Thiophosphorylated indoles as a promising platform for the creation of cytotoxic Pd(II) pincer complexes

Abstract

An important role of metal-based chemotherapeutics in cancer treatment prompts continuous investigations on the development of ligand scaffolds that could produce cytotoxic metal complexes. Herein, we present the results on application of thiophosphorylated indoles in the synthesis of new pincer ligands that can provide hemilabile coordination for Pd(II) ions. Isomeric 1- and 3-thiophosphorylated indoles bearing an additional pyridylmethyl or pyridylcarbonyl donor moieties were shown to readily undergo direct cyclopalladation under the action of PdCl2(NCPh)2, affording S,C,N-type Pd(II) pincer complexes in high yields. The structures of the latter were unambiguously confirmed by multinuclear NMR (including different 2D techniques) and IR spectroscopy as well as X-ray crystallography. The preliminary evaluation of their cytotoxic potency on several human cancer cell lines revealed high activity of the cyclopalladated derivatives featuring thiophosphoryl and pyridylmethyl pendant arms, which is well correlated with the stability of the compounds in solution. The most active complexes were also shown to induce cell apoptosis, affecting cancer cells to a greater extent than non-cancerous counterparts.