Role Of Hydrogen Bonding By Thiones In Protecting Biomolecules From Copper(I)-Mediated Oxidative Damage

The sulfur-containing antioxidant molecule ergothioneine with an ability to protect metalloenzymes from reactive oxygen species (ROS) has attracted significant interest in both chemistry and biology. Herein, we demonstrated the importance of hydrogen bonding in S-oxygenation reactions between various thiones and H2O2 and its significance in protecting the metal ion from H2O2-mediated oxidation. Among all imidazole- and benzimidazole-based thiones (1-10), Im(Me)S(H) (2) showed the highest reactivity toward H2O2-almost 10 and 75 times more reactive than N,N'-disubstituted Im(Me)S(Me) (5) and Bz(Me)S(Me) (10), respectively. Moreover, metal-bound Im(Me)S(H) (2) of [TpmCu(2)](+) (13) was found to be 51 and 1571 times more reactive toward H2O2 than the metal-bound Im(Me)S(Me) (5) of [TpmCu(5)](+) (16), and Bz(Me)S(Me) (10) of [TpmCu(10)](+) (21), respectively. The electron-donating N-Me substituent and the free N-H group at the imidazole ring played a very crucial role in the high reactivity of Im(Me)S(H) toward H2O2. The initial adduct formation between Im(Me)S(H) and H2O2 (Im(Me)S(H)center dot H2O2) was highly facilitated (-23.28 kcal mol(-1)) due to the presence of a free N-H group, which leads to its faster oxygenation than N,N'-disubstituted Im(Me)S(Me) (5) or Bz(Me)S(Me) (10). As a result, Im(Me)S(H) (2) showed a promising effect in protecting the metal ion from H2O2-mediated oxidation. It protected biomolecules from Cu(I)-mediated oxidative damage of through coordination to the Cu(I) center of [TpmCu(CH3CN)](+) (11), whereas metal-bound Im(Me)S(Me) or Bz(Me)S(Me) failed to protect biomolecules under identical reaction conditions.