A New Metabolic Pathway for a Sulfonamide Group

Clapp, J. W.

doi:10.1016/s0021-9258(18)65129-4

Cited by 43 publications

(4 citation statements)

References 5 publications

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“…Two reactions appear to compete for transformation of 14: S-glucuronidation and S-methylation (Scheme II). S-Glucuronidation of thiol 14 leads to thioglucuronide 4, a major in vivo metabolite whose formation is well precedented (Larsen and Bakke, 1978;Clapp, 1956).…”

Section: Resultsmentioning

confidence: 99%

Metabolism of triallate in Sprague-Dawley rats. 2. Identification and quantitation of excreted metabolites

Nadeau¹,

Chott²,

Fujiwara³

et al. 1993

J. Agric. Food Chem.

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Triallate was administered orally to Sprague-Dawley rats. Twelve excreted metabolites were identified, the most abundant being 2,3,3-trichloro-2-propenesulfinic acid. Five metabolites derived from 2,3,3-trichloro-2-propenethiol were identified in excreta, including a methyl sulfone mercapturate whose structure was confirmed by X-ray crystallography. Three 2-chloroacrylate metabolites were identified, including a 2-chloroacrylate mercapturate whose structure was confirmed by X-ray crystallography. 2,3,3-Trichloro-2-propenol and hydroxytriallate were also identified as metabolites. Dosing of radiolabeled thiol and sulfinic acid to separate animals resulted in excretion of only thiolderived metabolites in the urine of thiol-dosed rats, while sulfinic acid and sulfonic acid were excreted by sulfinic acid-dosed rats. Triallate metabolism in rats proceeds via three main pathways, i.e., S-oxidation leading to sulfur acids, S-oxidation/hydrolysis/reduction leading to thiol derivatives, and C-oxidation of the 2,3,3-trichloropropenethioI moiety. This study demonstrates that formation of readily excreted sulfur acids and thiol derivatives is the major route of triallate metabolism in rats.

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Section: Resultsmentioning

confidence: 99%

Metabolism of triallate in Sprague-Dawley rats. 2. Identification and quantitation of excreted metabolites

Nadeau¹,

Chott²,

Fujiwara³

et al. 1993

J. Agric. Food Chem.

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“…Although sulfonamides are generally considered to be metabolically stable ( , ), FOSA 9 was biotransformed to PFOS 10 in rat liver slices at a low rate, but no biotransformation was observed in microsomal, cytosolic, and 9000 g supernatant fractions. This is apparently the first observation of the metabolic hydrolysis of a sulfonamide.…”

Section: Discussionmentioning

confidence: 99%

Biotransformation of N-Ethyl-N-(2-hydroxyethyl)perfluorooctanesulfonamide by Rat Liver Microsomes, Cytosol, and Slices and by Expressed Rat and Human Cytochromes P450

Krenitsky

Seacat

et al. 2004

Chem. Res. Toxicol.

193

187

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Perfluorooctanesulfonic acid (PFOS) and its derivatives have been used in a range of industrial and commercial applications, including the manufacture of surfactants, adhesives, anticorrosion agents, and insecticides. PFOS is found at detectable concentrations in human and wildlife tissues and in the global environment. N-Substituted perfluorooctanesulfonamides are believed to be degraded to PFOS and, therefore, contribute to the accumulation of PFOS in the environment. N-Ethyl-N-(2-hydroxyethyl)perfluorooctanesulfonamide (N-EtFOSE) is converted to PFOS in experimental animals. The objective of this study was to elucidate the pathways for the biotransformation of N-EtFOSE, which is a major precursor and component of PFOS-based compounds. N-EtFOSE and several putative metabolites were incubated with liver microsomes and cytosol and with liver slices from male Sprague-Dawley rats. Microsomal fractions fortified with NADPH catalyzed the N-deethylation of N-EtFOSE to give N-(2-hydroxyethyl)perfluorooctanesulfonamide (FOSE alcohol) and of FOSE alcohol to give perfluorooctanesulfonamide (FOSA). These N-dealkylation reactions were catalyzed mainly by male rat P450 2C11 and P450 3A2 and by human P450 2C19 and 3A4/5. Rat liver microsomal fractions incubated with UDP-glucuronic acid catalyzed the O-glucuronidation of N-EtFOSE and FOSE alcohol and the N-glucuronidation of FOSA. Cytosolic fractions incubated with NAD(+) catalyzed the oxidation of FOSE alcohol to perfluooctanesulfonamidoacetate (FOSAA). The oxidation of N-EtFOSE to N-ethylperfluorooctanesulfonamidoacetate (N-EtFOSAA) was observed in liver slices but not in cytosolic fractions. FOSA was biotransformed in liver slices to PFOS, albeit at a low rate. These results show that the major pathway for the biotransformation of N-EtFOSE is N-dealkylation to give FOSA. The biotransformation of FOSA to PFOS explains the observation that PFOS is found in animals given N-EtFOSE.

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“…7,8 Examination of the medicinal chemistry literature, however, reveals several examples of seemingly "chemically inert" compounds, which are prone to nucleophilic displacement by GSH under nonenzymatic (pH 7.4, phosphate buffer, 37 °C) and/or enzymatic conditions. [9][10][11][12][13][14][15][16][17][18] In the case of enzyme-assisted reactions, GSH conjugation to electrophilic centers is mediated by microsomal, cytosolic and/or mitochondrial glutathione transferases (GST). [19][20][21][22] From a structure-activity relationship (SAR) perspective, a recurring structural theme in these examples is the presence of the methylsulfone/sulfonamide and/or halide leaving group, which is attached to an electron deficient heteroaromatic ring system (e.g., pyridine, pyridone, benzothiazole, thiadiazole, benzofuran, indole, etc.).…”

Section: ' Introductionmentioning

confidence: 99%

“…Such compounds can alkylate proteins, DNA, and/or the endogenous antioxidant glutathione (GSH), leading to toxicological outcomes. − Because of the potential safety concerns, electrophilic functional groups (e.g., alkyl halides, Michael acceptors, etc.) are generally avoided in drug design. , Examination of the medicinal chemistry literature, however, reveals several examples of seemingly “chemically inert” compounds, which are prone to nucleophilic displacement by GSH under nonenzymatic (pH 7.4, phosphate buffer, 37 °C) and/or enzymatic conditions. − In the case of enzyme-assisted reactions, GSH conjugation to electrophilic centers is mediated by microsomal, cytosolic and/or mitochondrial glutathione transferases (GST). − From a structure−activity relationship (SAR) perspective, a recurring structural theme in these examples is the presence of the methylsulfone/sulfonamide and/or halide leaving group, which is attached to an electron deficient heteroaromatic ring system (e.g., pyridine, pyridone, benzothiazole, thiadiazole, benzofuran, indole, etc.). The overall displacement mechanism is similar to the one described for GST-catalyzed nucleophilic aromatic substitution reactions and involves nucleophilic attack by the thiolate anion of GSH across the electrophilic center to yield the negatively charged σ-complex or Meisenheimer complex followed by elimination of the appropriate leaving group. − Accordingly, the chemical reactivity of electrophiles with GSH can be governed by steric and/or electronic factors that are predetermined by the nature and position of heteroaromatic substituents.…”

Section: Introductionmentioning

confidence: 99%

Intrinsic Electrophilicity of a 4-Substituted-5-cyano-6-(2-methylpyridin-3-yloxy)pyrimidine Derivative: Structural Characterization of Glutathione Conjugates in Vitro

Kalgutkar

Mascitti

Sharma

et al. 2011

Chem. Res. Toxicol.

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Isopropyl 9-anti-[5-cyano-6-(2-methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-3-oxa-7-aza-bicyclo[3.3.1]nonane-7-carboxylate (1) represents a prototypic compound from a lead chemical series of G protein-coupled receptor 119 agonists, intended for treatment of type 2 diabetes. When compound 1 was incubated with NADPH-supplemented human liver microsomes in the presence of glutathione, two thioether conjugates M4-1 and M5-1 were observed. Omission of NADPH from the microsomal incubations prevented the formation of M5-1 but not M4-1. The formation of M4-1 was also discerned in incubations of 1 and glutathione with human liver cytosol, partially purified glutathione transferase, and in phosphate buffer at pH 7.4. M4-1 was isolated, and its structure ascertained from LC-MS/MS and NMR analysis. The mass spectral and NMR data suggested that M4-1 was obtained from a nucleophilic displacement of the 6-(2-methylpyridin-3-yloxy) group in 1 by glutathione. In addition, mass spectral studies revealed that M5-1 was derived from an analogous displacement reaction on a monohydroxylated metabolite of 1; the regiochemistry of hydroxylation was established to be on the isopropyl group. Of great interest were the findings that replacement of the 5-cyano group in 1 with a 5-methyl group resulted in 2, which was practically inert toward reaction with glutathione. This observation suggests that the electron-withdrawing potential of the C5 cyano group serves to increase the electrophilicity of the C6 carbon (via stabilization of the transition state) and favors reaction with the nucleophilic thiol. The mechanistic insights gained from these studies should assist medicinal chemistry efforts toward the design of analogs that retain primary pharmacology but are latent toward reaction with biological nucleophiles, thus mitigating the potential for toxicological outcome due to adduction with glutathione or proteins.

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A New Metabolic Pathway for a Sulfonamide Group

Cited by 43 publications

References 5 publications

Metabolism of triallate in Sprague-Dawley rats. 2. Identification and quantitation of excreted metabolites

Metabolism of triallate in Sprague-Dawley rats. 2. Identification and quantitation of excreted metabolites

Biotransformation of N-Ethyl-N-(2-hydroxyethyl)perfluorooctanesulfonamide by Rat Liver Microsomes, Cytosol, and Slices and by Expressed Rat and Human Cytochromes P450

Intrinsic Electrophilicity of a 4-Substituted-5-cyano-6-(2-methylpyridin-3-yloxy)pyrimidine Derivative: Structural Characterization of Glutathione Conjugates in Vitro

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