Three pairs of enantiomers bearing mitochondria‐targeted TPP + groups as potential anti‐cancer agents

Six complexes with chiral Schiff-base ligands containing TPP+ groups, [VOLR,R/(S,S)](ClO4)(2)(1 for RR, 2 for SS), [NiLR,R/S,S](ClO4)(2)C2H5OH (3 for RR, 4 for SS) and [CuLR,R/S,S](ClO4)(2)CHCl3CH3CH2OH (5 for RR, 6 for SS) (L-R,L-R/S,L-S=N,N-Bis{5-[(triphenylphosphonium)-methyl]salicylidine}-(1R,2R/1S,2S)-diphenylethane-1,2-diamine, were synthesized to serve as mitochondrion-targeting anticancer drugs. The introduction of TPP+ group(s) might markedly influence the properties of complexes. Compounds 3 and 5 were structurally characterized by X-ray crystallography. Complexes 1-6 could be moderate intercalating agents to CT-DNA which is determined by several spectroscopy methods. DNA cleavage experiments revealed that all compounds could promote oxidative cleavage of pBR322 plasmid DNA in the presence of H2O2. MTT assay indicated 1-6 exhibited effective cytotoxicity on A549 and MCF-7 cell lines. Notably, the IC50 values of 5 (1.24 +/- 0.33M) or 6 (1.47 +/- 0.52M) were approximately 9-11 fold lower than that of cisplatin (IC50=13.56 +/- 0.88M) on A549 cells. 5 and 6 were picked for further study, which indicated that the cytotoxicity seems to result from multiple mechanisms of action, including effectively suppress the growth and proliferation of A549 cells, generation of reactive oxygen species, dissipation of mitochondrial membrane potential, cell cycle perturbation and apoptosis induction. Compounds 1-6 could highly accumulate in the mitochondria by means of ICP-MS assay. This study demonstrates that 1-6 with mitochondrion-targeting function could be efficient anticancer drugs.