Effect of chirality on the anticancer activity of Pt(II) and Pt(IV) complexes containing 1 R ,2 R and 1 S ,2 S enantiomers of the trans -1,2-diamino-4-cyclohexene ligand (DACHEX), an analogue of diaminocyclohexane used in oxaliplatin.

Six enantiomerically pure, oxaliplatin-like, platinum compounds (two platinum(II) and four platinum(IV)), all containing unsaturated cyclic diamine trans -1,2-diamino-4-cyclohexene (DACHEX) as a substitute for the trans -1,2-diaminocyclohexane used in oxaliplatin, were investigated. The complexes were characterized by elemental analyses, ESI-MS, and ¹ H-NMR spectroscopy. For the four Pt(IV) complexes the electrochemical redox behaviour, investigated by cyclic voltammetry, showed that all complexes possess reduction potentials suitable for activation in vivo . The antiproliferative activity was assessed in vitro on human cancer cell lines, also selected for resistance to platinum-based drugs or belonging to the MultiDrug-Resistant (MDR) phenotype. All complexes exhibited antiproliferative activity superior to that of cisplatin and almost equivalent to or better than that of oxaliplatin; moreover, most complexes were also capable of overcoming both the cisplatin- and the oxaliplatin-resistance. By comparing the effectiveness of the enantiomerically pure compounds with the racemic one, the R , R enantiomer emerged as the most effective in the case of Pt(II) complexes whereas the S , S enantiomer was the most effective in the case of the Pt(IV) derivatives. From the results obtained also against 3D spheroid tumor models, cis , trans , cis -[Pt(OXA)(OBz) ₂ (1 S ,2 S -DACHEX)] (OBz = benzoate) emerged as the most promising candidate for further preclinical investigation.