Cytotoxic Ni(II) Thiosemicarbazone Complexes: XRD and Biomolecular Interactions

Cancer accounts for nearly one in four deaths (22.8%) due to noncommunicable diseases globally. The urgence for new effective therapies is worsened by multi-drug resistance (MDR), which compromises current treatments. One way to face it is looking for multi-modal drugs, which undergo different pathways to achieve selective cytotoxicity. Our complexes consist of thiosemicarbazone ligands arranged around a Ni(II) core: this enables multiple synergistic modes of action, allowing both the metal and ligands to interact with ROS, proteins, and DNA through parallel pathways. We found that, in a list of four complexes, Ni2 and Ni4 displayed a good efficacy in inhibiting cell growth when used on different cancer cell lines, being particularly effective on A549 (lung carcinoma), with up to sixfold selectivity compared to healthy cells. This is probably due to strong interactions with albumin, a major transport protein in mammals enhancing drug delivery to tumors in place of healthy cells. We then looked into the mode of action of Ni2 and Ni4, finding that they both undergo at least two different mechanism simultaneously. Ni2 and Ni4 interact with the minor groove of the DNA via circular dichroism spectra of CT-DNA (incubated with Ni2 and Ni4).