by synthetic hydroxypyridinone siderophores and exchange with desferrioxamine B J. M. Harrington , 1 S. Dhungana, 1 S. Chittamuru, 2 H. K. Jacobs, 2 A. S. Gopalan, 2 and A.L. Crumbliss 1 1 Department of Chemistry, Duke University, Durham, NC 27708-0346 and 2 Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, 88003-8001
Iron(III) sequestration by synthetic hydroxypyridinone siderophores and exchange with desferrioxamine B. J. M. Harrington , 1 S. Dhungana, 1 S. Chittamuru, 2 H. K. Jacobs, 2 A. S. Gopalan, 2 and A.L. Crumbliss 1 - PowerPoint PPT Presentation
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Iron(III) sequestration by synthetic hydroxypyridinone siderophores and exchange with desferrioxamine B
J. M. Harrington,1 S. Dhungana,1 S. Chittamuru,2 H. K. Jacobs,2 A. S. Gopalan,2 and A.L. Crumbliss1
1Department of Chemistry, Duke University, Durham, NC 27708-0346 and 2Department of Chemistry and
Biochemistry, New Mexico State University, Las Cruces, NM, 88003-8001
The Iron Paradox Precipitation of Fe(OH)3 (Fe2O3, etc.) Redox chemistry
O2.-O2
H2O2 OH HO-
Fe2+
Fe3+
+
Haber-Weiss Cycle
Able to Participate inHaber-Weiss Cycle
Synthetic Siderophores
N
OH
O
X
3-hydroxy-2-pyridinone
N NN N
O OHOHO
N2(LH)2
N N
N
N
OHO
N
O OH
N O
OH
N3(LH)3
N2(LH)2 synthesisNN NN
OH
O O
OH
N2(LH)2
N
O
BnO +
MeSO3-
N
O
N N N
O
ORRO
1. Piperazine, Et3N, CH3CN 55 °C
2. Conc. HBr/glacial acetic acid (1:1), rt
R = Bn (93%)R = H (93%)
• 2HBr
Lambert, T. N.; Chittamuru, S.; Jacobs, H. K.; Gopalan, A. S. Tetrahedron Lett., 2002, 43/41, 7379
N
OH
HO OEt
O
N
O
HOOEt
O
CsF, CH3CN, reflux, 74%
N
O
BnOOH
1. PhCH2Br, K2CO3CH3CN, reflux
2. BH3•THF, rt90% (both steps)
N
O
BnOOMs
1.(CH3SO2)2O, Et3N,CH2Cl2, 0 °C to rt
2.ChCl3, rt, 92%N+
BnO
O
MeSO4-
N2(LH)2 ThermodynamicsNN NN
OH
O O
OH
N2(LH)2
N NN N
O OHOHOH H
pKa1 pKa4
pKa3pKa2
pKa1 = 3.8 ± .1 pKa2 = 5.91
± .09 pKa3 = 7.94
± .05 pKa4 = 9.21
± .02
Fe-N2(LH)2 Competition
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
350 450 550 650 750
Wavelength (nm)
Ab
s
[EDTA] = 0 M
[EDTA] = 1.96 x 10-3 M
+ 2 EDTA
2 [Fe(EDTA)] + 3
[Fe3+] = 2.47 x 10-4 M, [N2(LH)2] = 3.70 x 10-4 M, T = 25 °C, μ = 0.10.
NN NNOH
O O
OH
N2(LH)2
232
22
232
2
]][)([
][])([
EDTALNFe
FeEDTALHNK
N
N
Fe
O O
O
O
N N
N
N
Fe
O
OO
NN
O
NN NNO
O O
O
N NN N
O OHOHO
Fe-N2(LH)2 spectrophotometric titration
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
350 450 550 650 750
Wavelength (nm)
Ab
s
pH 3.5
pH 7.5
553 nm
[Fe3+] = 2.0 x 10-4 M, [N2(LH)2] = 3.0 x 10-4 M, T = 25 °C, μ = 0.10.
NN NNOH
O O
OH
N2(LH)2
2 + + 2 OH-
]][)([][
])([
222
22
322
2
OHLHNLFeN
LNFeK
N
N
Fe
O O
O
O
N N
N
N
Fe
O
OO
NN
O
NN NNO
O O
O
N
N
Fe
O
OO
NN
O
OH2OH2
N NN N
O OHOHO
Log βFeLH of Fe-N2(LH)2
log β230 = 60.46 ± .02
log β110 = 20.39 ± .02
log β111 = 21.3 ± .1
NN NNOH
O O
OH
N2(LH)2
2 Fe3+ + 3 N2(LH)2
Fe3+ + N2(LH)2
Fe3+ + N2(LH)2 + H+
N
N
Fe
O O
O
O
N N
N
N
Fe
O
OO
NN
O
NN NNO
O O
O
N
N
Fe
O
OO
NN
O
OH2OH2
N
N
Fe
O
O
HO
NN
O
OH2OH2
OH2OH2
3 5 7 9 11pH
0
20
40
60
80
100
% fo
rma
tion
rela
tive to
Fe
Speciation for Fe-N2(LH)2 system
Fe(N2L2
)
Fe2(N2L2)
3
NN NNOH
O O
OH
N2(LH)2
Fe2(N2L2)3Fe(N2L2)
Fe3+
Fe(OH)4-
[Fe3+] = 2 x 10-4 M, [N2(LH)2] = 3 x 10-4 M, T = 25 °C, μ = 0.10.
N
N
Fe
O O
O
O
N N
N
N
Fe
O
OO
NN
O
NN NNO
O O
O
N
N
Fe
O
OO
NN
O
OH2OH2
Fe(OH)2+
N3(LH)3 synthesis
N
O
BnO +
RO
NO
RO
N N
N
N
OOR
N
O
MeSO3-
1. 1, 4,7-Triazacyclononane, Et3N, CH3CN, rt
R = Bn (83%)R = H (87%)
2. Conc. HBr/glacial acetic acid (1:1), rt
• 3HBr
N N
N
N
OHO
N
O OH
N O
OH
N3(LH)3
N3(LH)3 Thermodynamics
N N
N
N
OHO
N
O OH
N O
OH
H
H
pKa1
pKa2
pKa3
pKa4
pKa5
pKa1 = 3.97 ± .07
pKa2 = 5.1 ± .1 pKa3 = 7.50
± .02 pKa4 = 8.84
± .03 pKa5 = 10.40
± .04
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
210 230 250 270 290 310 330 350 370 390
Wavelength (nm)
Ab
s
N N
N
N
OHO
N
O OH
N O
OH
N3(LH)3
Fe(N3(LH)3)-EDTA Competition
[Fe+3] = [N3(LH)3] = 4 x 10-4 M, [EDTA] = 0-10:1 equivalents, T = 25 °C, μ =0.10.
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
350 450 550 650 750
Wavelength (nm)
Ab
s
[EDTA] = 0 M
[EDTA] = 4.0 x 10-3
+ EDTA
Fe(EDTA) +
EDTALHNFe
LHNFeEDTAKeff ))((
)(
33
33
FeO
OO
O
OON
N N
N
N
N
N
N N
N
NN O
OH
O
HO
O
HO
N N
N
N
OHO
N
O OH
N O
OH
N3(LH)3
Fe-N3(LH)3 spectrophotometric titration
0
0.2
0.4
0.6
0.8
1
1.2
350 450 550 650 750
Wavelength (nm)
Ab
s
551 nm
pH 2.9
pH 8.02
pKa = 3.10 pKa2 = 13.22
0
0.2
0.4
0.6
0.8
1
1.2
350 450 550 650 750
Wavelength (nm)
Ab
s
397 nm pH 10.44
pH 8.0
1K
OH
•[Fe3+] = [N3(LH)3] = 4.4 x 10-4 M, T = 25 °C, μ =0.10
2K
OH Fe
OOH
OO
OO
N N N
N
N
N
H2O
H2O
FeO
OO
O
OON
N N
N
N
N
H2O
FeO
OO
O
OON
N N
N
N
N
HO
N N
N
N
OHO
N
O OH
N O
OH
N3(LH)3
log βFeLH of N3(LH)3
log β110 = 27.34 ± .04
log β111 = 30.44 ± .08
log β11-1 = 17.66 ± .09
Fe3+ + N3(LH)3 + H+
Fe3+ + N3(LH)3
Fe3+ + N3(LH)3 + OH-
Fe
OOH
OO
OO
N N N
N
N
N
H2O
H2O
FeO
OO
O
OON
N N
N
N
N
H2O
FeO
OO
O
OON
N N
N
N
N
HO
N N
N
N
OHO
N
O OH
N O
OH
N3(LH)3
4 8 12pH
0
20
40
60
80
100
% form
ation relative to
Fe
Speciation for Fe-N3L3 system
Fe
OOH
OO
OO
N N N
N
N
N
H2O
H2O
FeO
OO
O
OON
N N
N
N
N Fe(N3L3)H
Fe(N3L3
)Fe(N3L3)H
[Fe3+] = 1 x 10-4 M, [N3(LH)3] = 1 x 10-4 M, T = 25 °C, μ = 0.10.
Fe(N3L3) Fe(N3L3)OH
Fe3+
Fe(OH)4-
Fe(OH)2+
FeO
OO
O
OON
N N
N
N
N
HO
Fe(N3L3)OH-
N N
N
N
OHO
N
O OH
N O
OH
N3(LH)3
pFe valuespFe = -log[Fe3+]free
Ligand pFe1
Deferiprone 19.42
Rhodotorulic Acid 21.903
N2(LH)2 22.074
N3(LH)3 23.494
Deferasirox 23.55
Deferrioxamine B 26.63
Enterobactin 35.63
1 – [Fe+3] = 10-6, [L] = 10-5, pH = 7.42 – Liu, et al, J. Med. Chem., 1999, 42, 48143 – Harris, et al, JACS, 1979, 101, 2722
4 - This work 5 - Steinhauser, et al, Eur. J. Inorg. Chem., 2004, 2004, 4177
Exchange kinetics of [FeN3L3] with Desferrioxamine B
Abs vs Wavelength (nm)
0
0.2
0.4
0.6
0.8
1
1.2
1.4
400 450 500 550 600 650
Wavelength (nm)
Ab
s
Fe(N3L3)
FeHDFB+
Abs 510 nm vs Time (min)
0.3
0.4
0.5
0.6
0.7
0.80.9
1
1.1
1.2
1.3
0 200 400 600 800 1000 1200
Time (min)
Ab
s 5
10
nm
Fit to single exponential decay kobs = 8.8 x 10-5 sec-1, k2nd, app = 0.0242 M-1 sec-1.
+ +N
N N
N
NN O
OH
O
HO
O
HO
N
O OH NHO
O
NHO
NH
O
O
NHO
H3N
FeO
OO
O
OON
N N
N
N
N
+ HH
H
NN
OO
Fe
HN
OO
O
NH
O
O
O
Proposed exchange mechanism
+
+
…N
N N
N
NN O
OH
O
HO
O
HO
N
O OH NHO
O
NHO
NH
O
O
NHO
H3N
FeO
OO
O
OON
N N
N
N
N
FeO
OO
O
OON
N N
N
N
N
N
OHOHN
O
O
N OH
NH
O
O
N
OH
NH3+
FeO
OO
O
OON
N N
N
N
N
N
OHOHN
O
O
N OH
NH
O
O
N
OH
NH3+
+
HH H
N
N
OO
Fe
HN
OO
O
NH
O
O
O
Conclusions N2(LH)2 is a stable chelator of iron, and could
provide insight into development of more effective chelation therapy treatments for iron overload.
We also characterized the complexation reactions of N3(LH)3 with iron, showing that it can bind iron effectively.
An exchange reaction can be observed between N3(LH)3 and deferrioxamine B, but not N2(LH)2, suggesting that host-guest interaction may be involved in exchange mechanism.
Acknowledgements Thanks: Dr. Al Crumbliss Esther Tristani The Crumbliss Lab Group Duke University Center for Biomolecular and Tissue