Incorporating alkylthio groups provides potent in vitro anticancer activity to water-soluble and aqueous-stable diiron(I) bis-cyclopentadienyl complexes

Abstract

We synthesized five novel diiron(I) complexes with a varying S-functionalized vinyliminium ligand, 3a-e, which were structurally characterized by IR and NMR spectroscopy, and single crystal X-ray diffraction in one representative case. Based on NMR and UV–Vis methods, these complexes show adequate water solubility (3–19 mM), balanced amphiphilicity (Log P_ow values ranging from −0.46 to 0.16), and substantial stability in physiological-like solutions (>90 % unchanged after 24 h in DMEM cell culture medium). The cytotoxicity of the N-cyclohexyl complexes 3a-d was determined on human (A2780, A375, MCF-7) and murine cancer (B16F10, 4T1) cell lines. The leading compound 3d, featuring methylthio-group, N-cyclohexyl and 4-methoxyphenyl substituents, exhibited IC₅₀ values in the low micromolar range and demonstrated remarkable selectivity for malignant phenotypes. Several in-depth experiments were conducted to elucidate the biochemistry of 3d, including evaluation of cell death induction, proliferation rate and cellular redox status. Spectroelectrochemical and binding studies with DNA and bovine serum albumin (BSA) were also conducted. Despite its similarity to cisplatin in inducing apoptosis, the redox signature of 3d is distinct, characterized by a strong scavenging potential of reactive oxygen and nitrogen species (ROS and RNS).