Synthesis and structural elucidation of glutathione and N-aceyl-cysteine conjugates of 5-aminosalicylic acid

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Synthesis and structural elucidation of glutathione and N-aceyl-cysteine conjugates of 5-aminosalicylic acid. / Jensen, J.; Cornett, Claus; Olsen, C. E.; Tjornelund, J.; Hansen, S. H.

In: European Journal of Pharmaceutical Sciences, Vol. 1, No. 3, 1993, p. 143-150.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Jensen, J, Cornett, C, Olsen, CE, Tjornelund, J & Hansen, SH 1993, 'Synthesis and structural elucidation of glutathione and N-aceyl-cysteine conjugates of 5-aminosalicylic acid', European Journal of Pharmaceutical Sciences, vol. 1, no. 3, pp. 143-150.

APA

Jensen, J., Cornett, C., Olsen, C. E., Tjornelund, J., & Hansen, S. H. (1993). Synthesis and structural elucidation of glutathione and N-aceyl-cysteine conjugates of 5-aminosalicylic acid. European Journal of Pharmaceutical Sciences, 1(3), 143-150.

Vancouver

Jensen J, Cornett C, Olsen CE, Tjornelund J, Hansen SH. Synthesis and structural elucidation of glutathione and N-aceyl-cysteine conjugates of 5-aminosalicylic acid. European Journal of Pharmaceutical Sciences. 1993;1(3):143-150.

Author

Jensen, J. ; Cornett, Claus ; Olsen, C. E. ; Tjornelund, J. ; Hansen, S. H. / Synthesis and structural elucidation of glutathione and N-aceyl-cysteine conjugates of 5-aminosalicylic acid. In: European Journal of Pharmaceutical Sciences. 1993 ; Vol. 1, No. 3. pp. 143-150.

Bibtex

@article{916c4bae3d2941f7b66811de25d5a3e2,
title = "Synthesis and structural elucidation of glutathione and N-aceyl-cysteine conjugates of 5-aminosalicylic acid",
abstract = "The ability of 5-aminosalicylic acid (5-ASA) to be oxidized to a quinone monoimine compound capable of conjugating with nucleophilic compounds such as N-acetyl-cysteine (NAC) and glutathione (GSH) has been investigated in vitro. Three isomeric conjugates of 5-ASA and NAC as well as three isomeric conjugates of 5-ASA and GSH were found to be formed. 5-ASA was initially oxidized by PbO2 in a solution of TRIS-HCl buffer pH 9.3 followed by the in situ addition of N-acetyl-cysteine or glutathione to the oxidized 5-ASA at pH 7.5. The resulting conjugates were N-acetylated at the aromatic amino group in order to avoid autooxidation of the products formed. The N-acetylated conjugates were isolated by preparative HPLC and the structures were characterized by nuclear magnetic resonance (H-1-NMR and C-13-NMR) spectroscopy as well as by mass spectrometry (MS) and the data obtained confirmed the formation of thioether linkages between 5-ASA and the SH compounds. The chemical nature of the reactive intermediate capable of adding SH compounds was verified to be the 2-carboxy-quinone monoimine by H-1-NMR spectroscopy. The N-acetylated conjugates of 5-ASA and NAC were used as reference standards in order to investigate whether such conjugates are excreted in the urine from persons treated with 5-ASA. The N-acetyl-cysteine conjugates could be detected by fluorescense, which resulted in low detection limits ranging from 0.02 mug to 0.06 mug per ml corresponding to the transformation of about 0.003{\%} of the daily dose of 5-ASA into mercapturic acids of 5-ASA, when 1 g of 5-ASA was ingested. In spite of the low detection limits, none of the mercapturic acid conjugates was detected in the urine from persons treated with 5-ASA.",
keywords = "5-aminosalicylic acid oxidation 2-carboxy-1,4-benzoquinone monoimine n-acetyl-cysteine mercapturic acids of 5-aminosalicylic acid metabolites oxidation sulphasalazine acetaminophen mechanism products",
author = "J. Jensen and Claus Cornett and Olsen, {C. E.} and J. Tjornelund and Hansen, {S. H.}",
year = "1993",
language = "Udefineret/Ukendt",
volume = "1",
pages = "143--150",
journal = "European Journal of Pharmaceutical Sciences",
issn = "0928-0987",
publisher = "Elsevier",
number = "3",

}

RIS

TY - JOUR

T1 - Synthesis and structural elucidation of glutathione and N-aceyl-cysteine conjugates of 5-aminosalicylic acid

AU - Jensen, J.

AU - Cornett, Claus

AU - Olsen, C. E.

AU - Tjornelund, J.

AU - Hansen, S. H.

PY - 1993

Y1 - 1993

N2 - The ability of 5-aminosalicylic acid (5-ASA) to be oxidized to a quinone monoimine compound capable of conjugating with nucleophilic compounds such as N-acetyl-cysteine (NAC) and glutathione (GSH) has been investigated in vitro. Three isomeric conjugates of 5-ASA and NAC as well as three isomeric conjugates of 5-ASA and GSH were found to be formed. 5-ASA was initially oxidized by PbO2 in a solution of TRIS-HCl buffer pH 9.3 followed by the in situ addition of N-acetyl-cysteine or glutathione to the oxidized 5-ASA at pH 7.5. The resulting conjugates were N-acetylated at the aromatic amino group in order to avoid autooxidation of the products formed. The N-acetylated conjugates were isolated by preparative HPLC and the structures were characterized by nuclear magnetic resonance (H-1-NMR and C-13-NMR) spectroscopy as well as by mass spectrometry (MS) and the data obtained confirmed the formation of thioether linkages between 5-ASA and the SH compounds. The chemical nature of the reactive intermediate capable of adding SH compounds was verified to be the 2-carboxy-quinone monoimine by H-1-NMR spectroscopy. The N-acetylated conjugates of 5-ASA and NAC were used as reference standards in order to investigate whether such conjugates are excreted in the urine from persons treated with 5-ASA. The N-acetyl-cysteine conjugates could be detected by fluorescense, which resulted in low detection limits ranging from 0.02 mug to 0.06 mug per ml corresponding to the transformation of about 0.003% of the daily dose of 5-ASA into mercapturic acids of 5-ASA, when 1 g of 5-ASA was ingested. In spite of the low detection limits, none of the mercapturic acid conjugates was detected in the urine from persons treated with 5-ASA.

AB - The ability of 5-aminosalicylic acid (5-ASA) to be oxidized to a quinone monoimine compound capable of conjugating with nucleophilic compounds such as N-acetyl-cysteine (NAC) and glutathione (GSH) has been investigated in vitro. Three isomeric conjugates of 5-ASA and NAC as well as three isomeric conjugates of 5-ASA and GSH were found to be formed. 5-ASA was initially oxidized by PbO2 in a solution of TRIS-HCl buffer pH 9.3 followed by the in situ addition of N-acetyl-cysteine or glutathione to the oxidized 5-ASA at pH 7.5. The resulting conjugates were N-acetylated at the aromatic amino group in order to avoid autooxidation of the products formed. The N-acetylated conjugates were isolated by preparative HPLC and the structures were characterized by nuclear magnetic resonance (H-1-NMR and C-13-NMR) spectroscopy as well as by mass spectrometry (MS) and the data obtained confirmed the formation of thioether linkages between 5-ASA and the SH compounds. The chemical nature of the reactive intermediate capable of adding SH compounds was verified to be the 2-carboxy-quinone monoimine by H-1-NMR spectroscopy. The N-acetylated conjugates of 5-ASA and NAC were used as reference standards in order to investigate whether such conjugates are excreted in the urine from persons treated with 5-ASA. The N-acetyl-cysteine conjugates could be detected by fluorescense, which resulted in low detection limits ranging from 0.02 mug to 0.06 mug per ml corresponding to the transformation of about 0.003% of the daily dose of 5-ASA into mercapturic acids of 5-ASA, when 1 g of 5-ASA was ingested. In spite of the low detection limits, none of the mercapturic acid conjugates was detected in the urine from persons treated with 5-ASA.

KW - 5-aminosalicylic acid oxidation 2-carboxy-1,4-benzoquinone monoimine n-acetyl-cysteine mercapturic acids of 5-aminosalicylic acid metabolites oxidation sulphasalazine acetaminophen mechanism products

M3 - Tidsskriftartikel

VL - 1

SP - 143

EP - 150

JO - European Journal of Pharmaceutical Sciences

JF - European Journal of Pharmaceutical Sciences

SN - 0928-0987

IS - 3

ER -

ID: 38061698