Antitumor activity of copper(II) complexes with Schiff bases derived from N'-tosylbenzene-1,2-diamine

Abstract

The electrochemical oxidation of anodic metal copper in a solution of the ligands N-[(5-tert-butyl-2-hydroxyphenyl)methylidine]-N'-tosylbenzene-1,2-diamine [H₂L¹] and N-[(3,5-di-tert-butyl-2-hydroxyphenyl)methylidine]-N'-tosylbenzene-1,2-diamine, [H₂L²] afforded homoleptic [CuL] compounds or solvate [CuLS] complexes. The addition to the electrochemical cell of coligands (L') such as 2,2'-bipyridine (2-bpy), 4,4'-bipyridine(4-bpy) or 1,10-phenanthroline (phen) allowed the synthesis, in one step, of heteroleptic [CuLL'] compounds, namely [CuL¹(H₂O)] (1), [CuL¹(2,2'-bpy)]⋅CH₃CN (2), [CuL¹(phen)]·H₂O (3), [Cu₂L¹₂(4,4'-bpy)] (4), [CuL²(CH₃OH)] (5), [CuL²(2,2'-bpy)] (6), [CuL²(phen)] (7) and [Cu₂L²₂(4,4'-bpy)] (8). The crystal structures of both ligands, H₂L¹, H₂L², and those of the complexes (2), (4), (5), (6) and (7) have been determined by X-ray diffraction techniques. Coordination polyhedron around metal atom is square planar for [CuL²(CH₃OH)] (5) and [Cu₂L¹₂(4,4'-bpy)] (4) and square pyramid for the other complexes with additional chelating ligands. The cytotoxic activity of this new series of copper(II) complexes against the SH-SY5Y neuroblastoma cell line and U87-MG and U373-MG glioblastoma cell lines has been investigated. Most of the test compounds showed higher activity than cisplatin in the three cell lines. Among this series, compound [CuL¹(phen)] (3) displayed the highest activity with IC₅₀ equal to 1.77 μM on SH-SY5Y whereas compound [Cu₂L¹₂(4.4'-bpy)] (4) resulted the most potent compounds on U87 MG and U373 MG glioblastoma cell lines. Studies on the cytotoxic activity of these derivatives suggest that these compounds induce cell death by a mechanism other than apoptosis.

Keywords: Antitumoral activity; Copper; Electrochemical synthesis; Hydrogen bonds; Schiff bases ligands; Stacking interactions; Structure elucidation.