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.