| Abstract
| - Cobalt(III) andaluminum(III) complexes of nordesferriferrithiocin,NDFFTH2, a derivative of the siderophore desferrithiocin,have been characterized in solution and in the solid state. Fiveisomers have been observed for the[Co(DFFT)2]- complex.Nordesferriferrithiocin complexes are more labile than those ofdesferrithiocin. Two isomers of[Al(DFFT)2]- have been separated bychromatography; the most stable is meridional. The stabilityconstants of these complexes have beendetermined.
- Nordesferriferrithiocin, NDFFTH2, is a derivative ofthe siderophore desferriferrithiocin, DFFTH2, in whichthemethyl group is substituted by a hydrogen atom. Both compoundsshow high oral activity as possible drugs forthe treatment of iron overload. While DFFTH2 issignificantly toxic, NDFFTH2 exhibits a lower toxicityandoffers a much better therapeutic window than other orally active ironchelators. In this study, complexes ofDFFTH2 and NDFFTH2 with various trivalentmetals have been synthesized and characterized. Fiveisomers(the maximum possible) have been observed in the case of[Co(DFFT)2]- in solution, as proved by1H-NMRmeasurements. Although normally labile, complexes ofAl3+ ([Al(DFFT)2]-) havebeen separated by HPLC. Ingeneral, DFFTH2 forms kinetically inert complexes whereascomplexes of NDFFTH2 tend to isomerize quicklyin solution, as indicated by CD spectroscopy of separated HPLCfractions of [Cr(NDFFT)2]-. Themost stableisomers of the aluminum complexes of both ligands have beencharacterized by X-ray crystallography; K[Al(DFFT)2] crystallizes from methanol/diethyl ether in theorthorhombic space group P21212 witha = 11.238(3)Å, b = 31.719(11) Å, c = 7.684(2)Å, V = 2739.2(24) Å3, and Z= 4. This isomer has themer-(N,O-Λ)(S,S)configuration, while K[Al(NDFFT)2] crystallizes frommethanol/diethyl ether in the space group P61(a = 21.269(8) Å, c = 9.643(3) Å, V =3777.8(42) Å3, Z = 6) and has the samecoordination geometry. The solutionthermodynamics of the Al3+, Ga3+, andFe3+ complexes have been studied by spectrophotometrictitration. Thestability constants (log K) are 23.6(1), 29.2(3),and 31.04(3), respectively, for the DFFTH2 complexesand 22.0(1), 27.8(2), and 29.09(3), respectively, for theNDFFTH2 complexes. Cyclic voltammograms of bothironcomplexes have been recorded in water at a carbon disk workingelectrode and in DMF at a graphite workingelectrode. The reduction waves measured in DMF indicate noreversibility whereas in water a quasi-reversiblereduction is observed. The reduction potentials(E1/2's) in water are −166 mV for[Fe(DFFT)2]- and −97 mVfor [Fe(NDFFT)2]- versus NHE.These potentials are well in the range for biological reductants,which makespossible an in vivo reduction mechanism for the iron removalfrom the siderophore.
|
