Cu(ii) and V(iv)O complexes with tri- or tetradentate ligands based on (2-hydroxybenzyl)-l-alanines reveal promising anticancer therapeutic potential

Abstract

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 V^IVO (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 μM for HeLa cells, 4-17 μM for A-549 cells and >25 μM for MDA-MB-231 cells, except for [V^IVOL¹(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 V^IVO-compounds. Complexes [V^IVOL³(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.