Two novel SNS-donor palladium(II) complexes of benzoxazole and benzothiazole derivatives as potential anticancer agentsPlease do not adjust margins

Abstract

Two novel mononuclear palladium(II) complexes, [PdL1Cl]Cl (1) and [PdL2Cl]Cl (2) with SNS-donor ligands (where L1= N-(4-(benzo[d]oxazol-2-yl)phenyl)-2-(bis(2-ethylthioethyl)amino)acetamide, L2 = N-(4-(benzo[d]thiazol)-2-yl)phenyl)-2-(bis(2-ethylthioethyl)amino)acetamide), were synthesized and characterized. In vitro antiproliferative activity tests showed that the two palladium(II) complexes displayed excellent antiproliferative activity against all the tested cancer cell lines, especially the human colon cancer HCT-116, the human liver cancer HepG-2, and the human breast cancer MDA-MB-231 cells. Spectacularly, complexes 1 and 2 exhibited an approximate 8.49- and 6.88-fold higher antiproliferative activity as compared with cisplatin against HCT-116, respectively, but were less toxic to the human normal colon fibroblast CCD-18Co cell lines with the selectivity index (SI  IC50(CCD-18Co)/IC50(HCT-116)) values of 22.43 and 21.48 for 1 and 2, respectively, compared to cisplatin (SI, 1.74). The results suggested that the two palladium complexes have the potential to act as a candidate for the treatment of colorectal cancer. The interaction of the complexes with CT-DNA illustrated that both 1 and 2 could strongly bind to the DNA helix via intercalative mode and covalent interaction and DNA binding affinity of 1 was slightly higher than that of 2. Additionally, investigations of the reaction of the two complexes with 5-GMP and glutathione (GSH) showed that both 1 and 2 could readily react with 5-GMP and GSH to form the Pd-GMP adducts and the Pd-GS adducts, respectively, and when 5-GMP and GSH coexisted, the coordination binding of the complexes with GSH did not prevent the formation of the Pd-GMP adducts. Moreover, Hoechst 33342 staining and flow cytometry analysis demonstrated that the two palladium(II) complexes arrested the HCT-116 cells mainly at the G2/M phase, induced mitochondrial membrane depolarization, increased ROS generation, and triggered obvious cell apoptosis.