Design, synthesis, characterisation and chemical reactivity of mixed-ligand platinum(ii) oxadiazoline complexes with potential cytotoxic properties

Abstract

A series of mixed ligand platinum(II) oxadiazoline complexes bearing 7-nitro-1,3,5-triazaadamantane (7-NO₂TAA) as a labile and reactive nitrogen ligand has been synthesised from easily accessible starting materials. [2+3] cycloaddition of nitrones R¹R²C–N⁺(Me)O⁻ to only one of the nitrile ligands in trans-[PtX₂(PhCN)₂] (X = Cl, Br) results in the selective formation of mono-oxadiazoline complexes trans-[PtX₂(PhCN){NC(Ph)–O–N(Me)–CR¹R²}] from which the remaining nitrile can be replaced by 7-NO₂TAA. The resulting complexes trans-[PtX₂(7-NO₂TAA) {NC(Ph)–O–N(Me)–CR¹R²}] and their precursors were characterised by elemental analysis, IR and multinuclear NMR spectroscopy.

The suitability of the target complexes as anticancer agents was extrapolated from their general chemical reactivity. They are stable in DMSO, but react with thiols and undergo aquation of a chloro ligand. In the absence of a competing ligand, the coordinated 7-NO₂TAA ligand slowly hydrolyses in an aqueous medium under release of formaldehyde, and this could induce bioactivity independent of the one typically found with platinum compounds. With nitrogen heterocycles such as pyridine a slow exchange of the 7-NO₂TAA ligand occurs. A combined DFT/AIM study confirms the reaction observed in the experiment and predicts that other nitrogen heterocycles such as DNA nucleobases should react in the same way. Moreover, the 7-NO₂TAA should be even more labile in an aqueous medium where protonation of the remaining amines can occur. A PM6 molecular modelling study suggests that the PtCl(oxadiazoline) fragment formed after release of one chloro and the labile 7-NO₂TAA ligand fits well into the DNA groove and is able to form d(GpG) intrastrand crosslinks similar to the ones observed with cisplatin.