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

Ahmed Aboelmagd; Samir M El Rayes; Mohamed S Gomaa; Walid Fathalla; Ibrahim A I Ali; Mohamed S Nafie; Faheem H Pottoo; Firdos Alam Khan; Mohamed M Ibrahim

doi:10.1021/acsomega.0c05263

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

ACS Omega. 2021 Feb 15;6(8):5244-5254. doi: 10.1021/acsomega.0c05263. eCollection 2021 Mar 2.

Authors

Ahmed Aboelmagd¹, Samir M El Rayes¹, Mohamed S Gomaa², Walid Fathalla³, Ibrahim A I Ali¹, Mohamed S Nafie¹, Faheem H Pottoo⁴, Firdos Alam Khan⁵, Mohamed M Ibrahim⁶

Affiliations

¹ Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
² Department of Pharmaceutical, College of Clinical Pharmacy, ImamAbdulrahman Bin Faisal University, P. O. Box 1982, Dammam 31441, Kingdom of Saudi Arabia.
³ Department of Physics and Math, Faculty of Engineering, Port-Said University, Port-Said 42526, Egypt.
⁴ Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P. O. Box 1982, Dammam 31441, Kingdom of Saudi Arabia.
⁵ Department of Stem Cell Research, Institute of Research and Medical consultations (IRMC), Imam Abdulrahman Bin Faisal University, P. O. Box 1982, Dammam 31441, Saudi Arabia.
⁶ Department of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.

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 IC₅₀ = 0.154 and 0.18 mM and additionally compounds 3, 4b, and 6a with IC₅₀ = 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.