by triple quadrupole and by ion trap mass spectrometry.

This work describes a new method for the quantitation of trace amounts of sulfamethazine (SMZ) and its main metabolite, N4-acetylsulfamethazine (Ac-SMZ), in swine urine, using high-performance liquid chromatography (HPLC) tandem mass spectrometric analysis of crude urine after addition of internal standard and simple dilution with water. The aim was to determine whether residues of this sulfamidic drug, normally administered to swine in order to prevent infectious diseases, were present in urine at levels lower than those permitted by regulatory authorities before human consumption (EU Project SMT, contract number CT 96-2092). A 10 microL volume of diluted urine was injected into a very short, narrow-bore chromatographic column (Zorbax SB-C18 2.1 i. d. x30 mm length, 3.5 microm pore size). Elution of the analytes of interest was achieved in less than seven minutes using a rapid gradient (from 20 to 80% methanol in 3 minutes). Either a PE Sciex API 365 triple quadrupole (QqQ), operated in the selected reaction monitoring (SRM) mode, or a Finnigan LCQ ion trap (IT) mass spectrometer, operated in narrow-range product ion scan, was used as the final detector. Electrospray (ESI) was used as the ionization technique. A comparison of the two tandem mass spectrometers was performed by analyzing the same set of test samples, at three concentration levels, on three different days. Linearity of responses of the calibration standards, intra- and inter-assay precision of the samples, specificity and limits of detection were evaluated for both systems. Both the QqQ and the IT instrument was suitable for rapid, sensitive and specific determination of the analytes, although the overall performance of the QqQ was slightly superior in terms of linearity, precision and sensitivity.

Animals↗
PubMed1991

Interactions of proteins in human plasma with modified polystyrene resins.

Investigations are reported on the composition of protein layers adsorbed from plasma to various modified polystyrene resins. As well as polystyrene itself, polystyrene bearing sulfonate groups in the benzene rings, and polystyrene sulfonate in which the sulfonate groups were converted to amino acid sulfamide, were investigated. Some of these resins were shown in previous work to have anticoagulant properties. To study the adsorption of proteins from plasma, the resins were exposed to citrate anticoagulated human plasma for 3 h. Adsorbed proteins were then eluted sequentially by 1M Tris buffer and 4% SDS solution, and examined by SDS-PAGE. The gel patterns were similar on all resins except polystyrene. From the MWs of the gel bands, the major protein component appeared to be fibrinogen. Smaller amounts of plasminogen, transferrin, albumin, and IgG were also present. In addition, Ouchterlony immunoassay of the eluates from one resin gave positive identification of complement C3, fibronectin, IgG, and IgM. Many other minor gel bands remain unidentified. A consistent finding for all resins was the presence of plasmin-type fibrinogen degradation products though the amounts varied with resin type. It is concluded from this (and from experiments showing FDP formation when fibrinogen was absorbed to the resins, from buffer containing a trace of plasminogen) that the functional groups in these materials promote the adsorption of plasminogen and its activation to a plasmin-like molecule. It appears from the substantial quantities of fibrinogen adsorbed to these materials after 3 h exposure to plasma that the Vroman effect (giving transient adsorption of fibrinogen) is not operative on these materials. It is hypothesized that specific interactions occur between fibrinogen and sulfonate groups.

Adsorption↗
PubMed1993

Conformational changes of fibronectin induced by polystyrene derivatives with a heparin-like function.

It was previously reported that polystyrene substituted with the sulfonate group, PSSO3, which has anticoagulant heparin-like properties, and then coated with fibronectin supports the growth of human umbilical vein endothelial cells. On the other hand, polystyrene substituted with the amino acid sulfamide group, PSSO2-Asp, which has a higher anticoagulant activity, and then coated with fibronectin no longer supported the growth of endothelial cells. We report here that, while the affinity of fibronectin to either polymer is of the same order of magnitude, fibronectin is adsorbed onto the PSSO2-Asp polymer in a different conformation compared to the PSSO3 polymer. This was shown by a higher binding of polyclonal antifibronectin antibodies to fibronectin-coated PSSO2-Asp polymer, and by a decreased susceptibility of the coated fibronectin to proteolysis by thermolysin. This study provides evidence that a solid phase substrate with a strong heparin-like function may influence the conformation and biological properties of fibronectin.

Absorption↗
PubMed2002

New findings on degradation of famotidine under basic conditions: identification of a hitherto unknown degradation product and the condition for obtaining the propionamide intermediate in pure form.

The degradation behavior of famotidine (1) was investigated in 25% ammonia solution and in 2 M NaOH. The hydrolysis of the drug in ammonia resulted in separation of [3-[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propionamide (3), an impurity listed in British Pharmacopoeia. The treatment with 2 M NaOH resulted in formation of [3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propionyl]sulfamide (2) and 3. These products further decomposed to [3-[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propionic acid (4) and a heretofore unknown product, 5. The latter separated out in the reaction mixture as brown shiny crystals. Proton and carbon-13 nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis of the charcoal-treated product established the structure. The formation of 5 is postulated to involve abstraction of a proton from the alpha-carbon of intermediates 2 and 3 followed by elimination of the thiol moiety.

Amides↗
PubMed2003

Synthesis and anti-HIV activity of sulfonated amino ribofuranans.

New sulfonated amino ribofuranans were synthesized to elucidate the relationship between structure and specific biological activities such as anti-HIV and blood anticoagulant activities. The synthesis was performed by sulfonation of copolymers having various proportion of (1 --> 5)-alpha-D-ribofuranosidic unit. The sulfonation with piperidine N-sulfonic acid produced the sulfonated amino ribofuranans in high yield. The anti-HIV activity of sulfonated 3-amino-3-deoxy-(1 --> 5)-alpha-D-ribofuranan showed more potent by increasing the degree of sulfonation and the average molecular weights. This activity was almost equal to the activities of sulfonated ribofuranans and ribopyranans reported before in spite of low molecular weight. The blood anticoagulant activities was observed at 36-48 mg/units, more potent than standard dextran sulfonate, 22.7 mg/units. In addition, the blood anticoagulant activities of sulfamide-copolysaccharide consisting various proportion of (1 --> 5)-alpha-D-ribofuranan units were potentiated by increasing sulfonated amino-ribofuranan units from 13 to 21 mg/units.

Anti-HIV Agents↗
PubMed1986

Protonophoretic activity of hypoglycemic sulfonylureas in black lipid membranes.

The ability of glibenclamide and of gliclazide to act as protonophores has been studied in black lipid membranes made of glycerol monoleate as a function of pH and drug concentration. Protons may effectively be transported across lipid membranes with a maximum at a pH close to the pKa of the sulfamide (pKa of glibenclamide = 5.4). It is suggested therefore that hypoglycemic sulfonylureas may act in part as Ca2+ inward and H+ outward ionophores through plasma membranes of pancreatic B cells.

Biological Transport↗
PubMed1995

Synthetic sorbents for removal of factor VIII inhibitors from haemophilic A plasma.

Human factor VIII (FVIII) is a protein of the blood coagulation system that is absent or defective in patients with haemophilia A. A most serious complication following replacement therapy in 10-15% of patients treated with available FVIII concentrate is the development of inhibitors of FVIII (anti-FVIII). Some polymers functionalized with suitable chemical substituents which mimic part of the epitope of FVIII recognized by the inhibitors might be used in extracorporeal circulation to reduce the concentration of antibodies to FVIII. For this purpose, insoluble polystyrene bearing sulfonate and L-tyrosine methyl ester sulfamide groups have been synthesized. The in vitro removal of anti-FVIII inhibitors from plasmas of patients with haemophilia A was performed. Different chromatographic parameters were studied and optimized.

Adsorption↗
PubMed2004

[Cutaneous drug reactions: pharmacogenetic news].

Identifying genetic factors in severe drug eruption should improve efficacy and safety of drug prescription. The first pharmacogenetic studies concerned the polymorphism of genes encoding drug metabolism enzymes (especially for sulfamides reactions in AIDS and anticonvulsants reactions). Recent studies did not confirm the role of genotypic variation in metabolism enzymes in drug reaction. Genes controlling immune response are another research issue. Certain MHC phenotypes are linked to a higher risk of toxidermy, such as in abacavir hypersensitivity or fixed drug eruption. Indeed, severe drug eruptions seem to be linked to a specific immune response controlled by T lymphocytes.

Anticonvulsants↗
PubMed2004

Design, synthesis, and activity of caffeoyl pyrrolidine derivatives as potential gelatinase inhibitors.

The synthesis and biological evaluation of caffonyl pyrrolidine derivatives as MMPs inhibitors are reported in this paper. Inhibiting activities of synthesized compounds on gelatinase (MMP-2 and -9) were tested by using succinylated gelatin as substrate. Structure-activity relationship results from these tested compounds demonstrated that longer and more flexible side chain linked to the pyrrolidine ring at C(4) produced higher activity at gelatinase. Furthermore, aromatic heterocycle and sulfamide in the same position could enhance the activities. Compounds with free phenol hydroxyl group showed higher activity compared to methylated derivatives (or counterparts), which confirms the importance of phenol hydroxyl functionality in the interaction with gelatinase. The anti-metastasis model of mice bearing H(22) tumor cell was used to evaluate their in vivo inhibiting activities. All tested compounds were orally administered at a dose of 50 or 100mg/kg, 6days/week for two weeks. The test results demonstrated that most of these inhibitors showed significant anti-cancer activities (inhibitory rate>35%) and were devoid of toxic effects. Compound 29 showed the highest inhibitory rate at 69.25%, indicating that it might be a promising lead compound.

Animals↗
PubMed2006

Toward the control of Leptosphaeria maculans: design, syntheses, biological activity, and metabolism of potential detoxification inhibitors of the crucifer phytoalexin brassinin.

Brassinin (1), a crucial plant defense produced by crucifers, is detoxified by the phytopathogenic fungus Leptosphaeria maculans (Phoma lingam) to indole-3-carboxaldehyde using a putative brassinin oxidase. Potential inhibitors of brassinin detoxification were designed by replacement of its dithiocarbamate group (toxophore) with carbamate, dithiocarbonate, urea, thiourea, sulfamide, sulfonamide, dithiocarbazate, amide, and ester functional groups. In addition, the indolyl moiety was substituted for naphthalenyl and phenyl. The syntheses and chemical characterization of these potential detoxification inhibitors, along with their antifungal and cytotoxic activity, as well as screening using cultures of L. maculans are reported. Overall, three types of interaction were observed in cultures of L. maculans co-incubated with the potential inhibitors and brassinin: (1) a decrease on the rate of brassinin detoxification due to the strong inhibitory activity of the compound on fungal growth, (2) a decrease on the rate of brassinin detoxification due to the inhibitory activity of the compound on the putative brassinin oxidase, and (3) a low to no detectable effect on the rate of brassinin detoxification. A noticeable decrease in the rate of brassinin detoxification was observed in the presence of N'-methylbrassinin, methyl N-methyl-N-(naphthalen-2-ylmethyl) dithiocarbamate, tryptophol dithiocarbonate, and methyl 3-phenyldithiocarbazate. Tryptophol dithiocarbonate appeared to be the best inhibitor among the designed compounds, representing the first inhibitor of brassinin detoxification and potentially the first selective protecting agent of oilseed crucifers against L. maculans infestation.

Animals↗
PubMed2004

Carbonic anhydrase inhibitors. Inhibition of the beta-class enzyme from the methanoarchaeon Methanobacterium thermoautotrophicum (Cab) with anions.

The first inhibition study of the beta-class carbonic anhydrase (CA, EC 4.2.1.1) from the methanoarchaeon Methanobacterium thermoautotrophicum (Cab) with anions is reported here. Inhibition data of the alpha-class human isozymes hCA I and hCA II (cytosolic) as well as the membrane-bound isozyme hCA IV and the gamma-class enzyme from another archaeon, Methanosarcina thermophila (Cam) with a large number of anionic species such as halides, pseudohalides, bicarbonate, carbonate, nitrate, nitrite, hydrosulfide, bisulfite, sulfate, etc., are also provided for comparison. The best Cab anion inhibitors were thiocyanate and hydrogen sulfide, with inhibition constants in the range of 0.52-0.70 mM, whereas cyanate, iodide, carbonate, and nitrate were weaker inhibitors (Ki's in the range of 7.8-13.2 mM). Fluoride, chloride, and sulfate do not inhibit this enzyme appreciably, whereas the CA substrate bicarbonate, or other anions, such as bromide, nitrite, bisulfite, or sulfamate behave as weak inhibitors (Ki in the range of 40-45 mM). It is interesting to note that the metal poison, coordinating anions cyanide and azide are also rather weak Cab inhibitors (Ki in the range of 27-55 mM), whereas sulfamide is a very weak Cab inhibitor (Ki of 103 mM), although it strongly inhibits Cam (Ki of 70 microM). Surprisingly, phenylboronic and phenylarsonic acids, which have been investigated for the inhibition of all these CAs for the first time, showed very weak activity against the alpha-CA isozymes, but were effective Cab and Cam inhibitors. The best Cab inhibitors were just these two compounds (Ki's of 0.20-0.33 mM), whereas the best Cam inhibitor was sulfamic acid (Ki of 96 nM). These major differences of behavior between the diverse CAs investigated here toward anion inhibitors can be difficultly explained considering the convergent evolution of so diverse enzymes for the binding and turnover of small molecules such as carbon dioxide and anions.

Anions↗
PubMed2004

Carbonic anhydrase inhibitors: inhibition of the membrane-bound human isozyme IV with anions.

The membrane-associated human isozyme of carbonic anhydrase, hCA IV, has been investigated for its interaction with anion inhibitors, for the CO(2) hydration reaction catalyzed by this enzyme. Surprisingly, halides were observed to act as potent hCA IV inhibitors, with inhibition constants in the range of 70-90 microM, although most of these ions, and especially fluoride, the best hCA IV inhibitor among the halides, are weak inhibitors of other isozymes, such as hCA I, II and V. The metal poisons cyanate, cyanide and hydrogen sulfide were weaker hCA IV inhibitors (K(i)'s in the range of 0.6-3.9 mM), whereas thiocyanate, azide, nitrate and nitrite showed even weaker inhibitory properties (K(i)'s in the range of 30.8-65.1 mM). Sulfate was a good hCA IV inhibitor (K(i) of 9 mM), although it is a much weaker inhibitor of isozymes I, II, V and IX. Excellent hCA IV inhibitory properties showed sulfamic acid, sulfamide, phenylboronic acid and phenylarsonic acid, with K(i)'s in the range of 0.87-0.93 microM, whereas their affinities for the other investigated isozymes were in the millimolar range. The interaction of some anions with the mitochondrial isozyme hCA V has also been investigated for the first time here. It has been observed that among all these isozymes, hCA V has the lowest affinity for bicarbonate and carbonate (K(i)'s in the range of 82-95 mM), which may represent an evolutionary adaptation of this isozyme to the rather alkaline environment (pH 8.5) within the mitochondria, where hCA V plays important functions in some biosynthetic reactions involving carboxylating enzymes (pyruvate carboxylase and acetyl coenzyme A carboxylase). There are important differences of affinity for anions between the two membrane-associated isozymes, hCA IV and hCA IX.

Anions↗
PubMed2004

Carbonic anhydrase inhibitors. Inhibition of the prokariotic beta and gamma-class enzymes from Archaea with sulfonamides.

A detailed inhibition study of carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the beta- and gamma-families from Archaea with sulfonamides has been performed. Compounds included in this study were the clinically used sulfonamide CA inhibitors, such as acetazolamide, methazolamide, ethoxzolamide, topiramate, valdecoxib, celecoxib, dorzolamide, sulfanilamide, dichlorophanamide, as well as sulfanilamide analogs, halogenated sulfanilamides, and some 1,3-benzenedisulfonamide derivatives. The two gamma-CAs from Methanosarcina thermophila (Zn-Cam and Co-Cam) showed very different inhibitory properties with these compounds, as compared to the alpha-CA isozymes hCA I, II, and IX, and the beta-CA from Methanobacterium thermoautotrophicum (Cab). The best Zn-Cam inhibitors were sulfamic acid and acetazolamide, with inhibition constants in the range of 63-96 nM, whereas other investigated aromatic/heterocylic sulfonamides showed a rather levelled behavior, with KIs in the range of 0.12-1.70 microM. The best Co-Cam inhibitors were topiramate and p-aminoethyl-benzenesulfonamide, with KIs in the range of 0.12-0.13 microM, whereas the worst one was homosulfanilamide (KI of 8.50 microM). In the case of Cab, the inhibitory power of these compounds varied to a much larger extent, with sulfamic acid and sulfamide showing millimolar affinities (KIs in the range of 44-103 mM), whereas the best inhibitor was ethoxzolamide, with a KI of 5.35 microM. Most of these sulfonamides showed inhibition constants in the range of 12-100 microM against Cab. Thus, the three CA families investigated up to now possess a very diverse affinity for sulfonamides, the inhibitors with important medicinal, and environmental applications.

Archaea↗
PubMed2005

3-(2,5-Dihydro-1H-pyrrol-2-ylmethoxy)pyridines: synthesis and analgesic activity.

We disclose an efficient procedure for the preparation of ethers of 2-substituted 2-hydroxymethylpyrroline and of 2-aminomethyl-3-pyrrolines, involving, as a key step, formation and nucleophilic ring opening of a cyclic sulfamidate. Several new analogs of epibatidine (1) and tebanicline (ABT-594, 2) were prepared and tested for analgesic activity in the mouse formalin model.

Analgesics, Non-Narcotic↗
PubMed2005

1,3-Dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines as potent caspase-3 inhibitors.

Synthesis, biological evaluation and structure-activity relationships for a series of novel nonpeptide small molecule inhibitors of caspase-3 are described. Among the studied compounds, 8-sulfamide derivatives of 1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines have been identified as potent inhibitors of caspases-3. The most active compound within this series (8f) inhibited caspase-3 with IC(50)=4 nM.

Caspase 3↗
PubMed2005

Structure-activity relationships of 1-alkyl-5-(3,4-dichlorophenyl)-5-{2-[3-(substituted)-1-azetidinyl]-ethyl}-2-piperidones. Part 2: Improving oral absorption.

A series of piperidone analogues of 1b-q, seeking replacements for the polar sulfamide moiety in clinical candidate UK-224,671 1a, possessing reduced H-bonding potential as a strategy to improve oral absorption, were prepared. These studies led to the successful identification of 1n, which demonstrated equivalent pharmacology and metabolic stability to 1a, and greatly improved oral absorption as assessed in rat PK studies.

Administration, Oral↗
PubMed2006

3,4-Fused cyclohexyl sulfones as gamma-secretase inhibitors.

The 3,4-fused sulfamides, sulfonamides and sulfone have been identified as highly potent gamma-secretase inhibitors. Evaluation of the SAR of substitution within these series has allowed the identification of a range of compounds which significantly reduce brain A beta in transgenic mouse models and thus have potential as possible treatments for Alzheimer's disease.

Amyloid Precursor Protein Secretases↗
PubMed2006

Carbonic anhydrase inhibitors: inhibition of the cytosolic human isozyme VII with anions.

An inhibition study of the cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isozyme VII (hCA VII) with anions has been conducted. Cyanate, cyanide, and hydrogensulfite were weak hCA VII inhibitors (K(I)s in the range of 7.3-15.2 mM). Cl- and HCO3- showed good inhibitory activity against hCA VII (K(I)s of 0.16-1.84 mM), suggesting that this enzyme is not involved in metabolons with anion exchangers or sodium bicarbonate cotransporters. The best inhibitors were sulfamate, sulfamide, phenylboronic, and phenylarsonic acid (K(I)s of 6.8-12.5 microM).

Animals↗