Activation and detoxication of aminophenols. II. Synthesis and structural elucidation of various thiol addition products of 1,4-benzoquinoneimine and N-acetyl-1,4-benzoquinoneimine

Abstract

1. Nine thioethers of 4-aminophenol with β-hydroxyethylmercaptan, ranging from mono- to tetra-substituted thioadducts, were prepared from synthetic 1,4-benzoquinoneimine and characterized by ¹H-n.m.r. and u.v.spectroscopy. For each compound, extinction coefficients and pK_a values of the amino group were determined.

2. Five thioethers of 4-aminophenol with glutathione (GSH) were prepared and characterized by ¹H-n.m.r. and u.v. spectroscopy with their respective extinction coefficients and pK_a values. Two further thioadducts were tentatively assigned by their u.v. spectroscopic properties.

3. Reaction products of 1,4-[U-¹⁴C]benzoquinoneimine and GSH were studied, indicating formation of 4-amino-2-(glutathione-S-yl)phenol, 4-amino-3-(glutathione-S-yl)phenol, 4-amino-2,5-bis-(glutathione-S-yl)phenol, and 4-amino-2,3,6-tris-(glutathione-S-yl)phenol as the main products. Formation of glutathione disulphide (GSSG) was not detected. In contrast, N-acetyl-1,4-[U-¹⁴C]benzoquinoneimine was partly reduced by GSH and formed only the 2-substituted thioadduct.

4. Investigation of the product orientation in the reductive addition of GSH to 2-(glutathione-S-yl)-1,4-benzoquinoneimine and 3-(glutathione-S-yl)-1,4-benzoquinoneimine, respectively, showed that the 3-substituted derivative formed mainly the 3,5-di-substituted thioadduct, whereas the 2-substituted compound formed mainly the 2,3,6-tri-substituted thioadduct.

5. Formation of thioadducts which autoxidize markedly faster than the parent aminophenol indicates that thioether formation is not an obligatory detoxication process.