Luminescent cyclometalated platinum(II) complexes containing N-heterocyclic carbene ligands with potent in vitro and in vivo anti-cancer properties accumulate in cytoplasmic structures of cancer cells

Abstract

Contrary to most platinum-based anti-cancer agents which target DNA, coordination of N-heterocyclic carbene (NHC) ligands to cyclometalated platinum(II) complexes confers these luminescent complexes to other cellular target(s). The strong Pt-Ccarbene bond(s) renders the platinum(II) complexes to display unique photophysical properties and enhanced stability against biological reduction and ligand exchange reactions. The platinum complexes described in this work are highly cytotoxic and display high specificity to cancerous cells. Among them, [(C^N^N)PtII(N,N'-nBu2NHC)]PF6 (1a, where HC^N^N = 6-phenyl-2,2'-bipyridine) with a lipophilic carbon chain on the carbene ligand induces apoptosis in cancer cells, demonstrates an enhancing synergistic effect with cisplatin in vitro, and displays potent in vivo activities using nude mice models. As this complex is strongly emissive, its cellular localization can be traced using emission microscopy. In contrast to common platinum-based anti-cancer agents, 1a does not accumulate in the vicinity of DNA but preferentially accumulates in cytoplasmic structures including sites where active survivin, an inhibitor of apoptosis (IAP), is located. In vitro, 1a significantly inhibits the expression of survivin, activates poly(ADP-ribose) polymerase (PARP) and induces apoptosis in cancer cells. Given the ease of structural modification of NHC ligand to alter the overall biological activities, these [(C^N^N)PtII(NHC)]+ complexes having unique photophysical properties provide an entry to a new class of potential anti-cancer drug leads. © The Royal Society of Chemistry 2011.