Novel tetranuclear PdII and PtII anticancer complexes derived from pyrene thiosemicarbazones

Abstract

Cyclometallated palladium(II) and platinum(II) pyrenyl-derived thiosemicarbazone (H₂PrR) complexes of the type [M₄(μ-S-PrR-κ³-C,N,S)₄] (M = Pd^II, Pt^II; R = ethyl, cyclohexyl) have been synthesised in good yields and fully characterised. X-ray crystallography showed that the tetranuclear complex [Pt₄(μ-S-PrCh-κ³-C,N,S)₄](CH₃)₂COCHCl₃ contains an eight-membered ring of alternating M–S atoms. The ethyl derivatives [M₄(μ-S-PrEt-κ³-C,N,S)₄] exhibit potent antiproliferative activity towards A2780 human ovarian cancer cells, with IC₅₀ values of 1.27 μM (for M = Pd^II) and 0.37 μM (for M = Pt^II), the latter being an order of magnitude more potent than the anticancer drug cisplatin (IC₅₀ 1.20 μM). These promising complexes had low toxicity towards non-cancerous human MRC5 cells, which points towards an early indication of differential toxicity between cancer and normal cells. Experiments that investigated the effects of these tetranuclear complexes on the cell cycle, integrity of the cell membrane, and induction of apoptosis, suggested that their mechanism of action of does not involve DNA targeting, unlike cisplatin, and therefore could be promising for combatting cisplatin resistance.