Synthesis, structures and cytotoxic effects in vitro of cis- and trans-[PtIVCl4(NHC)2] complexes and their PtII precursors

Abstract

Four new bis(N,N-dialkylbenzimidazol-2-ylidene)dichlorido platinum(II) complexes 2 featuring N-alkyl substituents of increasing size (a: Me, b: Et, c: n-butyl, d: n-octyl) were synthesised and oxidised with PhICl₂ to give the corresponding [Pt^IVCl₄(N,N-dialkylbenzimidazol-2-ylidene)₂] complexes 4 as potential anticancer prodrugs. The known bis(N,N-dibenzylimidazol-2-ylidene)dichlorido platinum(II) complex 1 was likewise oxidised to [Pt^IVCl₄(N,N-dibenzylimidazol-2-ylidene)₂] 3. In contrast, oxidation of complexes 1 and 2 with H₂O₂ or hypochlorites, or exchange of chlorido for hydroxo ligands in tetrachlorido complexes 4 failed to give isolable complexes of type [Pt^IVCl_4−n(OH)_n(NHC)₂]. In MTT assays the [Pt^IICl₂(NHC)₂]/[Pt^IVCl₄(NHC)₂] complex couples 1/3, 2c/4c, and trans-2c/trans-4c, bearing either N-benzyl or N-butyl substituents, each showed similar single-digit micromolar IC₅₀ values against at least three out of five human cancer cell lines, presumably due to an intracellular reduction of the Pt^IV complexes to their active Pt^II congeners. Unlike cisplatin, whose anticancer effect requires functional p53, each of them was active both in wildtype and in p53-negative HCT116 colon carcinoma cells. In ethidium bromide saturation assays with isolated DNA, cis-(bis-NHC)Pt^II complexes such as 1 caused morphological DNA changes more pronounced than those initiated by cisplatin, while the corresponding cis-(bis-NHC)Pt^IV complexes such as 3 interacted with DNA in a less structure-modifying way.