A thiosemicarbazone-based dinuclear copper(II) complex: potent antiproliferative activity, distinct cell-type-specific anticancer mechanisms and robust in vivo antitumor efficacy.

A feasible way to avoid chemoresistance in cancer therapy is to endow a single drug with multiple anticancer mechanisms. In this work, we propose that a multinuclear metal complex may be a promising drug candidate when its metal centers possess different coordination environments. Our proposal has been demonstrated by our studies on a dinuclear Cu(II) complex [Cu2LCl2(H2O)] (1, H2L = 2,2'-Bis[1-(2-pyrazinyl)ethylidene]carbonothioic dihydrazide), in which the two Cu centers adopt square planar tetracoordination and square pyramidal pentacoordination, respectively. Such a characteristic structure not only induces potent antiproliferative activity against multiple human cancer cells (IC50 = 0.68-1.94 μM), but also leads to distinct cell-type-specific anticancer mechanisms: Suppression of proteasome activity in human colon cancer HCT-116 cells, but inhibition of protein tyrosine phosphatase 1B and T-cell protein tyrosine phosphatase in the human breast cancer MCF-7 cells. Together with the low toxicity to normal cells and high in vivo antitumor efficacy, 1 represents a promising candidate of the anticancer metallodrugs for overcoming chemoresistance.