Nordesferriferrithiocin. Comparative Coordination Chemistry of a Prospective Therapeutic Iron Chelating Agent(1)

Nordesferriferrithiocin, NDFFTH(2), is a derivative of the siderophore desferriferrithiocin, DFFTH(2), in which the methyl group is substituted by a hydrogen atom. Both compounds show high oral activity as possible drugs for the treatment of iron overload. While DFFTH(2) is significantly toxic, NDFFTH(2) exhibits a lower toxicity and offers a much better therapeutic window than other orally active iron chelators. In this study, complexes of DFFTH(2) and NDFFTH(2) with various trivalent metals have been synthesized and characterized. Five isomers (the maximum possible) have been observed in the case of [Co(DFFT)(2)](-) in solution, as proved by (1)H-NMR measurements. Although normally labile, complexes of Al(3+) ([Al(DFFT)(2)](-)) have been separated by HPLC. In general, DFFTH(2) forms kinetically inert complexes whereas complexes of NDFFTH(2) tend to isomerize quickly in solution, as indicated by CD spectroscopy of separated HPLC fractions of [Cr(NDFFT)(2)](-). The most stable isomers of the aluminum complexes of both ligands have been characterized by X-ray crystallography; K[Al(DFFT)(2)] crystallizes from methanol/diethyl ether in the orthorhombic space group P2(1)2(1)2 with a = 11.238(3) Å, b = 31.719(11) Å, c = 7.684(2) Å, V = 2739.2(24) Å(3), and Z = 4. This isomer has the mer-(N,O-Lambda)(S,S) configuration, while K[Al(NDFFT)(2)] crystallizes from methanol/diethyl ether in the space group P6(1) (a = 21.269(8) Å, c = 9.643(3) Å, V = 3777.8(42) Å(3), Z = 6) and has the same coordination geometry. The solution thermodynamics of the Al(3+), Ga(3+), and Fe(3+) complexes have been studied by spectrophotometric titration. The stability constants (log K) are 23.6(1), 29.2(3), and 31.04(3), respectively, for the DFFTH(2) complexes and 22.0(1), 27.8(2), and 29.09(3), respectively, for the NDFFTH(2) complexes. Cyclic voltammograms of both iron complexes have been recorded in water at a carbon disk working electrode and in DMF at a graphite working electrode. The reduction waves measured in DMF indicate no reversibility whereas in water a quasi-reversible reduction is observed. The reduction potentials (E(1/2)'s) in water are -166 mV for [Fe(DFFT)(2)](-) and -97 mV for [Fe(NDFFT)(2)](-) versus NHE. These potentials are well in the range for biological reductants, which makes possible an in vivo reduction mechanism for the iron removal from the siderophore.