New metal complexes of 1H-benzimidazole-2-yl hydrazones: Cytostatic, proapoptotic and modulatory activity on kinase signaling pathways
Year: 2024
Type: article
Abstract: The copper complexes of two 1 H -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-(1 H -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-(1 H -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. Copper complexes of 1 H -benzimidazole-2-yl hydrazones were synthesized and it was shown that the coordination significantly affects the cytotoxicity profile of the ligands. The proapoptotic and modulatory activity on key kinase signaling pathways was 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. • Cu complexes of 1 H -benzimidazole-2-yl hydrazones [CuLCl]. • Coordination process of both ligands significantly affects the cytotoxicity profile. • Modulatory activity on kinase signaling pathways in MCF-7 and AR-230. • Inhibition of JAK/STAT signaling pathway has key role in the antileukemic activity. • Recruitment and activation of the extrinsic apoptotic pathway in MCF-7.
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $2,940
OpenAlex ID: W4404852163