application) Current strategies to prevent iron toxicity associated with transfusion induced hemosiderosis have a number of limitations. Desferrioxamine (Desferal) a tri-hydroxamate, is the most commonly used iron chelator. Desferal, is expensive, has a short half-life in vivo, does not efficiently remove iron from transferrin, must be given on a regular, frequent basis by a subcutaneous or intravenous route and its use can result in significant, irreversible toxicity. The bidentate dimethyl-3-hydroxypyridine-4-one, known as L1, DMHP, CP20 or Deferiprone, can catalyze iron removal from transferrin and has been shown to be effective when given orally. However, toxicity results with this agent, due in part to its thermodynamic instability and high concentration required to obtain a therapeutic effect. This application describes a plan to develop and evaluate a series of new iron chelating agents that are effective when administered orally and have no toxicity. Our hypothesis is that multidentate, rather than bidentate, hydroxypyridonate ligands will be effective as oral iron chelating agents and will not be toxic.
Our specific aims will be to synthesize a variety of multidentate hydroxypyridonate ligands that are structurally designed so that they can decorporate iron from transferrin at low concentrations, have a long half-life in vivo, are therapeutically effective at removing excess iron when administered orally and are not toxic. Using a number of synthetic chemical steps, a series of novel iron chelating compounds with unique chemical structures, which have the potential to meet the above criteria, will be synthesized. The thermodynamics stability and kinetics of removal of iron from human transferrin will be determined for each compound. Two iron overloaded animal models will be used to evaluate toxicity, biological routes of iron excretion, and ability to remove iron from tissue stores. Our ultimate goal is to develop a safe, oral, clinically effective iron-chelating agent that will prevent the toxicity of iron accumulation in patients who require chronic red cell transfusions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK057814-01
Application #
6090906
Study Section
Special Emphasis Panel (ZDK1-GRB-1 (J2))
Program Officer
Badman, David G
Project Start
2000-06-01
Project End
2005-04-30
Budget Start
2000-06-01
Budget End
2001-04-30
Support Year
1
Fiscal Year
2000
Total Cost
$245,809
Indirect Cost
Name
University of California Berkeley
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Hook-Barnard, India G; Hinton, Deborah M (2007) Transcription initiation by mix and match elements: flexibility for polymerase binding to bacterial promoters. Gene Regul Syst Bio 1:275-93
Jurchen, Kristy M Clarke; Raymond, Kenneth N (2006) Terephthalamide-containing analogues of TREN-Me-3,2-HOPO. Inorg Chem 45:1078-90
Abergel, Rebecca J; Raymond, Kenneth N (2006) Synthesis and thermodynamic evaluation of mixed hexadentate linear iron chelators containing hydroxypyridinone and terephthalamide units. Inorg Chem 45:3622-31
Jurchen, Kristy M Clarke; Raymond, Kenneth N (2006) A bidentate terephthalamide ligand, TAMmeg, as an entry into terephthalamide-containing therapeutic iron chelating agents. Inorg Chem 45:2438-47
Hamilton, David H; Turcot, Isabelle; Stintzi, Alain et al. (2004) Large cooperativity in the removal of iron from transferrin at physiological temperature and chloride ion concentration. J Biol Inorg Chem 9:936-44
Chua, Anita C G; Ingram, Helen A; Raymond, Kenneth N et al. (2003) Multidentate pyridinones inhibit the metabolism of nontransferrin-bound iron by hepatocytes and hepatoma cells. Eur J Biochem 270:1689-98
Doble, Dan M J; Melchior, Marco; O'Sullivan, Brendon et al. (2003) Toward optimized high-relaxivity MRI agents: the effect of ligand basicity on the thermodynamic stability of hexadentate hydroxypyridonate/catecholate gadolinium(III) complexes. Inorg Chem 42:4930-7
Barnes, Carmen M; Petoud, Stephane; Cohen, Seth M et al. (2003) Competition studies in horse spleen ferritin probed by a kinetically inert inhibitor, [Cr(TREN)(H(2)O)(OH)](2+), and a highly luminescent Tb(III) reagent. J Biol Inorg Chem 8:195-205
Xu, Jide; O'Sullivan, Brendon; Raymond, Kenneth N (2002) Hexadentate hydroxypyridonate iron chelators based on TREN-Me-3,2-HOPO: variation of cap size. Inorg Chem 41:6731-42