Structurally diverse zinc(II) complexes containing tripodal tetradentate phenoxido-amines with promising antiproliferative effects.

Structurally diverse zinc(II) complexes with tripodal tetradentate phenolic-amines of variable substituents in the phenol and amine moieties were synthesized and thoroughly characterized. The two dinuclear [Zn ₂ (L ¹ ) ₂ ](ClO ₄ ) ₂ ·MeOH (1), [Zn ₂ (L ² ) ₂ ](ClO ₄ ) ₂ (2), and four mononuclear [Zn(L ³ )(H ₂ O)]·MeOH (3), [Zn(L ⁴ )] (4), [Zn(L ⁵ )] (5) and [Zn(L ⁶ )] (6) complexes revealed distorted octahedral, trigonal-bipyramidal or tetrahedral geometries. The free HL1 and H2L3-6 ligands, and complexes 1-6 were evaluated for in vitro cytotoxicity against human cancer cell lines (A2780, A2780R, PC-3 and 22Rv1) and normal healthy MRC-5 cells. Overall results revealed high-to-moderate cytotoxicity (with the best IC ₅₀ values for complex 6 ranging from 2.4 to 4.5 μM), which is however, significantly higher than that of the reference drug cisplatin. The moderately active complexes 1-4 showed considerable selectivity on A2780 cells (IC ₅₀ ≈ 16.3-19.5 μM) over MRC-5 ones (with IC ₅₀ >50 μM for 1, 2 and 4, and with IC ₅₀ >25 μM for 3). The complexes 1, 2, and 6 and the ligand H2L6 were chosen for subsequent deeper biological evaluations. Their time-resolved cellular uptake and other cellular effects in A2780 cells were studied, such as cell cycle profile, intracellular ROS production, induction of apoptosis and activation of caspases 3/7. Complexes 1 and 2 caused significant G0/G1 cell cycle arrest in A2780 cells and antioxidant effects at normal conditions. They showed only limited effects on cellular processes connected with cytotoxicity, i.e. induction of apoptosis, depletion of mitochondrial membrane potential, and autophagy. These findings can be at least partly attributed to the low ability of the complexes to enter the A2780 cells and the depression of metabolic activity of the target cancer cells.