Synthesis and biological evaluation of six L-tryptophan Schiff base copper(II) complexes as promising anticancer agents in vitro

Abstract

Six copper(II) complexes, [Cu(sal-trp)(phen)]·0.5H2O·0.5CH2Cl2·CH3OH (1), Cu(o-van-trp)(phen) (2), [Cu(naph-trp)(phen)]·H2O (3), Cu(sal-trp)(bipy) (4), Cu(o-van-trp)(bipy) (5) and Cu(naph-trp)(bipy) (6) [sal = salicylaldehyde; trp = L-tryptophan; phen = 1,10-phenanthroline; o-van = o-vanllin; naph = 2‑hydroxy-1- naphthaldehyde; bipy = 2, 2′-biprydine], have been synthesized and characterized. Comparative binding profiles between complexes 1∼6 and calf thymus DNA (CT-DNA) were investigated through various spectroscopic techniques, viscosity and thermal denaturation measurements. Furthermore, the calculated Kb, Ksq, and ΔTm values were used to quantify the binding strength of complexes 1∼6 to CT-DNA, which demonstrated that complex 1 exhibited the highest binding affinity and the binding strength followed the order as 1 > 2 > 3 >> 4 > 5 > 6. Results of DNA cleavage by 1∼6 showed that these complexes could cleave pBR322 DNA using 3-mercaptopropionic acid (MPA) as a reducing agent in the order of 1 > 2 > 3 >> 4 > 5 > 6. The phen complexes were efficient cleavers of plasmid DNA via the oxidative pathway. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell staining, flow cytometry, and western blotting were employed to illustrate the in vitro cytotoxicities and anticancer molecular mechanisms of these complexes. Notably, most of these complexes, especially complex 1, exhibited more potent anti-proliferative activities than cisplatin against MCF-7, SGC-7901, Eca-109 and HepG2 cells. Furthermore, complex 1 could induce cell cycle arrest in the G2/M phase and produce reactive oxygen species (ROS), autophagy and mitochondrial dysfunction in the Eca-109 cells. Additionally, complex 1 can induce apoptosis by changing the expression levels of the apoptotic-related and autophagy-related proteins.