nmr shielding and antimalarial drugs angel c. de dios georgetown university
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NMR Shielding and Antimalarial Drugs Angel C. de Dios Georgetown University. 13. CARB-NMR Day 2006. Chloroquine Resistance, 2002. http://www.cdc.gov/ travel/diseases/maps. Antimalarial Drugs. Red Blood Cell Hemoglobin Digestion. Heme. Hemozoin. - PowerPoint PPT PresentationTRANSCRIPT
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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
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Chloroquine Resistance, Chloroquine Resistance, 20022002
http://www.cdc.gov/ travel/diseases/maps
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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
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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
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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
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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)
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Casabianca, L. B.; de Dios, A. C. Magn. Reson. Chem., 44, 276-282 (2006)
Interactions between drug molecules
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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
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Biochemistry, 41 (32), 10245 -10255, (2002)
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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)
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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.
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Shielding Tensors in Aromatic RingsShielding Tensors in Aromatic Rings
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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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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)
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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
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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
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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
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Heme-DrugHeme-Drug
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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
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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)
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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)
Solid State NMR Studies
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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)
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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)
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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)
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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)
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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)