Synthesis, characterization and in vitro cytotoxic activity of new Pt(II) complexes with trans-cinnamic acid

Despite the success of the three platinum-based drugs approved worldwide by the Food and Drug Administration (cisplatin, oxaliplatin, and carboplatin), there has been over the years intense research to identify new metal-based anticancer drugs with enhanced and/or a broader spectrum of activity and a lower toxicity. To this aim, the interest in natural products has increased since they are relatively safe. Several studies report that cinnamic acid exhibits antioxidant, antimicrobial, anticancer, neuroprotective, anti-inflammatory, and antidiabetic properties. Thus, in this study we aimed to bind two trans-cinnamate residues to a Pt(II) complex with the aim to develop a potential multifunctional prodrug capable to release two pharmacologically active moieties after hydrolysis in the tumor cells. We synthesized three new Pt(II) complexes with ethylenediamine (en, 1), 1R,2R-diaminocyclohexane (1R,2R-DACH, 2) and cis-1,3-diaminocyclohexane (cis-1,3-DACH, 3) as carrier ligands and two trans-cinnamate as leaving ligands. Interestingly, complexes 1 and 2 underwent a transformation into the corresponding organometallic complexes in methanol. All the compounds were fully characterized by electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. Finally, as an initial stage of biological evaluation, the in vitro cytotoxic activity of the newly synthesized Pt(II) complexes was assessed against a selected panel of human cancer cell lines. In parallel, preliminary mechanistic studies were conducted to better elucidate the underlying cellular and molecular processes responsible for their anticancer effects and to gain deeper insight into their possible mode of action.