Reimagining Pt(II) Anticancer Agents: The Role of Ferrocene in Monofunctional Chemotherapeutic Compounds

The side effects and resistance to treatments associated with platinum compounds, such as cisplatin, underscore the present need for novel anticancer agents with improved properties. The development of hybrid drugs, combining two bioactive units, offers a promising approach by synergistically enhancing the biological activity of the two fragments while reducing the resistance of classic drugs. This work presents the synthesis of a novel family of heterobimetallic compounds, featuring a monofunctional Pt(II) complex with amino groups and a p-ferrocenylaniline ligand. Cytotoxic assays reveal that the derivatives with methylated and isopropylated substituted amines exhibit remarkably higher activity against several tumor cell lines compared with cisplatin and the unsubstituted diamino complex. Notably, these methylated and isopropylated complexes demonstrate high selectivity and present high antitumor activity in cell lines where cisplatin is ineffective. Classical molecular dynamics simulations targeting DNA reveal a consistent relation between the extent of distortion of the duplex upon complex coordination and the cytotoxic activity observed in biological assays. According to our simulations, coordination of the heterometallic complexes can produce a significant disruption of the H-bond pattern of the platinated guanine. Moreover, the distortion mechanism induced by the voluminous substituents of the amino ligands entails either the intercalation of the ferrocene moiety, facilitating new hydrogen bonds between originally non-interacting base pairs and new weak attractive stacking interactions between the Pt(II) complex and neighboring nucleobases, or the displacement of adjacent nucleotides from the pairing region toward the solvent environment.