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Zinc in Brain

Tailoring Tripodal Ligands for Zinc Sensing MARM 2008 05/20/2008 Zhaohua Dai Department of Chemistry & Physical Sciences, NY zdai@pace.edu. Zinc in Brain. The second most abundant transition metal in human body Stimulates ~200 enzymes and proteins More Zn 2+ in brain than in any other organ

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Zinc in Brain

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  1. Tailoring Tripodal Ligands for Zinc Sensing MARM 200805/20/2008Zhaohua DaiDepartment of Chemistry & Physical Sciences, NYzdai@pace.edu

  2. Zinc in Brain • The second most abundant transition metal in human body • Stimulates ~200 enzymes and proteins • More Zn2+ in brain than in any other organ • Zn2+ and Cu2+ are implicated in Alzheimer’s, Parkinson’s, and Amyotrophic Lateral Sclerosis (ALS) • Complicated roles • Tools are needed to image Zn2+ distribution and kinetics High sensitivy Poor Zn(II)/Cu(II) selectivity TSQ, Zinquin M. P. Cuajungco, G. J. Lees, R. R. Kydd, R. E. Tanzi, A. I. Bush, Nutr. Neurosci., 1999, 2(4), 191 C. J. Fahrni and T. V. O’Halloran, J. Am. Chem. Soc., 1999, 121, 11448 Koh et al. Science 1996, 272, 1013–1016

  3. Tripodal Ligands for Zinc Sensing

  4. Our First Generation Tripods 1 2 log Zn2+ Cu2+ 11.00 16.15 Zn2+/Cu2+ selectivity 10-5 Castagnetto, J.M.; Canary, J.W. Chem. Commun., 1998, 203 Anderegg, G. et al.Helv. Chim. Acta1977, 60, 123-140

  5. Sensitivity: 8-Hydroxyquinoline Based Tripods

  6. Ratiometric Time-Resolved Fluorescence No added Zn2+ f (1) = 0.64 ns f (2) = 24.9 ns Treated with zinc pyrithione A549 Cells Royzen, M.; Durandin, A.; Young, Jr., V.G.; Geacintov, N.E.; Canary, J.W. J. Am. Chem. Soc.,2006, 128, 3854-5.

  7. Chiral Fluorescent Probes for Zn2+ Higher Zn2+/Cu2+Selectivity Stereochemical Control 2. Better contrast Fertile Optical Information: Differential Circularly Polarized Fluorescence Excitation (CPE)

  8. Strategy to Higher Zn/Cu Selectivity: Preorganized Chiral Ligands The design of a metal ion selective ligand must involve a high degree of preorganization for a specific metal ion and also a high degree of ‘disorganization’ or ‘mismatch’ for other metal ions. ------------- Peter Comba Podands Piperidines Comba, P. Coord. Chem. Rev.1999, 185-186, 81

  9. Inner Sphere Requirements CuII d9 ZnII d10 STRONG GEOMETRICAL REQUIREMENTS FOR COORDINATION TO METAL 4 GEOMETRY DICTATED ONLY BY STERICS 3 Xu, X. E. A. Ambundo, M.-V. Deydier, A. J. Grall, N. Aguera-Vega, L. T. Dressel, T. H. Cooper, M. J. Heeg, L. A. Ochrymowycz and D. B. Rorabacher, Inorg. Chem., 1999, 38, 4233

  10. Binding Constants log Cu2+ Zn2+ 14.8 10.1 12.0 11.2 Zn2+/Cu2+ selectivity TPA: 10-5 10-1 10-4 Obtained by Xu, X. through potentiometric titration

  11. Fluorescent Sensors LIGHT BITE 16 Dai, Z.; Xu, X.; Canary, J.W. Chem. Commun., 2002, 1414-5.

  12. Zn(II)/Cu(II) Selectivity 17 16 Zn2+ 7.44 7.08 Cu2+7.647.06 Zn/Cu 0.6 1.0 logb

  13. More Highly Preorganized Chiral Ligangds Piperidines Quinuclidines

  14. Representative Synthesis

  15. X-Ray Structure of Cu(II) Complexes

  16. Stereochemical Approach to Improved Zn(II)/Cu(II) Selectivity Zn2+ 11.0 7.1 8.95 Cu2+ 16.157.17.0 10-5 1 90* logb Zn2+/Cu2+ Selectivity: 15% acetonitrile/aqueous buffer pH 7.19 * Z. Dai, et al. unpublished

  17. Increase Contrast: Reducing Background Chiral Fluorescent Sensors: Fertile Optical Information: Differential Circularly Polarized Fluorescence Excitation (CPE) • Lower sensor background • Diminish background from non-analyte

  18. Fluorescence-detected Circular Dichroism (FDCD) DF = J-8100 Circular Dichroism System with FDCD Attachment Two channels of data Conversion Nehira; Berova; Nakanishi; et al. J. Am. Chem. Soc. 1999, 121, 8681

  19. Differential Circularly Polarized Fluorescence Excitation (CPE) CPE utilized only DF part of FDCD raw data for analysis. q: CD ellipticity; F: Fluorescence quantum yield. Changes in DF will be very large when changes in BOTH fluorescence AND circular dichroism are large.

  20. Zn2+ CPE Reduces Background from Free Ligand Ellipticity  /mdeg Relative Intensity If Zn2+ /nm /nm [Zn(L)]2+ Zn2+ CPE F Free ligand Dai, Z.; Proni, G.; Mancheno, D.; Karimi, S.; Berova, N.; Canary, J.W. J. Am. Chem. Soc., 2004,126, 11760 /nm

  21. CPE SELECTS AGAINST PROTEIN-BASED BACKGROUND FLUORESCENCE Zn2+ Relative Intensity If Ellipticity  /mdeg Zn2+ Lysozyme /nm /nm Lysozyme CPEF Lysozyme + [Zn(L)]2+ Zn2+ Dai, Z.; Proni, G.; Mancheno, D.; Karimi, S.; Berova, N.; Canary, J.W. J. Am. Chem. Soc., 2004,126, 11760 /nm

  22. Tailoring Tripodal Ligands for Zinc Sensing Zhaohua Dai and James W. Canary,  New J. Chem., 2007, 31, 1708-1718.

  23. Conclusion Achieved solid Zn(II)/Cu(II) selectivity through a stereochemical approach Developed a new approach for analysis: CPE CPE may be used to improve contrast in detecting metal ions by fluorescent, chiral ligands with low background CPE may be used to diminish interference from fluorescent non-analytes CPE needs further development

  24. Chiral Fluorescent Sensor for Hg2+ We intend to use these ligands to further develop CPE.

  25. Acknowledgement • Prof. James W. Canary (NYU) • Prof. Nina Berova • Mike Isaacman • Cho Tan • Amanda Mickley • Patrick Carney • Nikhil Khosla NSF (JWC) Pace University (Startup Fund, Scholarly Research Fund, Kenan Award)

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