title: Iron(III) complexes of fluorescent hydroxamate ligands: preparation, properties, and cellular processing.
abstract: Iron(III) complexes containing hydroxamic acid fluorophores were investigated as models of hypoxia selective prodrugs in vitro. Two complexes were synthesised, [Fe(c343haH)(3)] and [Fe(salen)(c343haH)]. The fluorescence of the hydroxamate coumarin fluorophore was almost completely quenched on coordination to the iron(III) centre in [Fe(c343haH)(3)]. However, quenching was minimal for [Fe(c343haH)(salen)] in aqueous media and we propose that the fluorescence results from structural rearrangements that occur because of the inherent strain in the iron-salen structure. Fluorescence was also measured in the presence of the cellular reductants ascorbic acid and cysteine. Fluorescence intensity increased over time, with the most rapid return of fluorescence occurring over a two hr period. The rapid fluorescence return indicates that the complexes undergo ligand release, either via reduction followed by aquation, or via direct ligand exchange with the reductants. Electrochemical studies demonstrated that both complexes have very negative reduction potentials. Furthermore, [Fe(c343haH)(salen)] was shown to exhibit quasi-reversibility of reduction. The distribution of the free hydroxamate ligand and the complexes were monitored in A2780 cells. The free ligand displayed non-specific distribution, which differed from the nucleolar distribution of [Fe(c343haH)(3)] and the lysosomal accumulation of [Fe(c343haH)(salen)] over time. Thus the results of the present study show that iron(III) complexes present a viable model for monitoring hydroxamate fluorophore displacement in vitro to determine the fate of prodrugs.
authors.affiliation: School of Chemistry, The University of Sydney, NSW 2006, Australia.
authors.forename: Antonia J
authors.initials: AJ
authors.lastname: Clarke
authors.forename: Natsuho
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Paul
authors.initials: P
authors.lastname: Jensen
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Hambley
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D005290:Ferric Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000737:chemistry*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D007501:Iron / Q000737:chemistry*; D008024:Ligands; D008968:Molecular Conformation; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet
chemical_list: D005290:Ferric Compounds; D005456:Fluorescent Dyes; D006877:Hydroxamic Acids; D008024:Ligands; D011355:Prodrugs; D007501:Iron