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PubMed2002

Sulfonamides and sulfonylated derivatives as anticancer agents.

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti-carbonic anhydrase, diuretic, hypoglycemic and antithyroid activity among others. A host of structurally novel sulfonamide derivatives have recently been reported to show substantial antitumor activity in vitro and/or in vivo. Although they have a common chemical motif of aromatic/heterocyclic sulfonamide, there are a variety of mechanisms of their antitumor action, such as carbonic anhydrase inhibition, cell cycle arrest in the G1 phase, disruption of microtubule assembly, functional suppression of the transcriptional activator NF-Y, and angiogenesis (matrix metalloproteinase, MMP) inhibition among others. Some of these compounds selected via elaborate preclinical screenings or obtained based on computer-aided drug design, are currently being evaluated in clinical trials. This review summarizes recent classes of sulfonamides and related sulfonyl derivatives disclosed ultimately as effective tumor cell growth inhibitors, or for the treatment of different types of cancer.

Animals↗
PubMedDate not supplied

The management of patients with sulfonamide allergy.

To illustrate the variety of clinical strategies that may be used in treatment of patients allergic to sulfa medications, we report the management of eight sulfa allergic patients, seven of whom required readministration of the sulfa drug. Slow oral readministration of a sulfonamide over the course of four weeks was successful in two patients who had a history of cutaneous reactions to sulfa use and did not require sulfa urgently. Rapid oral or intravenous readministration of a sulfonamide was attempted unsuccessfully in three patients, each of whom urgently needed continuation of a sulfa drug. Occasionally a sulfa drug must be continued despite the presence of a cutaneous drug eruption secondary to that drug. In four patients, including two of the patients in whom rapid test dosing of a sulfonamide had been unsuccessful, treatment of the sulfa reaction with corticosteroids and antihistamines permitted continued sulfa administration. Readministration of a sulfonamide should not be attempted in patients who previously have had reactions such as Stevens-Johnson syndrome unless essential for survival of a patient.

Adult↗
PubMed1979

Metal sulfonamides as antibacterial agents in topical therapy.

The apparent efficacy of zinc and cerium sulfadiazine and the metabolic role of other trace metals suggested that sulfonamide salts of these might be of therapeutic value. There is also a possibility that metal salts of other sulfonamides might be useful. Accordingly other sulfonamide salts of zinc were prepared and studied in vitro and in vivo. Only zinc sulfathiazole and zinc methoxazole were as effective as zinc sulfadiazine in animal studies. The sulfadiazines of aluminum, chromium, cobalt, copper and iron were prepared and compared in vitro and in vivo. Only cobalt sulfadiazine appeared comparable to zinc and cerium sulfadiazine in healing burn wounds in rats. Studies on the molecular structure of silver sulfonamides disclosed the polymeric structure peculiar to silver sulfadiazine which appears to account for its unique properties. It is not yet known whether other metal sulfadiazines have this attribute.

Administration, Topical↗
PubMed2000

Carbonic anhydrase inhibitors: synthesis of Schiff bases of hydroxybenzaldehydes with aromatic sulfonamides and their reactions with arylsulfonyl isocyanates.

Reaction of o- or p-hydroxybenzaldehydes with sulfanilamide, homosulfanilamide and p-(2-aminoethyl)- benzene-sulfonamide afforded several new Schiff bases which were subsequently derivatized at the phenolic hydroxy moiety by reaction with arylsulfonylisocyanates. The new arylsulfonylcarbamates obtained in this way possessed interesting inhibitory properties against three carbonic anhydrase (CA) isozymes, hCA I, hCA II and bCA IV (h = human, b = bovine isozyme). All these new derivatives, the simple Schiff bases and the arylsulfonylcarbamates obtained as outlined above, were more inhibitory against all isozymes as compared to the corresponding parent sulfonamide from which they were obtained. Generally, the p-hydroxybenzaldehyde derivatives were more active than the corresponding ortho isomers. An interesting behavior was evidenced for some of the ortho-substituted arylsulfonylcarbamato-sulfonamides, which showed higher affinities for the isozyme hCA I, as compared to hCA II and bCA IV (generally hCA I is 10-1000 less sensitive to "normal" sulfonamide inhibitors, such as acetazolamide, methazolamide or dorzolamide, as compared to hCA II). This make the new derivatives attractive leads for designing isozyme I-specific inhibitors.

Animals↗
PubMed1976

[Renal excretion of long term sulfonamides under fluid administration and modification of the urinary pH value].

The renal excretion of sulfaclomide, sulfamerazine and sulfamethoxypyridazine is delayed by increased fluid application in rats. The simultaneous administration of sulfonamides and ammonium chloride or sodium hydrogen carbonate causes, respectively, retardation and acceleration of renal sulfonamide excretion which is consistent with the change in urinary pH value. The retarded renal sulfonamide excretion with increasing diuresis is explained by the ensuing change in the urinary pH value. For clinical uses, a speedy renal excretion of long-time sulfonamides by increased diuresis can be expected only if alkalization of the urine is achieved at the same time.

Ammonium Chloride↗
PubMed2000

Carbonic anhydrase inhibitors. Synthesis of topically effective intraocular pressure lowering agents derived from 5-(omega-aminoalkylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide.

Reaction of the acyl chlorides of phthalimido-glycine or phthalimido-beta-alanine with 5-amino-1,3,4-thiadiazole-2-sulfonamide afforded after hydrazinolysis and deprotection of the phthalimido group the corresponding 5-(omega-aminoalkylcarboxamido)-1,3,4-thiadiazole-2-sulfonamides. Reaction of 5-(beta-aminoethylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide with sulfonyl halides or acyl halides afforded a series of compounds possessing beta-alkyl/arylsulfonyl/carbonylamidoethylcarboxamido moieties in the 5 position of the thiadiazole-2-sulfonamide ring. The new derivatives were efficient inhibitors of three carbonic anhydrase (CA) isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form), but especially against CA II and CA IV (in nanomolar range), the two isozymes known to play an important role in aqueous humor secretion within the ciliary processes of the eye. Some of the synthesized inhibitors possessed good water solubility (as hydrochlorides or sodium salts) and were applied as 2% solutions directly into the eye of normotensive or glaucomatous albino rabbits. Very strong intraocular pressure (IOP) lowering was observed for many of them for prolonged periods of 1-2 h, and the active drug was detected in eye tissues and fluids indicating that the antiglaucoma effect is due to CA inhibition within the eye.

Administration, Topical↗
PubMed1976

Stevens-Johnson syndrome from ophthalmic sulfonamide.

A 71-year-old man, who had a history of a previous bullous drug reaction to a sulfonamide, began receiving an ophthalmic preparation that contained sulfacetamide sodium. The patient received only the ophthalmic sulfonamide, and it was used for one day, but he developed Stevens-Johnson syndrome. This is believed to be the first reported case of Stevens-Johnson syndrome caused by an ophthalmic sulfonamide. The sulfonamides are the best verified drug-trigger for erythema multiforme and Stevens-Johnson syndrome.

Aged↗
PubMed2003

[Study on separation of sulfonamides by capillary high-performance liquid chromatography and electrochromatography].

AIM: To establish separation methods of five sulfonamides by using capillary high performance liquid chromatography(mu-HPLC) and electrochromatography. The effect of mobile phase varies such as methanol content, pH, buffer solution concentration and voltage on their chromatographic behavior and electroosmesis flow was investigated. Capillary electrochromatography (CEC) was compared with mu-HPLC at the same condition. METHODS: Stationary phase was ODS, mobile phase was methanol and 2 mmol.L-1 H3PO4 buffer solution (pH 3.0-7.0), voltage was 0- -15 kV, flow rate was 10 microL.min-1, pressure was approximately 70 MPa and UV detection wavelength was 254 nm. RESULTS: Separations on base line have been respectively accomplished for five sulfonamides by mu-HPLC with mobile phase of methanol-2 mmol.L-1 H3PO4 buffer solution (30:70) at pH 5.0 in 67 min, and CEC with the same mobile phase at -5 kV voltage in 25 min. CONCLUSION: Electroosmesis flow of CEC decreased with the increase in methanol content, buffer solution concentration, increased with the increase in voltage and increase slightly with the increase in pH of mobile phase. Retention values (k) of solutes to be examined decreased with increasing methanol content of mobile phase in mu-HPLC and CEC. Retention values (k) of solutes increased slightly with increasing buffer solution concentration, decreased with increasing voltage in CEC. Trimethoprim(TMP) decreased obviously with increasing voltage in CEC. The effect of pH of mobile phase on retention values (k) was more complex. Five sulfonamides were separated at the same mobile phase condition by mu-HPLC and CEC. And separation speed of CEC was much faster than that of mu-HPLC. CEC was very fit for rapid separation of sulfonamides.

Anti-Infective Agents↗
PubMedDate not supplied

Determination of sulfonamide residues in the tissues of food animals using automated precolumn derivatization and liquid chromatography with fluorescence detection.

A liquid chromatographic method for the determination of sulfachloropyridazine, sulfadiazine, sulfadimethoxine, sulfadoxine, sulfaethoxypyridazine, sulfamethazine, sulfaquinoxaline, and sulfathiazole residues in the muscle, liver, and kidney of food animals using sulfapyridine as internal standard is reported. Tissues are extracted using a modified version of AOAC Official Method 983.31 (Sulfonamide Residues in Animal Tissues). The sample extract is reconstituted in pH 3.0 buffer-acetonitrile (60 + 40) and filtered into an autosampler vial. Using a programmable autosampler of a liquid chromatograph, a portion of the sample is derivatized precolumn with fluorescamine. The sulfonamide derivatives are separated by liquid chromatography using a C18 column with a mobile phase of 0.02M phosphoric acid-acetonitrile (60.5 + 39.5) and detected by fluorescence (excitation, 405 nm; emission, 495 nm). The method was applied to swine and cattle muscle, liver, and kidney; sheep and horse muscle and kidney; and chicken muscle and liver. The mean values for samples fortified with sulfonamides at levels between 0.05 and 0.2 microg/g agreed within 96-99% of spiked levels, with coefficients of variation ranging from 4-10%. The limit of detection (LOD) for all sulfonamides was 0.01 microg/g, with the exception of sulfaquinoxaline, for which the LOD was 0.015 microg/g.

Animals↗
PubMed1991

Antibiotic and sulfonamide agents in bob veal calf muscle, liver, and kidney.

During the fiscal year 1988, USDA-FSIS detected 3,095 antimicrobial violations in bob veal calves, using the calf antibiotic and sulfonamide test. Of the 3,095 carcass submissions involved, 945 were tested further to identify the causative agents. The results of tests on the available kidney, liver, and muscle specimens are reported. Kidney specimens yielded a specific agent most often (71.2%), with neomycin (42.6%) being cited most among agents found in kidneys. Neomycin was found less frequently in liver (4.5%) and muscle (0.2%). Among all tissues, unidentified microbial inhibitors were either the largest or second largest category found (kidney, 10.5%; liver, 27.1%; muscle, 7.8%), and no other agent exceeded 7.0% (streptomycin in kidney). The proportion of liver and muscle specimens that had unidentified microbial inhibitors is particularly important because the next most common classes were streptomycin in liver at 5.5% and sulfamethazine in muscle at 2%. The frequency of unidentified microbial inhibitors may justify the addition of tests to the FSIS battery for identification of agents. Not all tissues were tested for sulfonamides, hence these agents are likely to have been underreported. Less than 10% of the muscle specimens evaluated yielded an agent, suggesting most calf antibiotic and sulfonamide test-positive carcasses may have been safe with regard to residues in meat, although organs might have been adulterated. Specimens for verification were not selected completely randomly from the population of all calf antibiotic and sulfonamide test-positive animals and calves selected for testing were not chosen strictly by random sampling; therefore, extrapolation of the contents of this report to the bob veal calf industry must be done with caution.

Animals↗
PubMed1990

Peroxidase-dependent oxidation of sulfonamides by monocytes and neutrophils from humans and dogs.

The hydroxylamine and nitroso metabolites formed by N4-oxidation of sulfonamides are thought to be involved in the pathogenesis of idiosyncratic reactions to this class of drugs. Idiosyncratic reactions to sulfonamides are characterized by multisystemic toxicity, including hepatitis, nephritis, dermatitis, and blood dyscrasias (aplastic anemia, agranulocytosis). We have previously shown that cytochrome P-450 in the liver metabolizes sulfamethoxazole to its hydroxylamine metabolite. In this paper we report the N4-oxidation of sulfamethoxazole by activated monocytes and neutrophils (human and canine) to form sulfamethoxazole hydroxylamine and nitrosulfamethoxazole. The presumed nitroso intermediate was not detected. Purified myeloperoxidase and prostaglandin H synthase were also capable of mediating the oxidation of sulfamethoxazole. The present studies suggest that myeloperoxidase is responsible for the observed oxidation by phagocytic cells. Oxidation by neutrophils may play a role in agranulocytosis, and oxidation by monocytes may facilitate antigen presentation. Extrahepatic bioactivation of sulfonamides by peroxidases in phagocytic cells and other tissues may be important in determining the range of adverse reactions to sulfonamides that occur.

Animals↗
PubMed1989

Synthesis and cytotoxic activity of tetrahydropyridylidene-2- and -4-sulfonamides.

1,2,3,4-Tetrahydropyridylidene-4-sulfonamides, 1,2,3,4-tetrahydropyridylidene-2-sulfonamides, and 1,2,3,6-tetrahydropyridylidene-2-sulfonamides, of structures 10, 12 and 14, respectively (given in Table I), were synthesized in order to investigate the effect of nuclear substituents and the position of the sulfonamido group on cytotoxicity. The relative potency order was 12 greater than 10 greater than 14. Compounds possessing an R1 CONEt2 substituent were more potent than those possessing a R1 CN substituent. The nature of the aryl(alkyl)-sulfonamido substituent was a determinant of activity, the relative potency order being 4-chlorophenyl greater than phenyl, 4-methoxy- or 4-nitrophenyl greater than methyl. 1-Methyl-4-tert-butyl-5-diethylaminocarbonyl-1,2,3,4-tetrahydro pyridylidene- 2-(4-chlorophenyl)sulfonamide (12c) was the most active cytotoxic agent, exhibiting an ED50 of 5.4 micrograms/ml in the L1210 in vitro screen.

Animals↗
PubMedDate not supplied

Liquid chromatographic determination of fluorescent derivatives of six sulfonamides in bovine serum and milk.

A rapid and sensitive liquid chromatographic (LC) method with fluorometric detection was developed to detect sulfadiazine, sulfathiazole, sulfamethazine, sulfamonomethoxine, sulfamethoxazole, and sulfadimethoxine residues in bovine serum and milk. p-Aminobenzoic acid (PABA) was added as an internal standard. The sulfonamides were extracted from samples and derivatized with fluorescamine, and 50 microL was injected into a NovaPak C18 LC column and eluted with acetonitrile-10 mM potassium phosphate (30 + 70, v/v). The sulfonamides were detected fluorometrically (excitation, 390 nm; emission, 475 nm), and their retention times ranged from 6.2 to 16.5 min without interference from coextractives. The detection limit for standard sulfonamide solution was 0.1 ng/mL; the calibration curves were linear between 1 and 100 ng/mL in the presence of PABA as internal standard. Recovery rates of sulfonamides from spiked samples (1 and 10 ppb) were 95.4-107.2 and 81.4-89.6% for serum and 80.7-91.1 and 62.6-84.1% for milk, respectively.

Animals↗
PubMed1977

Antimicrobials commonly used for urinary tract infection: sulfonamides, trimethoprim-sulfamethoxazole, nitrofurantoin, nalidixic acid.

Sulfonamides, trimethoprim-sulfamethoxazole, nitrofurantoin, and nalidixic acid are excreted in the urine in high concentration and, with the exception of Pseudomonas aeruginosa and Serratia marcescens, are all active in vitro against usual aerobic gram-negative bacteria. They are useful for treatment of uncomplicated lower urinary tract infections in an outpatient setting but are probably not indicated for acute upper tract infections, especially in the hospitalized patient. Trimethoprim-sulfamethoxazole is a very effective combination agent in vitro, has appealing pharmacokinetic properties, and is usually well tolerated by patients. However, it is more expensive than the sulfonamides and is ordinarily not indicated for initial treatment. A sulfonamide is in our view still the agent of first choice, with either nitrofurantoin or nalidixic acid as an alternative if sulfonamides cannot be tolerated.

Anti-Infective Agents, Urinary↗
PubMedDate not supplied

Studies of the effect of physical and chemical interactions of cellulose ethers and sulfonamides in tablets on the drug release.

The paper reports results of the studies of sulfonamide tablets obtained by the incorporation in hydrophilic carrier (Cellulose ether). The rate of sulfonamide release was determined by the paddle method. The occurrence of physical and chemical interactions of sulfonamides and cellulose ethers in the solid phase was confirmed by X-ray diffraction and thermal (TG and DSC) studies. The influence of these interactions on the sulfonamide release from the tablets was analyzed.

Cellulose↗
PubMed1994

Immunochemical analysis of sulfonamide drug allergy: identification of sulfamethoxazole-substituted human serum proteins.

BACKGROUND: Sulfonamides undergo oxidative metabolism to yield reactive metabolites that haptenate proteins readily. Although it has been shown that sulfonamide metabolites bind covalently to murine microsomes, sulfonamide-conjugated serum proteins have not been analyzed in the peripheral blood of treated individuals. OBJECTIVE: We hypothesized that during treatment with sulfamethoxazole, intracellular proteins are haptenated by drug metabolites, and some of these are destined for secretion into the serum. METHODS: Using antibodies specific for sulfamethoxazole and an alkaline phosphatase immunoblotting technique, we attempted to demonstrate the presence of sulfamethoxazole-substituted proteins in the serum of individuals during a course of treatment. RESULTS: Five days into therapy, serum protein haptenation by sulfamethoxazole was demonstrated in two of the three individuals studied. In addition, Western blot analysis revealed that haptenation is not indiscriminate, but highly selective. A single 30 kd protein is the target of haptenation in all instances. A kinetic analysis revealed that substituted proteins can be detected early, within hours of administration. Moreover, haptenated proteins remain detectable in the serum 48 hours after discontinuation of the drug. CONCLUSION: The results presented here constitute the first direct evidence that sulfonamides, on being metabolized, covalently haptenate human serum proteins during a course of therapy.

Animals↗
PubMed2002

Generation of intramolecular and intermolecular sulfenamides, sulfinamides, and sulfonamides by hypochlorous acid: a potential pathway for oxidative cross-linking of low-density lipoprotein by myeloperoxidase.

Oxidized low-density lipoprotein (LDL) is implicated in atherogenesis, and human atherosclerotic lesions contain LDL oxidized by myeloperoxidase, a heme protein secreted by activated phagocytes. Using hydrogen peroxide (H(2)O(2)), myeloperoxidase generates hypochlorous acid (HOCl), a powerful oxidant. We now demonstrate that HOCl produces sulfenamides, sulfinamides, and sulfonamides in model peptides, which suggests a potential mechanism for LDL oxidation and cross-linking. When we exposed the synthetic peptide PFKCG to HOCl, the peptide's thiol residue reacted rapidly, generating a near-quantitative yield of products. Tandem mass spectrometric analysis identified the products as the sulfenamide, sulfinamide, and sulfonamide, all formed by intramolecular cross-linking of the peptide's thiol and lysine residues. An intramolecular sulfinamide was also observed after the peptide PFRCG was exposed to HOCl, indicating that the guanidine group of arginine can also form a sulfur-nitrogen cross-link. The synthetic peptide PFVCG, which contains a free thiol residue but lacks nucleophilic amino acid side chains, formed an intermolecular sulfonamide when exposed to HOCl. Tandem mass spectrometric analysis of the dimer revealed that the free N-terminal amino group of one PFVCG molecule cross-linked with the thiol residue of another. This peptide also formed intermolecular sulfonamide cross-links with N(alpha)-acetyllysine after exposure to HOCl, demonstrating that the epsilon-amino group of a lysine residue can undergo a similar reaction. Moreover, human neutrophils used the myeloperoxidase-H(2)O(2) system to generate sulfinamides in model peptides containing lysine or arginine residues. Collectively, our observations raise the possibility that HOCl generated by myeloperoxidase contributes to intramolecular and intermolecular protein cross-linking in the artery wall. Myeloperoxidase might also use this mechanism to form sulfur-nitrogen cross-links in other inflammatory conditions.

Amides↗
PubMed2000

N-Arylation of Sulfonamides on Solid Supports.

A general and mild method for the N-arylation of sulfonamides on solid supports is reported. Copper acetate, triethylamine mediated coupling of arylboronic acids at room temperature to solid-supported sulfonamides gave good to excellent yields of the desired N-arylsulfonamides. Sulfonamide bond cleavage of the o,p-dinitrobenzene(N-aryl)sulfonamide provides a route to N-arylated secondary amine products.

Journal Article↗