Effect of the hydroxamate group in the antitumoral activity and toxicity toward normal cells of new copper(II) complexes

Abstract

The synthesis, physico-chemical characterization and cytotoxicity of four copper(II) coordination complexes, i.e. [Cu(HBPA)Cl₂] (1), [Cu(BHA)₂] (2), [Cu(HBPA)(BHA)Cl] CH₃OH (3) and [Cu(HBPA)₂]Cl₂·4H₂O (4), are reported. HBPA is the tridentate ligand N-(2-hydroxybenzyl)-N-(2-pyridylmethyl)amine and HBHA is the benzohydroxamic acid. The reaction between the HBHA and CuCl₂.2H₂O has resulted in the new complex (2) and the reaction between complex (1) and HBHA has resulted in the new complex (3). X-ray diffraction studies for complex (3) indicated the effective coordination of HBHA as BHA^-. Their cytotoxicity was evaluated against three human tumoral cell lines (Colo-205, NCI-H460 and U937) and PBMC (peripheral blood mononuclear cells), using the MTT cytotoxic assay. The results toward PBMC reveal that the new copper(II) complex (2) presents lower toxicity toward normal cells. Furthermore, complex (2) presents IC₅₀ values lower than cisplatin toward NCI-H460 and the best selectivity index obtained towards NCI-H460 (SI = 2.2) and U937 cell lines (SI = 2.0), as a result of the presence of two molecules of HBHA in its structure. Complex (3) presents IC₅₀ values lower than cisplatin toward NCI-H460, Colo-205 and comparable to cisplatin toward U937. The evaluation of the cell death type promoted by complexes (2) and (4) was investigated toward NCI-H460 revealing better results than the standard drug cisplatin, according to the Annexin V and propidium iodide (PI) labeling experiment. Based on the studies here performed, HBHA seems to be related to lower toxicity toward PBMC and HBPA is improving directly the cytotoxity.

Keywords: Antitumor activity; Apoptosis; Benzo hydroxamic acid (HBHA); Copper(II) complex; PBMC.