title: Inhibition of copper-mediated aggregation of human γD-crystallin by Schiff bases.
abstract: Protein aggregation, due to the imbalance in the concentration of Cu2+and Zn2+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 Cu2+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 Cu2+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 Cu2+-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 Cu2+-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 Cu2+-mediated aggregation of HGD.
authors.affiliation: Department of Chemistry, National Institute of Technology Hamirpur, Hamirpur, Himachal Pradesh, 177005, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Chauhan
authors.affiliation: Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamilnadu, 613401, India.
authors.forename: Sai Brinda
authors.initials: SB
authors.lastname: Muralidharan
authors.affiliation: Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamilnadu, 613401, India.
authors.forename: Anand Babu
authors.initials: AB
authors.lastname: Velappan
authors.affiliation: Department of Chemistry, Indian Institute of Science Education and Research Pune, Pune, Maharashtra, 411008, India.
authors.forename: Dhrubajyoti
authors.initials: D
authors.lastname: Datta
authors.affiliation: Department of Chemical Sciences, Tezpur University, Tezpur, 784 028, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Pratihar
authors.affiliation: Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamilnadu, 613401, India. joydebnath@scbt.sastra.edu.
authors.forename: Joy
authors.initials: J
authors.lastname: Debnath
authors.affiliation: Department of Chemistry, National Institute of Technology Hamirpur, Hamirpur, Himachal Pradesh, 177005, India. kalyan@nith.ac.in.
authors.forename: Kalyan Sundar
authors.initials: KS
authors.lastname: Ghosh
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D066329:Protein Aggregates / Q000187:drug effects*; D011994:Recombinant Proteins / Q000378:metabolism; D012545:Schiff Bases / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D038222:gamma-Crystallins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000975:Antioxidants; C504903:CRYGD protein, human; D066329:Protein Aggregates; D011994:Recombinant Proteins; D012545:Schiff Bases; D038222:gamma-Crystallins; D003300:Copper
keywords: Copper complex; Cu2+-induced aggregation inhibition; Schiff base; α-Crystallin; γ-Crystallin