Anticancer Activity and Mode of Action of Copper(II)-Bis(thiosemicarbazonato) Complexes with Pendant Nitrogen Heterocycles

Exploring the potential of bis(thiosemicarbazones) (BTSC), a new family of BTSC ligands derived from GTSM (glyoxal-bis(N4-methylthiosemicarbazonato) and respective (CuBTSC)-B-II complexes were synthesized. These complexes, having pendant nitrogen heterocycles, exhibited increased water-solubility, lower lipophilicity at physiological pH and more negative Cu(II)/Cu(I) redox potential, when compared with the parental complex. The cytotoxic evaluation performed in a panel of cancer cells lines showed an important effect of the metal complexation, and furthermore correlated well with the cellular uptake of the compounds, which was determined using their Cu-64 congeners. The radiolabelling of the complexes also allowed more detailed uptake studies, with the results suggesting an active transport or facilitated diffusion mechanism for the cellular uptake of (64)CuGTSMpip and (64)CuGTSMmor, with pendant piperidine and morpholine rings, respectively. Additionally, a comparative study with the corresponding Cu(II) complexes derived from ATSM (diacetyl-bis(N-4-methylthiosemicarbazonato) that we have previously described, demonstrated a clear difference in their lysosomotropic properties in particular for the piperidine derivatives. From this study, CuGTSMpip emerged as the most promising compound to be further evaluated as an anticancer metallodrug.

Automated summary

The study explores a new family of BTSC ligands and their copper complexes with improved water-solubility, lower lipophilicity, more negative redox potential, and enhanced cellular uptake efficiency. The cytotoxic evaluation in cancer cells lines and detailed uptake studies suggest the potential of CuGTSMpip as a promising anticancer metallodrug.