1. Conclusions and Future Work Results and Discussion
Comparison of the Electrochemical Properties of Iron and Copper Complexes with Tris(pyrazolyl), Thiolate, and Selenolate Ligands Christopher C. Underwood*, Martin M. Kimani*, Joseph A. Giesen§, Rajashree Sathyamurthy*, Julia L. Brumaghim* *Department of Chemistry, Clemson University, Hunter Laboratories, Clemson, SC §Department of Chemistry, Sewanee: The University of the South, Woods Laboratories, Sewanee, TN 37383
Introduction
Experimental Design
The most abundant transition metals in the human body and other organisms are iron and copper.1 These metals have an important role in Fenton-type reactions:
Fe2+ or Cu+ + H2O2 → Fe3+ or Cu2+ + HO• + OH-
These reactions yield hydroxyl radical that damages DNA, leading to cancer, neurodegenerative and cardiovascular diseases.2,3 Sulfur- and selenium-containing antioxidants have been shown to prevent DNA damage from metal-generated hydroxyl radical.4-8 Studies by Brumaghim et al. have shown that metal coordination is required for the observed antioxidant activity.4-8
Our research involves the study of how selenium and sulfur act to prevent oxidative damage of DNA upon coordination to iron and copper. To achieve this, biologically relevant iron and copper selenolate and thiolate complexes were synthesized and characterized. Ligands such as tris(3,5-dimethylpyrazolyl)-methane (Tpm*), tris(3,5-diisopropylpyrazolyl)methane (TpmiPr)10, and tris(3,5-dimethylpyrazolyl)borate (Tp*) are used to synthesize the target metal complexes, since they mimic metal coordination environments in biological systems. Selenium and sulfur ligands used include diphenyl diselenide, diphenyl disulfide, N,N’-1,3-dimethylimidazolethione (SMe2Im), and N,N’-1,3-dimethyl-imidazoleselone (SeMe2Im).
Syntheses of [Fe(SePh)4](PPh4)2 and [Fe(SPh)4](PPh4)2 were conducted as reported.9 [Tpm*Cu(NCCH3)](BF4) and [TpmiPrCu(NCCH3)](PF6) were synthesized as reported.10 Copper selenone complexes were synthesized via reaction of a methanolic solution of (Tpm*)CuCl and (TpmiPr)CuCl10 with NaSeMe2Im, and was extracted using toluene and dried in vacuuo. 1H NMR and 77Se NMR confirmed formation of our target products.
Cyclic voltammetry (CV) experiments were carried out using a Ag/AgCl reference electrode, and converted to potentials vs. NHE. Trials for the iron complexes were conducted in CH3CN and in CH2Cl2 for the copper complexes, with 0.1 mM complex and 0.1 M tetra-n-butylammonium hexaflurophosphate (TBAPF6). Solutions were blanketed with nitrogen during experiments. Formal potentials were evaluated as E0 = (Epa+Epc)/2, where Epa and Epc are anodic and cathodic peak potentials. Peak potential separations were evaluated as ΔE = |Epa-Epc| relative to the ferrocene/ferricenium couple (0.46 V).
R = B, n = 1
C, n = 0
R1 = CH3, iPr
R2 = C5H8N2Se
Conclusions and Future Work
Project Goals
(1) Synthesize complexes that mimic the binding of iron and copper to both DNA
and selenium- and sulfur-containing amino acids to copper and iron.
(2) Determine and compare the changes in electrochemical potentials of iron and
copper when bound to these ligands.
Figure 1: Complexes under investigation
Addition of selenium or sulfur ligands stabilize Fe(II) over Fe(III), and addition of a selenium ligand stabilizes Cu(I) over Cu(II)
Addition of selenium or sulfur ligands to iron or copper complexes significantly lowers the redox potential of the metals
Because antioxidant activity of selenium and sulfur require metal binding, lower redox potentials upon selenium or sulfur binding may inhibit metal ion reduction and subsequent hydroxyl radical generation in vivo
In future, we plan to test the reactivity of these target metal complexes with hydrogen peroxide
Complex
E0 (V)
Tp*2Fe
0.241
[Tpm*Cu(NCCH3)](BF4)
0.121
[Tp*Fe(NCCH3)3]OTf
0.776
Tpm*CuCl
-0.110
[Tpm*2Fe](OTf)2
0.971
[TpmiPrCu(NCCH3)](PF6)
0.094
[Tpm*Fe(NCCH3)3](OTf)2
0.761
TpmiPrCuCl
-0.565
[Fe(SPh)4](PPh4)2
-0.277
Tpm*CuSeMe2Im
-0.790
[Fe(SePh)4](PPh4)2
-0.068
TpmiPrCuSeMe2Im
-0.746
Results and Discussion
References
Table 1: Fe2+/3+ and Cu+/2+ potentials for target complexes (E0 vs. NHE)
The cyclic voltammetry of metal complexes shown in Figure 1 were carried out, and the results are shown in Table 1
Mono-tris(pyrazolyl) complexes have reversible Fe2+/3+ potentials from to V and copper complexes have quasi-reversible Cu+/2+ potentials from to V
The more cationic the complex, the higher the Fe2+/3+ and Cu+/2+ potentials
The iron complexes [Fe(SPh)4](PPh4)2 and [Fe(SePh)4](PPh4)2 have the lowest iron redox potentials: and V, respectively
Addition of selenium ligands to Tpm*CuCl formed Tpm*CuSeMe2Im and changed the Cu+/2+ redox potential by V and in the similar reaction with TpmiPrCuCl, changed the TpmiPrCuSeMe2Im reduction potential by V
Iron and copper complexes with selenium or sulfur ligands showed complex electrochemistry due to the selenium or sulfur ligand
Coordination of a single selenium ligand to copper lowers the Cu+/2+ potential significantly below the ability of cellular reductants to reduce Cu2+ to the hydroxyl radical generating Cu+
S. J. Lippard, J. M. Berg Principles of Bioinorganic Chemistry, University Science Books, Mill Valley, 1994, ,
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M. Valko, et al. Chem. Biol. Interact. 2006, 160, 1-40.
Battin, E. E.; Perron, R. N.; Brumaghim, J. L. Inorg. Chem. 2006, 45,
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Battin, E. E.; Brumaghim J. L. J. Inorg. Biochem. 2008, in press.
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Fe(bipy) V
Rusticyanins V
H2O2 / OH + OH V
Plastocyanins V
NAD(P)H / NAD(P) V
NO reductase V
Cu(bipy)2, Fe2transferrin V
0.6
0.4
0.2
-0.2
-0.4
Redox potentials (V vs. NHE) at pH 7
Fe2+ and Cu+ cannot be oxidized
Approximate range for
oxidation  0.8 V
Fe3+ and Cu2+ cannot be reduced
Acknowledgements
The authors would like to thank the Clemson University chemistry department, NSF CAREER award CHE , and NSF-sponsored Clemson University Summer Undergraduate Research Program (CU-SURP) for funding this work.
Figure 2: Electrochemical potentials of iron and
copper in biological systems11