Two novel SNS-donor palladium(<scp>ii</scp>) complexes of benzoxazole and benzothiazole derivatives as potential anticancer agents

Two novel mononuclear palladium(II) complexes, [PdL1Cl]Cl (1) and [PdL2Cl]Cl (2) with SNS-donor ligands [where L1 = <i>N</i>-(4-(benzo[<i>d</i>]oxazol-2-yl)phenyl)-2-(bis(2-ethylthioethyl)amino)acetamide, L2 = <i>N</i>-(4-(benzo[<i>d</i>]thiazol-2-yl)phenyl)-2-(bis(2-ethylthioethyl)amino)acetamide], were synthesized and characterized. <i>In vitro</i> antiproliferative activity tests showed that the two palladium(II) complexes displayed excellent antiproliferative activity against all tested cancer cell lines, especially human colon cancer HCT-116, human liver cancer HepG-2, and human breast cancer MDA-MB-231 cells. Spectacularly, complexes 1 and 2 exhibited approximately 8.49- and 6.88-fold higher antiproliferative activity, as compared with cisplatin, against HCT-116, respectively, but were less toxic to human normal colon fibroblast CCD-18Co cell lines with selectivity index (SI = IC₅₀(CCD-18Co)/IC₅₀(HCT-116)) values of 22.43 and 21.48 for 1 and 2, respectively, compared to that of cisplatin (SI, 1.74). These results suggested that the two palladium complexes have the potential to act as candidates for the treatment of colorectal cancer. The interaction of the complexes with CT-DNA and pUC19 plasmid DNA illustrated that both 1 and 2 could strongly bind to the DNA helix <i>via</i> an intercalative mode and covalent interaction and perturb the tertiary structure of DNA, where the 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 Pd-GMP adducts and 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 HCT-116 cells mainly at the G2/M phase, induced mitochondrial-membrane depolarization, increased ROS generation, and triggered obvious cell apoptosis.