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The Iron Paradox

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

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The Iron Paradox

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  1. 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

  2. The Iron Paradox Able to Participate in Haber-Weiss Cycle • Precipitation of Fe(OH)3 (Fe2O3, etc.) • Redox chemistry

  3. Synthetic Siderophores

  4. N2(LH)2 synthesis

  5. N2(LH)2 Thermodynamics • pKa1 = 3.8 ± .1 • pKa2 = 5.91 ± .09 • pKa3 = 7.94 ± .05 • pKa4 = 9.21 ± .02

  6. Fe-N2(LH)2 Competition + 2 EDTA D 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.

  7. Fe-N2(LH)2 spectrophotometric titration • [Fe3+] = 2.0 x 10-4 M, [N2(LH)2] = 3.0 x 10-4 M, T = 25 °C, μ = 0.10. + 2 OH-D 2 +

  8. Log βFeLH of Fe-N2(LH)2 • log β230 = 60.46 ± .02 • log β110 = 20.39 ± .02 • log β111 = 21.3 ± .1 2 Fe3+ + 3 N2(LH)2D Fe3+ + N2(LH)2D Fe3+ + N2(LH)2 + H+D

  9. Speciation for Fe-N2(LH)2 system Fe(N2L2) Fe2(N2L2)3 Fe3+ Fe(N2L2) Fe(OH)2+ Fe(OH)4- Fe2(N2L2)3 [Fe3+] = 2 x 10-4 M, [N2(LH)2] = 3 x 10-4 M, T = 25 °C, μ = 0.10.

  10. N3(LH)3 synthesis

  11. N3(LH)3 Thermodynamics • pKa1 = 3.97 ± .07 • pKa2 = 5.1 ± .1 • pKa3 = 7.50 ± .02 • pKa4 = 8.84 ± .03 • pKa5 = 10.40 ± .04

  12. 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. + EDTA D Fe(EDTA) +

  13. Fe-N3(LH)3 spectrophotometric titration pKa = 3.10 pKa2 = 13.22 • [Fe3+] = [N3(LH)3] = 4.4 x 10-4 M, T = 25 °C, μ =0.10

  14. 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)3D Fe3+ + N3(LH)3 + H+D Fe3+ + N3(LH)3 + OH-D

  15. Speciation for Fe-N3L3 system Fe(N3L3) Fe(N3L3)OH Fe3+ Fe(N3L3)H Fe(OH)4- Fe(OH)2+ Fe(N3L3) Fe(N3L3)H Fe(N3L3)OH- [Fe3+] = 1 x 10-4 M, [N3(LH)3] = 1 x 10-4 M, T = 25 °C, μ = 0.10.

  16. pFe values pFe = -log[Fe3+]free 1 – [Fe+3] = 10-6, [L] = 10-5, pH = 7.4 2 – Liu, et al, J. Med. Chem., 1999, 42, 4814 3 – Harris, et al, JACS, 1979, 101, 2722 4 - This work 5 - Steinhauser, et al, Eur. J. Inorg. Chem., 2004, 2004, 4177

  17. Host-Guest complex formation Batinic-Haberle, I.; Spasojevic, I.; Crumbliss, A. L.; Inorg. Chem.; 1996, 35(8), 2352-2359. Dhungana, S.; White, P. S.; Crumbliss, A. L.; JACS; 2003, 125(48), 14760-14767.

  18. Host-Guest Complex EtOH/MeOH EtOH/MeOH

  19. Proposed Host-Guest complex • DFB: N3(LH)3 = 50:1 • ESI-MS peak: • Observed m/z = 1121.5 • Proposed H2O adduct

  20. Exchange kinetics of [FeN3L3] with Desferrioxamine B • Fit to single exponential decay • kobs = 8.8 x 10-5 sec-1, k2nd, app = 0.0242 M-1 sec-1. + D +

  21. Proposed exchange mechanism + D + D… D

  22. 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.

  23. Acknowledgements • Thanks: • Dr. Al Crumbliss • Esther Tristani • The Crumbliss Lab Group • Duke University • Center for Biomolecular and Tissue Engineering • NIH • NSF

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