NMR Shielding and Antimalarial Drugs Angel C. de Dios Georgetown University

1. NMR Shielding and Antimalarial Drugs Angel C. de Dios Georgetown University 13 CARB-NMR Day 2006

2. Chloroquine Resistance, 2002 http://www.cdc.gov/ travel/diseases/maps

3. Antimalarial Drugs Red Blood CellHemoglobin Digestion Heme Hemozoin Pagola, S.; Stephens, P. W.; Bohle, D. S.; Kosar, A. D.; Madsen, S. K. Nature, 404, 307 (2000) Leed, A.; DuBay, K.; Ursos, L. M. B.; Sears, D. N.; de Dios, A. C.; Roepe, P. D. Biochemistry, 41, 10245 (2002)

4. Amodiaquine Chloroquine Quinine Casabianca, L. B.; de Dios, A. C. J. Phys. Chem. A,108 (40), 8505 -8513, (2004)

5. J. Phys. Chem. A,108 (40), 8505 -8513, 2004 Quinine carbon 8

6. Casabianca, L. B.; de Dios, A. C. J. Phys. Chem. A,108 (40), 8505 -8513, (2004)

7. Interactions between drug molecules Casabianca, L. B.; de Dios, A. C. Magn. Reson. Chem., 44, 276-282 (2006)

8. Solution structures of drug-heme complex Leed, A.; DuBay, K.; Ursos, L. M. B.; Sears, D. N.; de Dios, A. C.; Roepe, P. D. Biochemistry, 41, 10245 (2002) de Dios, A.C.; Casabianca, L.B.; Kosar, A.; Roepe, P.D. Inorg. Chem., 43, 8078-8084, (2004)

9. Biochemistry,41 (32), 10245 -10255, (2002)

10. Chemical shifts and p electron density Search for a Quantitative Structure-Activity Relationship (QSAR) Experimental Chemical Shift* I II Carbon Difference 2 165.5 152.2 -13.3 3 119.8 119.4 -0.4 4 147.9 137.5 -10.4 5 125.3 126.4 1.1 6 128.4 127.8 -0.6 7 125.1 129.8 4.7 8 129.4 120.8 -8.6 9 126.4 128.9 2.5 10 146.7 140.9 -5.8 1,8-bis(2-isopropyl-4-quinolyl)naphthalene Tumambac, G. E.; Wolf, C. J. Org. Chem.69, 2048 (2004) Tumambac, G. E.; Wolf, C. J. Org. Chem. 70, 2930 (2005)

11. Ramsey’s Equations for Calculating Chemical Shielding Ramsey, N. F. Phys. Rev. 1950, 78, 699-703. de Dios, A.C. Prog. NMR Spectrosc.1996, 29, 229-278.

12. Shielding Tensors in Aromatic Rings

13. Strub, H.; Beeler, A. J.; Grant, D. M.; Michl, J.; Cutts, P. W.; Zilm, K. W. J. Am. Chem. Soc., 105, 3333, (1983)

14. Calculated Shielding Differences Casabianca, L.B.; Faller, C.M. Faller; de Dios, A.C. J. Phys. Chem. A, 110, 234-240, (2006)

15. Quinine

16. Maps of 11 “-electron density” B A B A

17. Heme

18. Heme-Drug

19. Heme-Drug Solution Structures Electron-Rich Electron-Poor Leed, A.; DuBay, K.; Ursos, L. M. B.; Sears, D. N.; de Dios, A. C.; Roepe, P. D. Biochemistry41, 10245 (2002) de Dios, A. C.; Casabianca, L. B.; Kosar, A. D.; Roepe, P. D. Inorg. Chem. 43, 8078 (2004)

20. Substituted Aminoquinolines Log K values from Kaschula, C. H.; Egan, T. J.; Hunter, R.; Basilico, N.; Parapini, S.; Taramelli, D.; Pasini, E.; Monti, D. J. Med. Chem.45, 3531 (2002)

21. Solid State NMR Studies de Dios, A.C.; Tycko, R.; Ursos, L.M.B.; Roepe, P.D. J. Phys. Chem. A,107 (30), 5821 -5825, (2003)

22. de Dios, A.C.; Tycko, R.; Ursos, L.M.B.; Roepe, P.D. J. Phys. Chem. A,107 (30), 5821 -5825, (2003)

23. de Dios, A.C.; Tycko, R.; Ursos, L.M.B.; Roepe, P.D. J. Phys. Chem. A,107 (30), 5821 -5825, (2003)

24. de Dios, A.C.; Tycko, R.; Ursos, L.M.B.; Roepe, P.D. J. Phys. Chem. A,107 (30), 5821 -5825, (2003)

25. de Dios, A.C.; Tycko, R.; Ursos, L.M.B.; Roepe, P.D. J. Phys. Chem. A,107 (30), 5821 -5825, (2003)

26. Acknowledgements Alison Leed • National Institutes of Health • Georgetown University • Luce Foundation • ARCS Foundation Prof. Paul Roepe, PhD Lyann Ursos, PhD Leah Casabianca Prof. Christian Wolf, PhD Caitlyn Faller Devin Sears, PhD Kateri DuBay NIH (Robert Tycko’s group)