Vanadium(V) Pyridine‐Containing Schiff Base Catecholate Complexes are Lipophilic, Redox‐Active and Selectively Cytotoxic in Glioblastoma (T98G) Cells

Abstract

Two new series of complexes with pyridine‐containing Schiff bases, [VVO(SALIEP)L] and [VVO(Cl‐SALIEP)L] (SALIEP = N‐(salicylideneaminato)‐2‐(2‐aminoethylpyridine; Cl‐SALIEP = N‐(5‐chlorosalicylideneaminato)‐2‐(2‐aminoethylpyridine, L = catecholato(2‐) ligand) were synthesized. Characterization by 1H and 51V NMR and UV‐Vis spectroscopies confirmed that: 1) most complexes form two major geometric isomers in solution, and [VVO(SALIEP)(DTB)] (DTB = di‐tert‐butylcatecholato(2‐)) forms two isomers that equilibrate in solution; and 2) tert‐butyl substituents was necessary to stabilize the reduced V(IV) species (EPR spectroscopy and cyclic voltammetry). The pyridine moiety within the Schiff base ligands significantly changed their chemical properties with unsubstituted catecholate ligands compared with the parent HSHED (N‐(salicylideneaminato)‐Nˊ‐(2‐hydroxyethyl)‐1,2‐ethanediamine) Schiff base complexes. Immediate reduction to V(IV) occurred for the unsubstituted‐catecholato V(V) complexes on dissolution in DMSO. By contrast, the pyridine moiety within the Schiff base significantly improved the hydrolytic stability of [VVO(SALIEP)(DTB)] compared with [VVO(HSHED)(DTB)]. [VVO(SALIEP)(DTB)] had moderate stability in cell culture media. There was significant cellular uptake of the intact complex by T98g (human glioblastoma) cells and very good anti‐proliferative activity (IC50 6.7 ± 0.9 μM, 72 h), which was ~five‐fold higher compared with the non‐cancerous human cell line, HFF‐1 (IC50 34 ± 10 μM). This made it a potential drug candidate for the treatment of advanced gliomas by intracranial injections.

Substitution Kinetics, Albumin and Transferrin Affinities, and Hypoxia All Affect the Biological Activities of Anticancer Vanadium(V) Complexes

“…Notably, the UV–vis–NIR spectrum of 1 in aqueous media in the presence of HSA resembled that in polar nonaqueous solvents, such as DMSO (Figure S12 in SI), which is consistent with the noncovalent binding of intact complex 1 to hydrophobic pockets of HSA. , The presence of HSA, but not Tf, also significantly changed the UV–vis–NIR spectra of decomposition products of 1 in neutral aqueous media (Figures b and S12). The presence of new absorbance bands at ∼530 and ∼930 nm in the spectra of decomposition products of 1 in the presence of HSA (red line in Figure b) pointed to the formation of V­(IV) species , (see SI for details).…”

“…The Schiff base ligand hydrolyzed further to the aldehyde and amine precursors. , In addition, oxido-V­(V) species reacted with the components of the cell culture medium to probably form a mixture of five-coordinate V­(V) and six-coordinate V­(IV) species, designated as V­(V/IV)-medium in Figure . Recently, the reduction of noninnocent V­(V) Schiff base complexes related to 1 to their V­(IV) counterparts under biologically relevant conditions has been reported . These V­(V/IV) species efficiently bind to the metal-binding sites of Tf; a proposed structure of the binding site is shown as V­(V/IV)-Tf in Figure .…”

“…53,100 The presence of HSA, but not Tf, also significantly changed the UV−vis− NIR spectra of decomposition products of 1 in neutral aqueous media (Figures 6b and S12). The presence of new absorbance bands at ∼530 and ∼930 nm in the spectra of decomposition products of 1 in the presence of HSA (red line in Figure 6b) pointed to the formation of V(IV) species 101,102 (see SI for details). 1 and Figures 3−5) of two closely related V(V) complexes, 1 and 2 (Figure 1).…”

“…Recently, the reduction of noninnocent V(V) Schiff base complexes related to 1 to their V(IV) counterparts under biologically relevant conditions has been reported. 102 These V(V/IV) species efficiently bind to the metal-binding sites of Tf; 54 a proposed structure of the binding site 34 is shown as V(V/IV)-Tf in Figure 7.…”

Halogenated non-innocent vanadium(v) Schiff base complexes: chemical and anti-proliferative properties

“…8,9,20 The key properties of the most potent anti-cancer complexes from this series are complexes that contain a sterically hindered catechol and high hydrophobicity. 8,9,20–22 However, little is known about the effects of electronics on the biological properties of the compounds. Considering the reported effects of electronics on the HOMO–LUMO gap, 7 we set out to investigate the effects of a range of substituents on complex stability, biological activity, and electrochemistry as the electronic substituents were changed.…”