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Antithyroid Drugs and their Analogues Protect Against Peroxynitrite‐Mediated Protein Tyrosine Nitration—A Mechanistic Study
Author(s) -
Bhabak Krishna P.,
Mugesh Govindasamy
Publication year - 2010
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200902145
Subject(s) - moiety , nitration , chemistry , peroxynitrite , thiouracil , tyrosine , stereochemistry , oxidative phosphorylation , medicinal chemistry , biochemistry , organic chemistry , superoxide , enzyme , medicine , thyroid
In this paper, the effect of some commonly used antithyroid drugs and their analogues on peroxynitrite‐mediated nitration of proteins is described. The nitration of tyrosine residues in bovine serum albumin (BSA) and cytochrome c was studied by Western blot analysis. These studies reveal that the antithyroid drugs methimazole (MMI), 6‐ n ‐propyl‐2‐thiouracil (PTU), and 6‐methyl‐2‐thiouracil (MTU), which contain thione moieties, significantly reduce the tyrosine nitration of both BSA and cytochrome c. While MMI exhibits good peroxynitrite (PN) scavenging activity, the thiouracil compounds PTU and MTU are slightly less effective than MMI. The S‐ and Se‐ methylated compounds show a weak inhibitory effect in the nitration of tyrosine, indicating that the presence of a thione or selone moiety is important for an efficient inhibition. Similarly, the replacement of NH moiety in MMI by N ‐methyl or N ‐ m ‐methoxybenzyl substituents dramatically reduces the antioxidant activity of the parent compound. Theoretical studies indicate that the substitution of NH moiety by NMe significantly increases the energy required for the oxidation of sulfur center by PN. However, such substitution in the selenium analogue of MMI increases the activity of parent compound. This is due to the facile oxidation of the selone moiety to the corresponding selenenic and seleninic acids. Unlike N,N′ ‐disubstituted thiones, the corresponding selones efficiently scavenge PN, as they predominantly exist in their zwitterionic forms in which the selenium atom carries a large negative charge.