Extended Family of Thiophosphoryl-Appended Pd(II) Pincer Complexes with a Deprotonated Amide Core: Synthesis and Biological Evaluation

The development of new, more effective, and selective anticancer agents is one of the most important tasks of modern medicinal chemistry. Recently, we have found that non-classical Pd(II) pincer complexes derived from thiophosphoryl-appended picolinamides exhibit promising cytotoxic properties. In this work, the potential of this class of metal-based derivatives was studied on an extended family of Pd(II) complexes with a deprotonated amide core featuring thiophosphoryl pendant arms, readily obtained by the direct cyclopalladation of new functionalized amide ligands upon interaction with PdCl₂(NCPh)₂ under mild conditions. The ligands, in turn, were obtained by conventional amide coupling methods using (aminobenzyl)- and (aminomethyl)diphenylphosphine sulfides as the key precursors and different <i>N</i>- and <i>S</i>-donor-substituted carboxylic acids. The effect of an acid component and carbon chirality in the ligand framework on the bioactivity of the resulting Pd(II) pincer complexes was elucidated by evaluating their cytotoxicity against different solid and blood cancer cell lines, apoptosis induction ability, and P-glycoprotein (P-gp) affinity, which revealed the high anticancer potential of some of them, and in particular, the potential to overcome drug resistance associated with P-gp overexpression. The representative palladocycle was also shown to possess moderate antibacterial activity.