This proposal seeks continuation of support for a project to develop new approaches to the chelation therapy of human iron overload that is a consequence of beta-thalassemia (Cooley's anemia). The project will continue to focus on three goals: 1) The development of new ligands for Fee+. 2) The thermodynamic evaluation of new ligands. 3) The biological evaluation of new ligands. For goal #1, the failure of 3-hydroxy-l, 2- dimethyl-4(1H) -pyridinone (L1) in clinical trials has again emphasized the need for a new chelating agent for human iron overload. The research in our laboratories and the early promise of L1 continue to point toward hydroxypyridonate (HOPO) ligands as promising. However the limited thermodynamic stability of a simple bidentate ligand such as L1 makes such ligands poor candidates relative to analogous hexadentate ligands. We now have synthetic procedures to introduce either 3,4-HOPO or 3,2-HOPO ligand groups into hexadentate ligands with a geometry optimal for octahedral coordination to Fe3+. This has not been true of other hexadentate ligands reported to date. Several new - synthetic routes to 3,2- and 3,4-HOPO ligands have been found and are being explored. We have also found that the incorporation of one catechol group into a multidentate ligand such as desferrioxamine B (the trihydroxamate ligand in current clinical use) increases the rate of iron removal from the human iron transport protein transferrin by two orders of magnitude. It is proposed that this feature be exploited by combining catechol groups into mixed function ligands. The thermodynamic stability of new ligands with Fe3+ and competing physiological metal ions will be examined. An initial biological screen will be the rate of iron removal from transferrin. The kinetics and mechanisms of iron exchange with mammalian iron storage and transport proteins will be studied. Preliminary toxicity studies will be carried out in collaboration with Dr. P. Durbin. Screening for iron removal will be carried out for the most promising compounds in collaboration with Dr. R. Bergeron.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK032999-14
Application #
2138948
Study Section
Metallobiochemistry Study Section (BMT)
Program Officer
Badman, David G
Project Start
1983-11-30
Project End
1998-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
14
Fiscal Year
1995
Total Cost
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
Jurchen, Kristy M Clarke; Raymond, Kenneth N (2006) Terephthalamide-containing analogues of TREN-Me-3,2-HOPO. Inorg Chem 45:1078-90
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
Barnes, Carmen M; Theil, Elizabeth C; Raymond, Kenneth N (2002) Iron uptake in ferritin is blocked by binding of [Cr(TREN)(H(2)O)(OH)](2+), a slow dissociating model for [Fe(H(2)O)(6)](2+). Proc Natl Acad Sci U S A 99:5195-200
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
Sunderland, C J; Botta, M; Aime, S et al. (2001) 6-carboxamido-5,4-hydroxypyrimidinones: a new class of heterocyclic ligands and their evaluation as gadolinium chelating agents. Inorg Chem 40:6746-56
Johnson, A R; O'Sullivan, B; Raymond, K N (2000) Synthesis of a ligand based upon a new entry into the 3-hydroxy-N-alkyl-2(1H)-pyridinone ring system and thermodynamic evaluation of its gadolinium complex. Inorg Chem 39:2652-60
Cohen, S M; O'Sullivan, B; Raymond, K N (2000) Mixed hydroxypyridinonate ligands as iron chelators. Inorg Chem 39:4339-46
Turcot, I; Stintzi, A; Xu, J et al. (2000) Fast biological iron chelators: kinetics of iron removal from human diferric transferrin by multidentate hydroxypyridonates. J Biol Inorg Chem 5:634-41
Yokel, R A; Fredenburg, A M; Durbin, P W et al. (2000) The hexadentate hydroxypyridinonate TREN-(Me-3,2-HOPO) is a more orally active iron chelator than its bidentate analogue. J Pharm Sci 89:545-55