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.

Introducing Metallosalens into Biological Studies: The Renaissance of Traditional Coordination Complexes

“…However, Fe(salen) probes could be functionalized with extra fluorescent appendants. Fe(salen) with an axial coumarin hydroxamate ligand has a negative reduction potential and the intracellular fluorescence increases along with the axial ligand release, possibly through a process of reduction of the metal center . It is noteworthy that whereas the free coumarin ligand displays non‐specific distribution, the Fe(salen) complex shows lysosomal accumulation of the coumarin fluorescence (Figure ).…”

“…(B–C) Fluorescent imaging pictures of A2780 cells. Reprinted, with permission, from ref . Copyright 2009, Royal Society of Chemistry.…”

“…Some Fe(salen)s show cytotoxicity specific to tumor cells while normal cells remain unaffected . Furthermore, Fe(salen)s are also used for drug delivery and magnetic resonance imaging, as mentioned above, making them candidates as multi‐functional theranostic agents.…”

Synthesis, characterization and magnetic study of two new octahedral iron(III) complexes with pendant zwitterionic Schiff bases

“…Among them, H 2 salen type tetradentate Schiff bases, prepared by 1:2 condensations of any diamines with salicylaldehyde derivatives, are, of course, receiving the most attention [20][21][22][23][24]. In the octahedral iron(III)-salen complexes with other co-ligands, two different arrangements of four donor atoms around the iron(III) is found; one in which the donors occupy the four equatorial positions [25][26][27][28][29] the other in which one oxygen is displaced from the equatorial plane, occupying an axial position of the coordination polyhedron [30][31][32][33].…”

DNA interaction of CuII, NiII and ZnII functionalized salphen complexes: studies by linear dichroism, gel electrophoresis and PCR

“…Several DNA binding studies of metal complexes of salentype ligands have been reported in the literature. [10][11][12][13][14][15][16] For example, it has been recently reported that some salphen complexes are able to stabilize human telomeric quadruplex DNA structures, potential targets for novel anticancer drugs. 10,[17][18][19] In previous studies some of us reported on the interaction between native DNA and nickel(II), copper(II) and zinc(II) complexes of N,N′-bis-5-(triethyl ammonium methyl salicylidene)-1,2-phenylenediamine (see Fig.…”