Fluorine-Substituted Rhenium(I) Metallocycle: A New Class of Potent Anticancer Agent

Fluorine and nonfluorine substituted rhenium(I) metallocycles, fac-[{Re(CO)₃}₂(μ-SO₄)(L1)₂] (C1) and fac-[{Re(CO)₃}₂(μ-SO₄)(L2)₂] (C2), respectively, were synthesized using Re₂(CO)₁₀, sodium bisulfite, fluorobenzimidazolyl/benzimidazolyl-based ditopic nitrogen-donor ligands (L1/L2), and toluene-acetone via coordination-driven one-pot solvothermal approach. The metallocycles were characterized using elemental analysis, ESI-TOF-MS, ATR-IR, NMR, and PXRD methods. The molecular structures of C1·9(DMSO), C1·(toluene)(acetone), and C2·(toluene) were determined using SCXRD analysis. The in vitro cytotoxicity study of C1 and C2 was performed against cervical (HeLa) and skin (B16) cancer cells. Murine fibroblast (L929) and mouse myoblast (C2C12) cells were used as noncarcinogenic model cell lines for biocompatibility determination. The metallocycles exhibited potent anticancer activity against both cancer cell lines, showing greater efficacy than the commonly used cisplatin. Moreover, fluorine-substituted C1 metallocycle exhibited significantly higher anticancer activity than nonfluorinated C2 metallocycle, indicating a fluorine effect. Further, in-depth studies of C1 on HeLa cells showed elevated intracellular ROS generation, disruption of mitochondrial membrane potential, and antiproliferative properties. The in vitro studies also revealed its ability to bind with DNA and induce changes in cellular morphology, thus leading to DNA damage and cancer cell death by apoptosis. Molecular docking studies of the metallocycles with B-DNA macromolecule revealed the binding sites, binding affinity, and type of noncovalent interactions.