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

Abstract

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, (1<i>S</i>,2<i>S<i>,5</i>R</i>)-<b>1c</b> and (1<i>R</i>,2<i>R</i>,5<i>S</i>)-<b>1c</b>, 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, (1<i>R</i>,2<i>R</i>,5<i>S</i>)-<b>1c</b> also exhibited antiproliferative activity against lung cancer (A549), skin cancer (B16F10), and multidrug-resistant mammary tumor (EMT6/AR1) cell lines. Interestingly, (1<i>R</i>,2<i>R</i>,5<i>S</i>)-<b>1c</b> 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. (1<i>R</i>,2<i>R</i>,5<i>S</i>)-<b>1c</b> inhibited tumor-cell proliferation by blocking the cells at the G2 phase. (1<i>R</i>,2<i>R</i>,5<i>S</i>)-<b>1c</b> caused DNA damage in MCF-7 cells, leading to mitochondrial reactive oxygen species production and subsequently cell death. We also present evidence indicating that (1<i>R</i>,2<i>R</i>,5<i>S</i>)-<b>1c</b> induced p53-dependent programmed cell death in MCF-7 cells.