A Novel Trigonal Prismatic Rhenium Complex of 2-Hydroxythiobenzhydrazide as a Potent and Selective Anticancer Agent

The clinical utility of platinum-based chemotherapeutics is limited by severe toxicity and acquired resistance, motivating the development of alternative metallo drugs. Here, we report a series of rhenium complexes, Re[HL1-4]3, synthesized via reduction of Re(VII) precursors followed by coordination with aromatic thiohydrazide ligands. The lead complex, Re[HL2]3, adopts an unusual trigonal-prismatic geometry and a favorable redox profile, correlating with enhanced cytotoxic potency. It demonstrates selective antiproliferative activity against cancer cells with minimal toxicity toward nonmalignant cells in both 2D and 3D culture systems. Mechanistic studies reveal DNA binding, induction of DNA damage, and reactive oxygen species (ROS) generation, triggering apoptosis via PARP and caspase 3 cleavage. Pharmacokinetic analysis indicates moderate stability and plasma retention, supporting sustained therapeutic levels while limiting accumulation-related toxicity. In a syngeneic 4T1 murine breast cancer model, Re[HL2]3 significantly inhibited tumor growth without observable systemic toxicity, supporting its further preclinical evaluation.