New metal complexes of 1H-benzimidazole-2-yl hydrazones: Cytostatic, proapoptotic and modulatory activity on kinase signaling pathways

Abstract

The copper complexes of two 1H-benzimidazole-2-yl hydrazones were obtained by complexation with copper chloride. The molecular structure of the complexes was studied by microchemical analysis, SEM-EDX, IR and micro-Raman spectroscopy and DFT calculations. It was found that both ligands form 1:1 complexes with the copper, where the Cu ions are coordinated by N-atom from the benzimidazole ring, N-atom of the azomethine bond, O-atom from the ortho-OH group of the aromatic ring and one chlorine atom. The coordination process significantly affected their cytotoxicity profile. The conversion of 2-(2-hydroxybenzylidene)-1-(1H-benzimidazol-2-yl)hydrazine 1.1. into a Cu complex 2.1. led to a 2.4-fold increase in its antileukemic activity against AR-230 cells and an 8-fold increase in the cytostatic activity against MCF-7 breast cancer cell line. The growth-inhibitory effect of the Cu complex of 2-(2-hydroxy-4-methoxybenzylidene)-1-(1H-benzimidazol-2-yl)hydrazine 2.2. on the MCF-7 cells was comparable to that of the respective ligand, however lacked towards the leukemic AR-230 cell population. Regarding their cytotoxic potential towards CCL-1 cells, both Cu complexes exhibited a weaker selectivity pattern as compared to their ligands. The proapoptotic and modulatory activity of 1.1 and 2.1. on key kinase signaling pathways was further studied in the ER + breast cancer (MCF-7) and bcr-abl + leukemic (AR-230) in vitro tumor models in a comparative manner to the reference drugs tamoxifen and imatinib, respectively. Inhibition of the JAK/STAT signaling pathway was outlined as a prominent mechanism in the antileukemic activity against the Ph + AR-230 in vitro model, whereas recruitment and activation of the extrinsic apoptotic pathway was established in the MCF-7 cells.