Iron(III) sequestration by synthetic hydroxypyridinone siderophores and exchange with desferrioxamine B J. M. Harrington, 1 S. Dhungana, 1 S. Chittamuru,

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Presentation transcript:

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 1 Department of Chemistry, Duke University, Durham, NC and 2 Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM,

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

Synthetic Siderophores

N 2 (LH) 2 synthesis

N 2 (LH) 2 Thermodynamics pK a1 = 3.8 ±.1 pK a2 = 5.91 ±.09 pK a3 = 7.94 ±.05 pK a4 = 9.21 ±.02

Fe-N 2 (LH) 2 Competition + 2 EDTA  2 [Fe(EDTA)] + 3 [Fe 3+ ] = 2.47 x M, [N 2 (LH) 2 ] = 3.70 x M, T = 25 °C, μ = 0.10.

Fe-N 2 (LH) 2 spectrophotometric titration [Fe 3+ ] = 2.0 x M, [N 2 (LH) 2 ] = 3.0 x M, T = 25 °C, μ = OH - 

Log β FeLH of Fe- N 2 (LH) 2 log β 230 = ±.02 log β 110 = ±.02 log β 111 = 21.3 ±.1 2 Fe N 2 (LH) 2  Fe 3+ + N 2 (LH) 2  Fe 3+ + N 2 (LH) 2 + H + 

Speciation for Fe-N 2 (LH) 2 system Fe(N 2 L 2 ) Fe 2 (N 2 L 2 ) 3 Fe(N 2 L 2 ) Fe 3+ Fe(OH) 4 - [Fe 3+ ] = 2 x M, [N 2 (LH) 2 ] = 3 x M, T = 25 °C, μ = Fe(OH) 2+

N 3 (LH) 3 synthesis

N 3 (LH) 3 Thermodynamics pK a1 = 3.97 ±.07 pK a2 = 5.1 ±.1 pK a3 = 7.50 ±.02 pK a4 = 8.84 ±.03 pK a5 = ±.04

Fe(N 3 (LH) 3 )-EDTA Competition [Fe +3 ] = [N 3 (LH) 3 ] = 4 x M, [EDTA] = 0- 10:1 equivalents, T = 25 °C, μ = EDTA  Fe(EDTA) +

Fe-N 3 (LH) 3 spectrophotometric titration pK a = 3.10pK a2 = [Fe 3+ ] = [N 3 (LH) 3 ] = 4.4 x M, T = 25 °C, μ =0.10

log β FeLH of N 3 (LH) 3 log β 110 = ±.04 log β 111 = ±.08 log β 11-1 = ±.09 Fe 3+ + N 3 (LH) 3 + H +  Fe 3+ + N 3 (LH) 3  Fe 3+ + N 3 (LH) 3 + OH - 

Speciation for Fe-N 3 L 3 system Fe(N 3 L 3 )H Fe(N 3 L 3 ) Fe(N 3 L 3 )H [Fe 3+ ] = 1 x M, [N 3 (LH) 3 ] = 1 x M, T = 25 °C, μ = Fe(N 3 L 3 ) Fe(N 3 L 3 )OH Fe 3+ Fe(OH) 4 - Fe(OH) 2+ Fe(N 3 L 3 )OH -

pFe values pFe = -log[Fe 3+ ] free LigandpFe 1 Deferiprone Rhodotorulic Acid N 2 (LH) N 3 (LH) Deferasirox Deferrioxamine B Enterobactin – [Fe +3 ] = 10 -6, [L] = 10 -5, pH = – Liu, et al, J. Med. Chem., 1999, 42, – Harris, et al, JACS, 1979, 101, This work 5 - Steinhauser, et al, Eur. J. Inorg. Chem., 2004, 2004, 4177

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

Host-Guest Complex EtOH/MeOH

Proposed Host-Guest complex DFB: N 3 (LH) 3 = 50:1 ESI-MS peak: Observed m/z = Proposed H 2 O adduct

Exchange kinetics of [FeN 3 L 3 ] with Desferrioxamine B Fit to single exponential decay k obs = 8.8 x sec -1, k 2nd, app = M -1 sec  +

Proposed exchange mechanism +   + ……

Conclusions N 2 (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 N 3 (LH) 3 with iron, showing that it can bind iron effectively. An exchange reaction can be observed between N 3 (LH) 3 and deferrioxamine B, but not N 2 (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 Engineering NIH NSF