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

NMR Shielding and Antimalarial Drugs Angel C. de Dios

Georgetown University

13

160 150 140 130 120 110 100

' 'C

12

019

8

7

6

5

4

3

2

ppm

Chloroquine Resistance, Chloroquine Resistance, 20022002

http://www.cdc.gov/ travel/diseases/maps

Antimalarial DrugsAntimalarial Drugs

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)

Red Blood Cell Hemoglobin Digestion

Heme

Hemozoin

NH

N

NCl2

3

5

6

7

4

8

9

10

A

NCl

NH

OH

N

2

3

45

6

7

8

9

10

1'

4'

3'

2'

5'

6'

B

N

O

H

OH

N

2

3

456

7

8

9

10

1'2'

C

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

ChloroquineChloroquine

AmodiaquineAmodiaquine

QuinineQuinine

131.45

131.50

131.55

131.60

131.65

131.70

131.75

131.80

131.85

0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35

concentration (M)

tddmKC

KCobs YC

t

t 4

811

Quinine carbon 8

J. Phys. Chem. A, 108 (40), 8505 -8513, 2004

Quinine        

  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)

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

Interactions between drug molecules

0

0.5

1

1.5

2

2.5

3

3.5

0 0.01 0.02 0.03 0.04 0.05

E0/(Kd+S0)

1/T

1obs

1

2

3

4

5

6

7

8

9

10

11

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)

c

beN

r

SSgcomplexR

6

2222

0 1

4)(

Solution structures of drug-heme complexSolution structures of drug-heme complex

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

Tumambac, G. E.; Wolf, C. J. Org. Chem. 69, 2048 (2004)

Tumambac, G. E.; Wolf, C. J. Org. Chem. 70, 2930 (2005)

Experimental Chemical Shift*

Carbon I II 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

Chemical shifts and electron densitySearch for a Quantitative Structure-Activity Relationship (QSAR)

00

2 3

22

2

2

i i

ii

e

dxx

r

zy

cm

e

pd

0 0

3

2

2 00

2 q q

i

xi

i i

xi

e

pxx

EE

LqqrL

cm

e

Ramsey’s Equations for Calculating Chemical Ramsey’s Equations for Calculating Chemical ShieldingShielding

Ramsey, N. F. Phys. Rev. 1950, 78, 699-703. de Dios, A.C. Prog. NMR Spectrosc. 1996, 29, 229-278.

Shielding Tensors in Aromatic RingsShielding Tensors in Aromatic Rings

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

Difference

Carbon σ11 σ22 σ33 Isotropic

2 39.99 7.33 -6.82 13.50

3 -4.67 2.39 -7.36 -3.21

4 19.40 13.33 1.47 11.40

5 -2.07 -1.62 0.48 -1.07

6 -3.30 -4.09 1.20 -2.06

7 1.20 -4.91 1.36 -0.78

8 4.10 -8.22 27.53 7.80

9 -0.05 0.95 -8.67 -2.59

10 14.54 16.69 -18.63 4.20

Calculated Shielding DifferencesCalculated Shielding Differences

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

0

20

40

60

80

2 3 4 5 6 7 8 9 10

Carbon

Iso

tro

pic

Sh

ield

ing

(p

pm

)

Quinoline

Quinine

-100

-80

-60

-40

-20

0

2 3 4 5 6 7 8 9 10

Carbon

σ11 (

pp

m)

-40

-20

0

20

40

60

80

2 3 4 5 6 7 8 9 10

Carbon

σ22 (

pp

m)

100

120

140

160

180

200

2 3 4 5 6 7 8 9 10

Carbon

σ33 (

pp

m)

QuinineQuinine

Maps of Maps of 11 11 ““-electron density”-electron density”

-90

-70

-50

-30

-10

10

2 3 4 5 6 7 8 9 10

Carbon

σ11

(p

pm

)

0

20

40

60

80

100

2 3 4 5 6 7 8 9 10

Quinoline

Amodiaquine

Chloroquine

-100

-80

-60

-40

-20

0

2 3 4 5 6 7 8 9 10

Carbon

σ11 (

pp

m)

0

20

40

60

80

2 3 4 5 6 7 8 9 10

Quinoline

Quinine

B A B A

0102030405060708090

100

Iso

tro

pic

sh

ield

ing

-80

-70

-60

-50

-40

-30

-20

-10

0

10

σ11

-40

-20

0

20

40

60

80

100

σ22

110

120

130

140

150

160

170

180

σ33

Heme

Heme-DrugHeme-Drug

Heme-Drug Solution Heme-Drug Solution StructuresStructures

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)

Electron-RichElectron-RichElectron-PoorElectron-Poor

Substituted Substituted AminoquinolinesAminoquinolines

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)

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

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)

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

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

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

AcknowledgemeAcknowledgementsnts

• National Institutes of National Institutes of Health Health

• Georgetown UniversityGeorgetown University• Luce FoundationLuce Foundation• ARCS FoundationARCS Foundation

Prof. Paul Roepe, PhD

Leah Casabianca

Lyann Ursos, PhD

Alison Leed

Kateri DuBay

Devin Sears, PhD Caitlyn Faller

Prof. Christian Wolf, PhD

NIH (Robert Tycko’s group)