Cu(II) and V(IV)O complexes with tri- or tetradentate ligands based on (2-hydroxybenzyl)-L-alanines reveal promising anticancer therapeutic potential

Four new ligand precursors (H2L1-H2L4), derived from the Mannich condensation of two amino acids (L-Val and L-Phe) and two 3,5-disubstituted phenols (t-Bu or Me), and the corresponding oxidovanadium(IV) (1-4) and copper(II) (6-7) complexes are synthesized. Two other related compounds (H2L5 and H2L6), containing an additional 2-methyl-pyridine arm, and the corresponding (VO)-O-IV (5) and Cu-II (8-9) complexes were also obtained. All metal complexes are monomeric in the solid state, having a solvent molecule or a chloride ion in the coordination sphere. The in vitro cytotoxic activity of all compounds is evaluated against cancer cells from different origins. The IC50 values at 72 h are in the range of 6-15 mu M for HeLa cells, 4-17 mu M for A-549 cells and >25 mu M for MDA-MB-231 cells, except for [(VOL1)-O-IV(CH3OH)] (1) and [CuL6(H2O)] (9). With the exception of H2L6, overall, the metal complexes are more cytotoxic than the corresponding ligand precursors. Globally, the cellular viability data show that (i) the L-Phe derived compounds are more cytotoxic than the corresponding L-Val complexes; (ii) the presence of the bulkier t-Bu groups increases the cytotoxicity; (iii) the presence of a 2-methyl-pyridine arm increases considerably the cytotoxicity; and (iv) the Cu-II-complexes are more cytotoxic than the (VO)-O-IV-compounds. Complexes [(VOL3)-O-IV(CH3OH)] (3), [CuL3(H2O)] (7) and [CuL5(H2O)] (8) were further evaluated and their mechanism of action was determined to be apoptosis, evidenced by AnnexinV staining and the increase in caspase 3/7 activity. Compounds 3, 7 and 8 also exhibit DNA cleavage activity, involving the formation of reactive oxygen species and were able to induce genomic damage in cells as determined by COMET assay.