Synthesis and Cytotoxic Activity of Novel Metal Complexes Derived from Methyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate as Potential CDK8 Kinase Inhibitors

Abstract

Several metal complexes of methyl-3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoate derivatives were synthesized and tested for their anti-tumor activities. The ligands include 3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanoic acid ( 1), 3-(4-chlorophenyl)-3-hydroxy-2,2-dimethylpropanehydrazide ( 2), and 3-(4-chlorophenyl)- N′-(4-(dimethylamino)benzylidene)-3-hydroxy-2,2-dimethylpropanehydrazide ( 3). The ligands were reacted with Cu (II), Ni (II), and La (III) ions. The formed complexes were characterized using elemental analysis (M%), molar conductivity in DMF (0.001 M), DTA, TG, FTIR, ICP-AES, and magnetic susceptibility. The chemical structures of the obtained complexes were interpreted, and their chemical formulas were postulated. The anti-cancer activities of these complexes were examined on human colorectal carcinoma cells (HCT-116) and also on normal cells (HEK-293). The 48 h post treatments showed that out of 12 compounds, 10 compounds showed inhibitory actions on HCT-116 cells, whereas two compounds did not show any inhibitory actions. Compounds 6c and 4a showed the highest inhibitory actions with IC ₅₀ = 0.154 and 0.18 mM and additionally compounds 3, 4b, and 6a with IC ₅₀ = 0.267, 0.205, and 0.284 mM, respectively. All tested compounds did not show any inhibitory action on normal HEK-293 cells. Molecular docking results provided a good evidence for activity of the lead compounds 3 and 4a as CDK8-CYCC kinase inhibitors, which may proposed the mechanism of action toward colon cancer therapy.