Mononuclear Nonoxido vs Dinuclear Oxido V ^IV Metallodrugs: Solution Behavior, Biomolecular Binding, Cytotoxicity, and Internalization in Cells

The synthesis and characterization of a series of mononuclear nonoxido [V^IV(L^2,3)₂] (<b>1</b>-<b>2</b>) and dinuclear oxido [(V^IVO)₂(L^1-3)₂] (<b>3</b>-<b>5</b>) V^IV complexes have been achieved using ONS donor halogen-substituted thiosemicarbazone (TSC) ligands (H₂L^1-3). The synthesized complexes (<b>1</b>-<b>5</b>) were characterized in the solid state and in aqueous media by using various physicochemical techniques. A comparison of the solution-phase stability and biological potential of the complexes indicated that <b>1</b>-<b>2</b> keep their identity in aqueous solution, while <b>3</b>-<b>5</b> partially transform into [V^IVO(L^1-3)(H₂O)] and [V^VO₂(L^1-3)]^-. Analysis of <b>1</b>-<b>5</b> using spectroscopic methods as well as density functional theory (DFT) and docking studies demonstrated that they or their transformation products interact with bovine serum albumin (BSA) and calf thymus DNA (CT-DNA) through noncovalent and covalent binding. Cytotoxic assays against A549 (lung cancer) and MCF-7 (breast cancer) cell lines demonstrated that <b>1</b>-<b>5</b> exhibit significant activity, with IC₅₀ values from 8.9 to 19.2 μM. Among them, <b>5</b> and its transformation fragments are more effective against both cells, indicating their potential efficacy against cancer. Potential V-based drugs <b>1</b>-<b>2</b> reveal efficient cellular internalization, with lysosomes being the primary targets, followed by mitochondria and the nucleus, leading to lysosomal disruption, an increase of reactive oxygen species (ROS) levels, and, ultimately, cellular apoptosis.