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

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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.

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References

  1. Miller LM, Wang Q, Telivala TP, Smith RJ, Lanzirotti A, Miklossy J (2006) Synchrotron-based infrared and X-ray imaging shows focalized accumulation of Cu and Zn co-localized with β-amyloid deposits in Alzheimer’s disease. J Struct Biol 15:530–537

    Google Scholar 

  2. Gaggelli E, Kozlowski H, Valensin D, Valensin G (2006) Copper homeostasis and neurodegenerative disorders (Alzheimer’s, prion, and Parkinson’s diseases and amyotrophic lateral sclerosis). Chem Rev 106:1995–2044

    Article  CAS  PubMed  Google Scholar 

  3. Davies KM, Bohic S, Carmona A, Ortega R, Cottam V, Hare DJ, Finberg JPM, Reyes S, Halliday GM, Mercer JFB, Double KL (2014) Copper pathology in vulnerable brain regions in Parkinson’s disease. Neurobiol Aging 35:858–866

    Article  CAS  PubMed  Google Scholar 

  4. Bonda DJ, Lee HG, Blair JA, Zhu X, Perry G, Smith MA (2011) Role of metal dyshomeostasis in Alzheimer disease. Metallomics 3:267–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hureau C, Faller P (2009) Aβ-mediated ROS production by Cu ions: structural insights, mechanisms and relevance to Alzheimer’s disease. Biochimie 91:1212–1217

    Article  CAS  PubMed  Google Scholar 

  6. Mayes J, Mill CT, Kolosov O, Zhang H, Tabner BJ, Allsop D (2014) β-amyloid fibrils in Alzheimer’s disease are not inert when bound to copper ions but can degrade hydrogen peroxide and generate reactive oxygen species. J Biol Chem 289:12052–12062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhu X, Su B, Wang X, Smith MA, Perry G (2007) Causes of oxidative stress in Alzheimer disease cell. Mol Life Sci 64:2202–2210

    Article  CAS  Google Scholar 

  8. Eskici G, Axelsen PH (2012) Copper and oxidative stress in the pathogenesis of Alzheimer’s disease. Biochemistry 51:6289–6311

    Article  CAS  PubMed  Google Scholar 

  9. Garland D (1990) Role of site-specific, metal-catalyzed oxidation in lens aging and cataract: a hypothesis. Exp Eye Res 50:677–682

    Article  CAS  PubMed  Google Scholar 

  10. Atalay A, Ogus A, Bateman O, Slingsby C (1998) Vitamin C induced oxidation of eye lens gamma crystallins. Biochimie 80:283–288

    Article  CAS  PubMed  Google Scholar 

  11. Garner B, Roberg K, Qian M, Brunk UT, Eaton JW, Truscott RJW (1999) Redox availability of lens iron and copper: implications for HO· generation in cataract. Redox Rep 4:313–315

    Article  CAS  PubMed  Google Scholar 

  12. Padgaonkar VA, Leverenz VR, Fowler KE, Reddy VN (2000) The effects of hyperbaric oxygen on the crystallins of cultured rabbit lenses: a possible catalytic role for copper. Exp Eye Res 71:371–383

    Article  CAS  PubMed  Google Scholar 

  13. Ortwerth BJ, James HL (1999) Lens proteins block the copper-mediated formation of reactive oxygen species during glycation reactions in vitro. Biochem Biophys Res Commun 259:706–710

    Article  CAS  PubMed  Google Scholar 

  14. Ahmad MF, Singh D, Taiyab A, Ramakrishna T, Raman B, Rao CM (2008) Selective Cu2+ binding, redox silencing, and cytoprotective effects of the small heat shock proteins αA- and αB-crystallin. J Mol Biol 38:2812–2824

    Google Scholar 

  15. Ganadu ML, Aru M, Mura GM, Coi A, Mlynarz P, Kozlowski H (2004) Effects of divalent metal ions on the alphaB-crystallin chaperone-like activity: spectroscopic evidence for a complex between copper (II) and protein. J Inorg Biochem 98:1103–1109

    Article  CAS  PubMed  Google Scholar 

  16. Biswas A, Das KP (2008) Zn2+ enhances the molecular chaperone function and stability of alpha-crystallin. Biochemistry 47:804–816

    Article  CAS  PubMed  Google Scholar 

  17. Horwitz J (1992) α-Crystallin can function as a molecular chaperone. Proc Natl Acad Sci 89:10449–10453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sampson LA, King J (2010) Partially folded aggregation intermediates of human γD-, γC-, and γS-crystallin are recognized and bound by human αB-crystallin chaperone. J Mol Biol 401:134–152

    Article  Google Scholar 

  19. Ghosh KS, Pande A, Pande J (2011) Binding of γ-crystallin substrate prevents the binding of copper and zinc ions to the molecular chaperone α-crystallin. Biochemistry 50:3279–3281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rasi V, Costantini S, Moramarco A, Giordano R, Giustolisi R, Gabrieli CB (1992) Inorganic element concentrations in cataractous human lenses. Ann Ophthalmol 24:459–464

    CAS  PubMed  Google Scholar 

  21. Srivastava VK, Varshney N, Pandey DC (1992) Role of trace elements in senile cataract. Acta Ophthalmol 70:839–841

    Article  CAS  Google Scholar 

  22. Cekic O (1998) Effect of cigarette smoking on copper, lead, and cadmium accumulation in human lens. Br J Ophthalmol 82:186–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Quintanar L, Domínguez-Calva JA, Serebryany E, Rivillas-Acevedo L, Haase-Pettingell C, Amero C, King JA (2016) Copper and zinc ions specifically promote nonamyloid aggregation of the highly stable human γ-D crystallin. ACS Chem Biol 11:263–272

    Article  CAS  PubMed  Google Scholar 

  24. Grossi C, Francese S, Casini A, Rosi MC, Luccarini I, Fiorentini A, Gabbiani C, Messori L, Moneti G, Casamenti F (2009) Clioquinol decreases amyloid-β burden and reduces working memory impairment in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis 17:423–440

    Article  CAS  PubMed  Google Scholar 

  25. Greenough MA, Camakaris J, Bush AI (2013) Metal dyshomeostasis and oxidative stress in Alzheimer’s disease. Neurochem Int 62:540–555

    Article  CAS  PubMed  Google Scholar 

  26. Oliveri V, Attanasio F, Puglisi A, Spencer J, Sgarlata C, Vecchio G (2014) Multifunctional 8-hydroxyquinoline-appended cyclodextrins as new inhibitors of metal-induced protein aggregation. Chem Eur J 20:8954–8964

    Article  CAS  PubMed  Google Scholar 

  27. Choi J, Braymer JJ, Nanga RPR, Ramamoorthy A, Lim MH (2010) Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity. Proc Natl Acad Sci 107:21990–21995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sharma AK, Pavlova ST, Kim J, Finkelstein D, Hawco NJ, Rath NP, Kim J, Mirica LM (2012) Bifunctional compounds for controlling metal-mediated aggregation of the Aβ42 peptide. J Am Chem Soc 134:6625–6636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gomes LMF, Vieira RP, Jones MR, Wang MCP, Dyrager C, Souza-Fagundes EM, Da JG, SilvaStorr T, Beraldo H (2014) 8-hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated Aβ peptide aggregation. J Inorg Biochem 139:106–116

    Article  CAS  PubMed  Google Scholar 

  30. Bareggi SR, Cornelli U (2012) Clioquinol: review of its mechanisms of action and clinical uses in neurodegenerative disorders. CNS Neurosci Ther 18:41–46

    Article  CAS  PubMed  Google Scholar 

  31. Cherny RA, Ayton S, Finkelstein DI, Bush AI, McColl G, Massa SM (2012) PBT2 reduces toxicity in a C. elegans model of polyQ aggregation and extends lifespan, reduces striatal atrophy and improves motor performance in the R6/2 mouse model of Huntington’s disease. J Huntingtons Dis 1:211–219

  32. Kumar BD, Rawat DS (2013) Synthesis and antioxidant activity of thymol and carvacrol based Schiff bases. Bioorg Med Chem Lett 23:641–645

    Article  PubMed  Google Scholar 

  33. Li C, Xu X, Wang XJ, Pan Y (2014) Imine resveratrol analogues: molecular design, Nrf2 activation and SAR analysis. PLoS One 9:e101455

    Article  PubMed  PubMed Central  Google Scholar 

  34. Huber D, Andermann G, Leclerc G (1988) Selective reduction of aromatic/aliphatic nitro groups by sodium sulfide. Tetrahedron Lett 29:635–638

    Article  CAS  Google Scholar 

  35. Leleu S, Papamicae C, Marsais F, Dupas G, Levacher V (2004) Preparation of axially chiral quinolinium salts related to NAD+ models: new investigations of these biomimetic models as ‘chiral amide-transferring agents. Tetrahedron Asymmetry 15:3919–3928

    Article  CAS  Google Scholar 

  36. Benesi HA, Hildebrand JH (1949) A spectrophotometric investigation of the interaction of iodine with aromatic hydrocarbons. J Am Chem Soc 71:2703–2707

    Article  CAS  Google Scholar 

  37. Kao S, Lin W, Venkatesan P, Wu S (2014) Colorimetric detection of Cu(II): Cu(II)-induced deprotonation of NH responsible for color change. Sens Actuators B 204:688–693

    Article  CAS  Google Scholar 

  38. Kim KB, Park GJ, Kim H, Song EJ, Bae JM, Kim C (2014) A novel colorimetric chemosensor for multiple target ions in aqueous solution: simultaneous detection of Mn(II) and Fe(II). Inorg Chem Commun 46:237–240

    Article  CAS  Google Scholar 

  39. Goswami S, Aich K, Das S, Das AK, Manna A, Halder S (2013) A highly selective and sensitive probe for colorimetric and fluorogenic detection of Cd2+ in aqueous media. Analyst 138:1903–1907

    Article  CAS  PubMed  Google Scholar 

  40. Ghule NV, Bhosale RS, Puyad AL, Bhosale SV, Bhosale SV (2016) Naphthalenediimide amphiphile based colorimetric probe for recognition of Cu2+ and Fe3+ ions. Sens Actuators B 227:17–23

    Article  CAS  Google Scholar 

  41. Frisch MJ et al (2009) Gaussian 03, revision D.02. Gaussian, Inc., Pittsburgh

  42. Shimada K, Fujikawa K, Yahara K, Nakamura T (1992) Antioxidative properties of xanthan on the autooxidation of soybean oil in cyclodextrin emulsion. J Agric Food Chem 40:945–948

    Article  CAS  Google Scholar 

  43. Pande A, Pande J, Asherie N, Lomakin A, Ogun O, King JA, Lubsen NH, Walton D, Benedek GB (2000) Molecular basis of a progressive juvenile-onset hereditary cataract. Proc Natl Acad Sci 97:1993–1998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Andley UP, Mathur S, Griest TA, Petrash JM (1996) Cloning, expression, and chaperone like activity of human alphaA-crystallin. J Biol Chem 271:31973–31980

    Article  CAS  PubMed  Google Scholar 

  45. Horwitz J, Huang QL, Ding L, Bova MP (1998) Lens alpha-crystallin: chaperone-like properties. Methods Enzymol 290:365–383

    Article  CAS  PubMed  Google Scholar 

  46. Spector A (1964) Methods of isolation of alpha, beta, and gamma crystallins and their subgroups. Invest Ophthalmol 3:182–193

    CAS  PubMed  Google Scholar 

  47. Wu G, Wang G, Fu X, Zhu L (2003) Synthesis, crystal structure, stacking effect and antibacterial studies of a novel quaternary copper (II) complex with quinolone. Molecules 8:287–296

    Article  CAS  Google Scholar 

  48. Wright JS, Johnson ER, DiLabio GA (2001) Predicting the activity of phenolic antioxidants: theoretical method, analysis of substituent effects, and application to major families of antioxidants. J Am Chem Soc 123:1173–1183

    Article  CAS  PubMed  Google Scholar 

  49. Chen W, Guo P, Song J, Cao W, Bian J (2006) The ortho hydroxy-amino group: another choice for synthesizing novel antioxidants. Bioorg Med Chem Lett 16:3582–3585

    Article  CAS  PubMed  Google Scholar 

  50. Bendary E, Francis RR, Ali HMG, Sarwat MI, Hady SE (2013) Antioxidant and structure–activity relationships (SARs) of some phenolic and anilines compounds. Ann Agric Sci 58:173–181

    Google Scholar 

  51. Ordoudi SA, Tsimidou MZ, Vafiadis AP, BakalBassis EG (2006) Structure-DPPH. Scavenging activity relationships: parallel study of catechol and guaiacol acid derivatives. J Agric Food Chem 54:5763–5768

    Article  CAS  PubMed  Google Scholar 

  52. Valgimigli L, Amorati R, Fumo MG, Dilabio GA, Pedulli GF, Ingold KU, Pratt DA (2008) The unusual reaction of semiquinone radicals with molecular oxygen. J Org Chem 73:1830–1841

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

KSG is grateful to Science and Engineering Research Board (SERB) under Department of Science and Technology (DST), Govt. of India, for funding through its sanctioned project (No. SB/FT/LS-277/2012). JD is grateful to DST (SB/FT/CS-008/2013), New Delhi, India, for financial support. AB thanks DST for a fellowship. JD is thankful to CARISM and CRF, SASTRA University, for availing their 300 MHz NMR and UV–Vis spectrophotometer. PC and KSG are thankful to CMSE, NIT Hamirpur, for providing some of the instrumentation facilities. KSG is also grateful to Prof. D. Balasubramanian, L.V. Prasad Eye Hospital, Hyderabad, and Prof. K.P. Das, Bose Institute, Kolkata, for proving the clones of HGD and HAA, respectively.

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Authors and Affiliations

  1. Department of Chemistry, National Institute of Technology Hamirpur, Hamirpur, Himachal Pradesh, 177005, India

    Priyanka Chauhan & Kalyan Sundar Ghosh

  2. Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamilnadu, 613401, India

    Sai Brinda Muralidharan, Anand Babu Velappan & Joy Debnath

  3. Department of Chemistry, Indian Institute of Science Education and Research Pune, Pune, Maharashtra, 411008, India

    Dhrubajyoti Datta

  4. Department of Chemical Sciences, Tezpur University, Tezpur, 784 028, India

    Sanjay Pratihar

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  1. Priyanka Chauhan
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Correspondence to Joy Debnath or Kalyan Sundar Ghosh.

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Chauhan, P., Muralidharan, S.B., Velappan, A.B. et al. Inhibition of copper-mediated aggregation of human γD-crystallin by Schiff bases. J Biol Inorg Chem 22, 505–517 (2017). https://doi.org/10.1007/s00775-016-1433-0

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