NMR Shielding and Antimalarial Drugs

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 Cell Hemoglobin 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
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Quinine        
  observed chemical shift observed chemical shift
Carbon 310 mM 9.5 mM ?d ?m
2 148.03 148.27 147.81 148.30
3 120.48 120.60 120.38 120.63
4 147.11 146.87 147.37 146.87
5 102.12 102.25 102.00 102.29
6 160.23 160.32 160.17 160.38
7 123.87 123.53 124.18 123.55
8 131.51 131.83 131.24 131.87
9 127.42 127.52 127.34 127.57
10 144.62 144.87 144.43 144.93
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)
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Biochemistry, 41 (32), 10245 -10255, (2002)
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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)
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Ramseys 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.
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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)
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Calculated Shielding Differences
Casabianca, L.B. Faller, C.M. Faller de Dios,
A.C. J. Phys. Chem. A, 110, 234-240, (2006)
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Quinine
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Maps of ?11 ?-electron density
B A
B A
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Heme
18
Heme-Drug
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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. Biochemistry 41,
10245 (2002) de Dios, A. C. Casabianca, L. B.
Kosar, A. D. Roepe, P. D. Inorg. Chem. 43, 8078
(2004)
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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)
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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)
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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)
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Acknowledgements

• National Institutes of Health
• Georgetown University
• Luce Foundation
• ARCS Foundation

Alison Leed
Prof. Paul Roepe, PhD
Lyann Ursos, PhD
Leah Casabianca
Prof. Christian Wolf, PhD
Caitlyn Faller
Devin Sears, PhD
Kateri DuBay
NIH (Robert Tyckos group)