Substituent Effect of Superhalogens on the Metallodrug IMeAuCl: A DFT Study

Halogens are usually involved in numerous anticancer drugs and play an important role in anticancer activity. Taking the IMeAuCl, a potent anticancer drug as an example, the substituent effect of superhalogens X@B₁₂N₁₂ (X=F, Cl, and Br) on the structures, electronic properties, and chemical reactivity with biomolecular targets of this metallodrug has been investigated. Substituting X@B₁₂N₁₂ for the Cl atom of IMeAuCl results in polar covalent bonds between Au and N atoms in the resulting Au-X (X=F, Cl, and Br) derivatives. The introduction of superhalogens enhances the polarity and solubility of Au-X, which enables them to directly react with biological target molecules without undergoing hydrolysis. In particular, it is found that the higher electron affinity (EA) of X@B₁₂N₁₂ results in the lower energy barrier of the reaction between Au-X and target molecules, which maybe benefit its high biological activity. With regard to this, another complex Au-BF₄ with better anticancer activity has been also designed by replacing the Cl atom of IMeAuCl with BF₄, a well-known superhalogen with higher EA value than X@B₁₂N₁₂. Thus, this study provides a new strategy to improve the antitumor activity of halogen-containing drugs from a theoretical point of view.