Potent Anticancer Activity with High Selectivity of a Chiral Palladium N‑Heterocyclic Carbene Complex

Five enantiomeric
pairs of palladium complexes of 1,2,4-triazole-derived
chiral N-heterocyclic carbene ligands were investigated to probe the
influence of chirality on the compound’s anticancer activity.
Although no chirality-related influence was observed for any of the
enantiomeric pair, strong anticancer activity was seen for a particular
pair, (1S,2S,5R)-1c and (1R,2R,5S)-1c, which was significantly more active
than the benchmark drug cisplatin for human breast cancer cells, MCF-7
(ca. 24–27-fold), and human cervical cancer cells, HeLa (ca.
three- to fourfold). Broadening its scope of application, (1R,2R,5S)-1c also exhibited antiproliferative activity against lung cancer (A549),
skin cancer (B16F10), and multidrug-resistant mammary tumor (EMT6/AR1)
cell lines. Interestingly, (1R,2R,5S)-1c displayed 8- and 16-fold stronger
antiproliferative activity toward B16F10 and MCF-7 relative to their
respective noncancerous counterparts, L929 (fibroblast skin cells)
and MCF10A (epithelial breast cells), thereby upholding the potential
of these complexes for further development as anticancer agents. (1R,2R,5S)-1c inhibited tumor-cell proliferation by blocking the cells at the
G2 phase. (1R,2R,5S)-1c caused DNA damage in MCF-7 cells, leading to mitochondrial
reactive oxygen species production and subsequently cell death. We
also present evidence indicating that (1R,2R,5S)-1c induced p53-dependent
programmed cell death in MCF-7 cells.