Chauhan Priyanka, Muralidharan Sai Brinda, Velappan Anand Babu, Datta Dhrubajyoti, Pratihar Sanjay, Debnath Joy, Ghosh Kalyan Sundar
Department of Chemistry, National Institute of Technology Hamirpur, Hamirpur, Himachal Pradesh, 177005, India.
Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamilnadu, 613401, India.
J Biol Inorg Chem. 2017 Jun;22(4):505-517. doi: 10.1007/s00775-016-1433-0. Epub 2017 Jan 5.
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.
由于铜离子和锌离子浓度失衡导致的蛋白质聚集被发现与各种生理紊乱有关。已知铜会促进老年眼晶状体中β/γ-晶状体蛋白的氧化损伤，并导致其聚集，进而引发白内障。因此，合成一种对铜具有互补抗氧化作用的小分子“螯合剂”，将在对抗β/γ-晶状体蛋白聚集方面找到潜在应用。在本文中，我们报道了不同席夫碱的合成，并研究了它们与铜的络合能力（使用紫外可见光谱、傅里叶变换红外光谱和电喷雾质谱）以及抗氧化活性。进一步基于它们的铜络合效率，席夫碱被用于抑制重组人γD-晶状体蛋白（HGD）和β/γ-晶状体蛋白（从白内障患者眼晶状体中分离）的铜介导聚集。在这些合成分子中，化合物8在浓度为100μM时，对100μM铜诱导的聚集表现出约95%的抑制作用。化合物8在浓度为5 - 15μM时，对人αA-晶状体蛋白（HAA）在铜诱导HGD聚集过程中的抑制活性也表现出正协同效应。最终，它使聚集过程额外抑制了约20%。然而，化合物8（100μM）对β/γ-晶状体蛋白（从白内障患者眼晶状体中分离）的铜介导聚集有50%左右的抑制作用。尽管亚胺的还原胺化产物由于其较低的铜络合能力而表现出更好的抗氧化活性，但发现它们对铜介导的HGD聚集无效。
