Using Density Functional Theory (DFT) Calculations to Reinterpret the Biological Activity of Square Planar Pt (II), Au (III), and Cu (II) Complexes From Molecular Level

ABSTRACT The geometric structures and electronic properties of three experimentally reported anticancer Pt (II), Au (III), and Cu (II) complexes (named complexes 1–3 ) as well as the interactions of these complexes with biological target molecules have been explored in detail by density functional theory (DFT) calculations. Significant differences in the polarity of M‐Cl (M = Pt, Au, and Cu) bonds and the nucleophilic reactivity of metal centers were revealed for these complexes. Further research shows that the differences in the hydrolysis and the ligand exchange reactions with biological targets of these complexes are the main reasons for their different antitumor activities. Based on these findings, four novel complexes 4–7 have been rationally designed by replacing the Cu (II) center of 3 with Ni (II), Zn (II), Pd (II), and Fe (II) ions for the first time. Therein, the obtained Zn (II)–centered complex 5 is predicted to exhibit the highest similarity to complex 3 . This study not only provides a profound theoretical insight into the activity difference of the reported metal complexes from molecular level but also proposes an effective strategy to design new anticancer drugs.