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

Abstract 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@B 12 N 12 (X=F, Cl, and Br) on the structures, electronic properties, and chemical reactivity with biomolecular targets of this metallodrug has been investigated. Substituting X@B 12 N 12 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@B 12 N 12 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‐BF 4 with better anticancer activity has been also designed by replacing the Cl atom of IMeAuCl with BF 4 , a well‐known superhalogen with higher EA value than X@B 12 N 12 . Thus, this study provides a new strategy to improve the antitumor activity of halogen‐containing drugs from a theoretical point of view.