Copper and Manganese Complexes of Pyridinecarboxaldimine Induce Oxidative Cell Death in Cancer Cells

Leveraging the versatile redox behavior of transition
metal complexes
with heterocyclic ligands offers significant potential for discovering
new anticancer therapeutics. This study presents a systematic investigation
of a pyridinecarboxaldimine ligand (PyIm) with late 3d-transition
metals inhibiting cancer cell proliferation and the mechanism of action.
Synthesis and thorough characterization of authentic metal complexes
of redox-active late 3d-transition metals enabled the validation of
antiproliferative activity in liver cancer cells. Notably, (PyIm)2Mn(II) (1) and (PyIm)2Cu(II) (5) complexes exhibited a good inhibitory profile against liver
cancer cells (EC50: 4.0 μM for 1 and
1.7 μM for 5) with excellent selectivity over
normal kidney cells (Selectivity index, SI = 17 for 5). Subsequently, evaluation of these complexes in cancers cell lines
from four different sites of origin (liver, breast, blood, and bone)
demonstrated a predominant selectivity to liver and a moderate selectivity
to breast cancer and leukemia cells over the normal kidney cells.
The mechanism of action studies highlighted no expected DNA damage
in cells, rather, the enhancement of extracellular and intracellular
reactive oxygen species (ROS) resulting in mitochondrial damage leading
to oxidative cell death in cancer cells. Notably, these complexes
potentiated the antiproliferative effect of commercially used cancer
therapeutics (cisplatin, oxaliplatin, doxorubicin, and dasatinib)
in liver cancer cells. These findings position redox-active metal
complexes for further evaluation as promising candidates for developing
anticancer therapeutics and combination therapies.