Mixed Hydroxypyridinonate Ligands as Iron Chelators¹

Abstract

New ligands based on hydroxypyridinonate (HOPO) and other bidentate ligands are explored as iron(III) sequestering agents. These are based on the N,N',N"-tris[(3-hydroxy-1-methyl- 2-oxo-1,2-didehydropyrid-4-yl)-carboxamidoethyl]amine (TREN-Me-3,2-HOPO) platform in which one Me-3,2-HOPO ligand group is substituted with either a 2-hydroxyisophthalamide (TREN-Me-3,2-HOPOIAM) or a 2,3-dihydroxyterephthalamide (TREN-Me-3,2-HOPOTAM) moiety. The ferric complexes have been prepared and structurally characterized by X-ray diffraction: Fe[TREN-Me-3,2-HOPOIAM] crystallizes in the monoclinic space group C2/c with cell parameters a = 18.1186(3) A, b = 17.5926(2) A, c = 25.0476(2) A, beta = 98.142(1) degrees, Z = 8. Fe[TREN-Me-3,2-HOPOTAM]- crystallizes in the monoclinic space group C2/c with cell parameters a = 31.7556(12) A, b = 14.0087(6) A, c = 22.1557(9) A, beta = 127.919(1) degrees, Z = 8. The aqueous coordination chemistry of these ligands with both the ferric and ferrous redox states of iron has been examined using spectroscopic and electrochemical methods, giving log formation constants of 26.89(3) (beta 110), 31.16(6) (beta 111) for the ferric TREN-Me-3,2-HOPOIAM complexes and 33.89(2) (beta 110), 38.45(2) (beta 111) for the ferric TREN-Me-3,2-HOPOTAM complexes. For the reduced (ferrous) complexes values of 10.03(9) (beta 110) and 13.7(2) (beta 110) were observed for the Fe[TREN-Me-3,2-HOPOIAM]- and Fe[TREN-Me-3,2-HOPOTAM]2- complexes, respectively. These data provide a complete description of metal-ligand speciation as a function of pH and of redox activity. The ligands described in this work are part of a new class of heteropodate ligands which exploit the various chelating properties of several binding units within a single tripodal ligand and allow for systematic variation of the properties for medical or other applications.

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

“…Hexadentate hydroxypyridinone analogs. In another attempt to reduce the production of redox active partial complexes and increase complex stability, various hexadentate hydroxypyridinone analogs have been synthesized and analyzed (Streater et al, 1990;Cohen et al, 2000;Xu et al, 2002). One hexadentate ligand known as TREN-(Me-3,2-HOPO) (Fig.…”

Biotechnology of siderophores in high-impact scientific fields

“…The structural modification caused a differentiation in the lipophilicity of the molecule when compared to the parent molecule chelator. Other synthetic heteropodate iron and metal chelators have been developed which eventually could have medical applications (18).…”

Synthesis and Thermodynamic Evaluation of Mixed Hexadentate Linear Iron Chelators Containing Hydroxypyridinone and Terephthalamide Units1

“…7,8,11 Titration solutions and equipment Corning high performance combination glass electrodes (response to [H + ] was calibrated before each titration) 19 were used together with either an Accumet pH meter or a Metrohm Titrino to measure the pH of the experimental solutions. Metrohm autoburets (Dosimat or Titrino) were used for incremental addition of acid or base standard solutions to the titration cell.…”

“…4 While desferrioxamine B (Desferal ® ) has been the drug of choice for chelation therapy for the past forty years, the use of this natural siderophore still presents disadvantages, 5 and considerable effort has been invested in developing new iron chelating agents. [6][7][8][9][10][11][12] iron chelator, 13 the three hydroxamate binding units of desferrioxamine B are arranged in a linear fashion along a single chain, which may be part of the ligand's therapeutic advantage ( Figure 1). In this research project, a series of hexadentate ligands has been designed to investigate the effect on iron complex stability of the scaffold geometry and of the incorporation of specific binding units such as hydroxypyridinone (Me-3,2-HOPO) and terephthalamide (TAMmeg) units.…”

“…In this research project, a series of hexadentate ligands has been designed to investigate the effect on iron complex stability of the scaffold geometry and of the incorporation of specific binding units such as hydroxypyridinone (Me-3,2-HOPO) and terephthalamide (TAMmeg) units. [7][8][9]11 Previous studies showed that the iron complex stability increases markedly upon progressive replacement of Me-3,2-HOPO units by TAMmeg units on a TREN scaffold. 8 Moreover, incorporation of a bifunctional terephthalamide unit in the ligand backbone through alkylamine linkers provides linear ligands with high affinity for iron.…”