Inhibition of copper-mediated aggregation of human γD-crystallin by Schiff bases.

Protein aggregation, due to the imbalance in the concentration of Cu and Zn ions is found to be allied with various physiological disorders. Copper is known to promote the oxidative damage of β/γ-crystallins in aged eye lens and causes their aggregation leading to cataract. Therefore, synthesis of a small-molecule 'chelator' for Cu with complementary antioxidant effect will find potential applications against aggregation of β/γ-crystallins. In this paper, we have reported the synthesis of different Schiff bases and studied their Cu complexation ability (using UV-Vis, FT-IR and ESI-MS) and antioxidant activity. Further based on their copper complexation efficiency, Schiff bases were used to inhibit Cu-mediated aggregation of recombinant human γD-crystallin (HGD) and β/γ-crystallins (isolated from cataractous human eye lens). Among these synthesized molecules, compound 8 at a concentration of 100 μM had shown ~95% inhibition of copper (100 μM)-induced aggregation. Compound 8 also showed a positive cooperative effect at a concentration of 5-15 μM on the inhibitory activity of human αA-crystallin (HAA) during Cu-induced aggregation of HGD. It eventually inhibited the aggregation process by additional ~20%. However, ~50% inhibition of copper-mediated aggregation of β/γ-crystallins (isolated from cataractous human eye lens) was recorded by compound 8 (100 μM). Although the reductive aminated products of the imines showed better antioxidant activity due to their lower copper complexing ability, they were found to be non-effective against Cu-mediated aggregation of HGD.