(Aminoalkyl)diphenylphosphine sulfides: synthesis and application as building blocks in the design of multidentate ligands for cytotoxic Pd(II) complexes.

Amino-functionalized phosphoryl compounds are among the most useful molecular scaffolds in medicinal chemistry, while the potential of their thiophosphorylated analogs, especially those having an alkylamino moiety, is still uncovered. This is mainly due to the lack of convenient synthetic routes to these organophosphorus derivatives. To address this issue, we have suggested the facile approaches to α-(aminomethyl)- and substituted/unsubstituted α-(aminobenzyl)diphenylphosphine sulfides based on either the sequential transformations of (hydroxymethyl)diphenylphosphine sulfide, with the Staudinger reaction of an azide derivative as the key stage, or the addition of Ph2P(S)H to hydrobenzamides followed by the acid hydrolysis. The compounds obtained were reacted with picolinyl chloride to yield functionalized amides which readily underwent direct cyclopalladation, resulting in new representatives of non-classical N-metalated Pd(II) pincer complexes. The latter exhibit promising cytotoxic activity against several human cancer cell lines and apoptosis inducing ability along with the remarkable cytotoxic effects on doxorubicin-resistant cell sublines.

Modulation of the Cytotoxic Properties of Pd(II) Complexes Based on Functionalized Carboxamides Featuring Labile Phosphoryl Coordination Sites.

Platinum-based drugs are commonly recognized as a keystone in modern cancer chemotherapy. However, intrinsic and acquired resistance as well as serious side effects often caused by the traditional Pt(II) anticancer agents prompt a continuous search for more selective and efficient alternatives. Today, significant attention is paid to the compounds of other transition metals, in particular those of palladium. Recently, our research group has suggested functionalized carboxamides as a useful platform for the creation of cytotoxic Pd(II) pincer complexes. In this work, a robust picolinyl- or quinoline-carboxamide core was combined with a phosphoryl ancillary donor group to achieve hemilabile coordination capable of providing the required level of thermodynamic stability and kinetic lability of the ensuing Pd(II) complexes. Several cyclopalladated derivatives featuring either a bi- or tridentate pincer-type coordination mode of the deprotonated phosphoryl-functionalized amides were selectively synthesized and fully characterized using IR and NMR spectroscopy as well as X-ray crystallography. The preliminary evaluation of the anticancer potential of the resulting palladocycles revealed a strong dependence of their cytotoxic properties on the binding mode of the deprotonated amide ligands and demonstrated certain advantages of the pincer-type ligation.