A critical re-evaluation of the Ta(V) half-sandwich scaffold: Synthesis, hydrolytic behaviour, and the challenge of lung cancer cell viability

Tantalum(V) complexes remain a significantly underexplored class of potential metallodrugs. This study provides a critical re-evaluation of the half-sandwich Ta(V) Schiff-base [Ta( η 5 -Cp*)Cl 2 (salaph)] scaffold ( 1 , Cp* = pentamethylcyclopentadienyl, H 2 salaph = 2-{( E )-[(2-hydroxyphenyl)imino]methyl}phenol)) based on targeted structural modifications involving halogen substitution on salaph and the coordination of different chelating or monodentate ligands. This approach resulted in eleven new complexes with the general composition [Ta( η 5 -Cp*)(L n )X 2 ] ( 2 – 12 , H 2 L n = O,N,O′ -donor ligand, X = Cl − , dichloroacetate, trifluoroacetate), which were synthesized and extensively characterized. NMR stability studies showed chlorido complexes ( 1 – 8 ) as inert to hydrolysis under the used conditions, while carboxylato complexes ( 9 – 12 ) demonstrated a higher hydrolysis rate dependent both on water content (NMR results) and complex concentration (UV–Vis study), with half-lives ranging from minutes to hours. The in vitro antiproliferative activity was initially assessed against non-small cell lung cancer lines (A549, MOR, cisplatin resistant MOR/CPR), where the complexes proved inactive (IC 50 > 20 μM). However, further screening against monocytic THP-1 cells - a key model for lung tumour microenvironment - revealed a selective cytotoxic response. Cytotoxicity results correlated with increasing lipophilicity determined by RP-HPLC, with iodine-substituted complex 7 being the most potent (IC 50 = 8.8 ± 1.1 μM). Furthermore, the coordination of dichloroacetate in 10 improved the activity compared to its inactive chlorido precursor 3 , highlighting the potential of multimodal Ta(V)-carboxylato systems. These results suggest that while the Ta(V) scaffold faces challenges in treating solid tumours, it represents a promising lead for targeting haematological malignancies and the immune components of the tumour microenvironment.