Comparison Between Polypyridyl and Cyclometalated Ruthenium(II) Complexes: Anticancer Activities Against 2D and 3D Cancer Models

The aim of this study was to illustrate the dramatically different anticancer activities between coordinatively saturated polypyridyl (1 a–4 a) and cyclometalated (1 b–4 b) ruthenium(II) complexes. The cyclometalated complexes 1 b–4 b function as DNA transcription inhibitors, exhibiting switch-on cytotoxicity against a 2D cancer cell monolayer, whereas the polypyridyl complexes 1 a–4 a are relatively inactive. Moreover, complexes 1 b–4 b exhibit excellent cytotoxicity against 3D multicellular tumor spheroids (MCTSs), which serve as an intermediate model between in vitro 2D cell monolayers and in vivo 3D solid tumors. The hydrophobicity, efficient cell uptake, and nucleus targeting ability, as well as the high DNA binding affinity of complexes 1 b–4 b, likely contribute to their enhanced anticancer activity. We surmise that cyclometalation could be a universal approach to significantly enhance the anticancer activity of substituted polypyridyl RuII complexes. We also suggest that 3D MCTSs may be a more practical platform for anticancer drug screening than 2D cancer monolayer approaches.