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Synthesis and iron sequestration equilibria of novel exocyclic 3-hydroxy-2-pyridinone donor group siderophore mimics.

Publication ,  Journal Article
Harrington, JM; Chittamuru, S; Dhungana, S; Jacobs, HK; Gopalan, AS; Crumbliss, AL
Published in: Inorganic chemistry
September 2010

The synthesis of a novel class of exocyclic bis- and tris-3,2-hydroxypyridinone (HOPO) chelators built on N(2) and N(3) aza-macrocyclic scaffolds and the thermodynamic solution characterization of their complexes with Fe(III) are described. The chelators for this study were prepared by reaction of either piperazine or N,N',N''-1,4,7-triazacyclononane with a novel electrophilic HOPO iminium salt in good yields. Subsequent removal of the benzyl protecting groups using HBr/acetic acid gave bis-HOPO chelators N(2)(etLH)(2) and N(2)(prLH)(2), and tris-HOPO chelator N(3)(etLH)(3) in excellent yields. Solution thermodynamic characterization of their complexes with Fe(III) was accomplished using spectrophotometric, potentiometric, and electrospray ionization-mass spectrometry (ESI-MS) methods. The pK(a)'s of N(2)(etLH)(2), N(2)(prLH)(2), and N(3)(etLH)(3), were determined spectrophotometrically and potentiometrically. The Fe(III) complex stability constants for the tetradentate N(2)(etLH)(2) and N(2)(prLH)(2), and hexadentate N(3)(etLH)(3), were measured by spectrophotometric and potentiometric titration, and by competition with ethylenediaminetetraacetic acid (EDTA). N(3)(etLH)(3) forms a 1:1 complex with Fe(III) with log β(110) = 27.34 ± 0.04. N(2)(prLH)(2) forms a 3:2 L:Fe complex with Fe(III) where log β(230) = 60.46 ± 0.04 and log β(110) = 20.39 ± 0.02. While N(2)(etLH)(2) also forms a 3:2 L:Fe complex with Fe(III), solubility problems precluded determining log β(230); log β(110) was found to be 20.45 ± 0.04. The pFe values of 26.5 for N(3)(etLH)(3) and 24.78 for N(2)(prLH)(2) are comparable to other siderophore molecules used in the treatment of iron overload, suggesting that these hydroxypyridinone ligands may be useful in the development of new chelation therapy agents.

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Published In

Inorganic chemistry

DOI

EISSN

1520-510X

ISSN

0020-1669

Publication Date

September 2010

Volume

49

Issue

18

Start / End Page

8208 / 8221

Related Subject Headings

  • Spectrophotometry
  • Siderophores
  • Pyridines
  • Protons
  • Ligands
  • Iron
  • Inorganic & Nuclear Chemistry
  • 3403 Macromolecular and materials chemistry
  • 3402 Inorganic chemistry
  • 0399 Other Chemical Sciences
 

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Harrington, J. M., Chittamuru, S., Dhungana, S., Jacobs, H. K., Gopalan, A. S., & Crumbliss, A. L. (2010). Synthesis and iron sequestration equilibria of novel exocyclic 3-hydroxy-2-pyridinone donor group siderophore mimics. Inorganic Chemistry, 49(18), 8208–8221. https://doi.org/10.1021/ic902595c
Harrington, James M., Sumathi Chittamuru, Suraj Dhungana, Hollie K. Jacobs, Aravamudan S. Gopalan, and Alvin L. Crumbliss. “Synthesis and iron sequestration equilibria of novel exocyclic 3-hydroxy-2-pyridinone donor group siderophore mimics.Inorganic Chemistry 49, no. 18 (September 2010): 8208–21. https://doi.org/10.1021/ic902595c.
Harrington JM, Chittamuru S, Dhungana S, Jacobs HK, Gopalan AS, Crumbliss AL. Synthesis and iron sequestration equilibria of novel exocyclic 3-hydroxy-2-pyridinone donor group siderophore mimics. Inorganic chemistry. 2010 Sep;49(18):8208–21.
Harrington, James M., et al. “Synthesis and iron sequestration equilibria of novel exocyclic 3-hydroxy-2-pyridinone donor group siderophore mimics.Inorganic Chemistry, vol. 49, no. 18, Sept. 2010, pp. 8208–21. Epmc, doi:10.1021/ic902595c.
Harrington JM, Chittamuru S, Dhungana S, Jacobs HK, Gopalan AS, Crumbliss AL. Synthesis and iron sequestration equilibria of novel exocyclic 3-hydroxy-2-pyridinone donor group siderophore mimics. Inorganic chemistry. 2010 Sep;49(18):8208–8221.
Journal cover image

Published In

Inorganic chemistry

DOI

EISSN

1520-510X

ISSN

0020-1669

Publication Date

September 2010

Volume

49

Issue

18

Start / End Page

8208 / 8221

Related Subject Headings

  • Spectrophotometry
  • Siderophores
  • Pyridines
  • Protons
  • Ligands
  • Iron
  • Inorganic & Nuclear Chemistry
  • 3403 Macromolecular and materials chemistry
  • 3402 Inorganic chemistry
  • 0399 Other Chemical Sciences